Full text data of PTPN11
PTPN11
(PTP2C, SHPTP2)
[Confidence: low (only semi-automatic identification from reviews)]
Tyrosine-protein phosphatase non-receptor type 11; 3.1.3.48 (Protein-tyrosine phosphatase 1D; PTP-1D; Protein-tyrosine phosphatase 2C; PTP-2C; SH-PTP2; SHP-2; Shp2; SH-PTP3)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Tyrosine-protein phosphatase non-receptor type 11; 3.1.3.48 (Protein-tyrosine phosphatase 1D; PTP-1D; Protein-tyrosine phosphatase 2C; PTP-2C; SH-PTP2; SHP-2; Shp2; SH-PTP3)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q06124
ID PTN11_HUMAN Reviewed; 597 AA.
AC Q06124; A8K1D9; Q96HD7;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 20-DEC-2005, sequence version 2.
DT 22-JAN-2014, entry version 172.
DE RecName: Full=Tyrosine-protein phosphatase non-receptor type 11;
DE EC=3.1.3.48;
DE AltName: Full=Protein-tyrosine phosphatase 1D;
DE Short=PTP-1D;
DE AltName: Full=Protein-tyrosine phosphatase 2C;
DE Short=PTP-2C;
DE AltName: Full=SH-PTP2;
DE Short=SHP-2;
DE Short=Shp2;
DE AltName: Full=SH-PTP3;
GN Name=PTPN11; Synonyms=PTP2C, SHPTP2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=T-cell;
RX PubMed=1281790; DOI=10.1016/0014-5793(92)81500-L;
RA Adachi M., Sekiya M., Miyachi T., Matsuno K., Hinoda Y., Imai K.,
RA Yachi A.;
RT "Molecular cloning of a novel protein-tyrosine phosphatase SH-PTP3
RT with sequence similarity to the src-homology region 2.";
RL FEBS Lett. 314:335-339(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY.
RX PubMed=1280823; DOI=10.1073/pnas.89.23.11239;
RA Freeman R.M. Jr., Plutzky J., Neel B.G.;
RT "Identification of a human src homology 2-containing protein-tyrosine-
RT phosphatase: a putative homolog of Drosophila corkscrew.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:11239-11243(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), MUTAGENESIS OF CYS-463, AND
RP TISSUE SPECIFICITY.
RX PubMed=8216283; DOI=10.1006/bbrc.1993.2224;
RA Bastien L., Ramachandran C., Liu S., Adam M.;
RT "Cloning, expression and mutational analysis of SH-PTP2, human
RT protein-tyrosine phosphatase.";
RL Biochem. Biophys. Res. Commun. 196:124-133(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY.
RC TISSUE=Umbilical cord;
RX PubMed=7681589; DOI=10.1073/pnas.90.6.2197;
RA Ahmad S., Banville D.L., Zhao Z., Fischer E.H., Shen S.H.;
RT "A widely expressed human protein-tyrosine phosphatase containing src
RT homology 2 domains.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:2197-2201(1993).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND PHOSPHORYLATION.
RX PubMed=7681217; DOI=10.1126/science.7681217;
RA Vogel W., Lammers R., Huang J., Ullrich A.;
RT "Activation of a phosphotyrosine phosphatase by tyrosine
RT phosphorylation.";
RL Science 259:1611-1614(1993).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP PHOSPHORYLATION, AND INTERACTION WITH PDGFRB.
RX PubMed=7691811;
RA Lechleider R.J., Sugimoto S., Bennett A.M., Kashishian A.S.,
RA Cooper J.A., Shoelson S.E., Walsh C.T., Neel B.G.;
RT "Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2
RT by its binding site, phosphotyrosine 1009, on the human platelet-
RT derived growth factor receptor.";
RL J. Biol. Chem. 268:21478-21481(1993).
RN [11]
RP PHOSPHORYLATION BY PDGFRB.
RX PubMed=8041791; DOI=10.1073/pnas.91.15.7335;
RA Bennett A.M., Tang T.L., Sugimoto S., Walsh C.T., Neel B.G.;
RT "Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth
RT factor receptor beta to Ras.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:7335-7339(1994).
RN [12]
RP INTERACTION WITH PTPNS1.
RX PubMed=8810330; DOI=10.1074/jbc.271.41.25569;
RA Ohnishi H., Kubota M., Ohtake A., Sato K., Sano S.;
RT "Activation of protein-tyrosine phosphatase SH-PTP2 by a tyrosine-
RT based activation motif of a novel brain molecule.";
RL J. Biol. Chem. 271:25569-25574(1996).
RN [13]
RP INTERACTION WITH PTPNS1.
RX PubMed=9062191; DOI=10.1038/386181a0;
RA Kharitonenkov A., Chen Z., Sures I., Wang H., Schilling J.,
RA Ullrich A.;
RT "A family of proteins that inhibit signalling through tyrosine kinase
RT receptors.";
RL Nature 386:181-186(1997).
RN [14]
RP INTERACTION WITH FLT1.
RX PubMed=9600074; DOI=10.1006/bbrc.1998.8578;
RA Igarashi K., Isohara T., Kato T., Shigeta K., Yamano T., Uno I.;
RT "Tyrosine 1213 of Flt-1 is a major binding site of Nck and SHP-2.";
RL Biochem. Biophys. Res. Commun. 246:95-99(1998).
RN [15]
RP INTERACTION WITH GAB2.
RX PubMed=10068651;
RA Nishida K., Yoshida Y., Itoh M., Fukada T., Ohtani T., Shirogane T.,
RA Atsumi T., Takahashi-Tezuka M., Ishihara K., Hibi M., Hirano T.;
RT "Gab-family adapter proteins act downstream of cytokine and growth
RT factor receptors and T- and B-cell antigen receptors.";
RL Blood 93:1809-1816(1999).
RN [16]
RP INTERACTION WITH SIT1.
RX PubMed=10209036; DOI=10.1084/jem.189.8.1181;
RA Marie-Cardine A., Kirchgessner H., Bruyns E., Shevchenko A., Mann M.,
RA Autschbach F., Ratnofsky S., Meuer S., Schraven B.;
RT "SHP2-interacting transmembrane adaptor protein (SIT), a novel
RT disulfide-linked dimer regulating human T-cell activation.";
RL J. Exp. Med. 189:1181-1194(1999).
RN [17]
RP FUNCTION, AND INTERACTION WITH EPHA2.
RX PubMed=10655584; DOI=10.1038/35000008;
RA Miao H., Burnett E., Kinch M., Simon E., Wang B.;
RT "Activation of EphA2 kinase suppresses integrin function and causes
RT focal-adhesion-kinase dephosphorylation.";
RL Nat. Cell Biol. 2:62-69(2000).
RN [18]
RP INTERACTION WITH MZPL1, AND DEPHOSPHORYLATION OF MZPL1.
RX PubMed=10681522; DOI=10.1074/jbc.275.8.5453;
RA Zhao R., Zhao Z.J.;
RT "Dissecting the interaction of SHP-2 with PZR, an immunoglobulin
RT family protein containing immunoreceptor tyrosine-based inhibitory
RT motifs.";
RL J. Biol. Chem. 275:5453-5459(2000).
RN [19]
RP INTERACTION WITH FCRL3.
RX PubMed=11162587; DOI=10.1006/bbrc.2000.4213;
RA Xu M.-J., Zhao R., Zhao Z.J.;
RT "Molecular cloning and characterization of SPAP1, an inhibitory
RT receptor.";
RL Biochem. Biophys. Res. Commun. 280:768-775(2001).
RN [20]
RP INTERACTION WITH CD84.
RX PubMed=11389028; DOI=10.1182/blood.V97.12.3867;
RA Sayos J., Martin M., Chen A., Simarro M., Howie D., Morra M.,
RA Engel P., Terhorst C.;
RT "Cell surface receptors Ly-9 and CD84 recruit the X-linked
RT lymphoproliferative disease gene product SAP.";
RL Blood 97:3867-3874(2001).
RN [21]
RP INTERACTION WITH CD84.
RX PubMed=11414741; DOI=10.1006/clim.2001.5035;
RA Lewis J., Eiben L.J., Nelson D.L., Cohen J.I., Nichols K.E.,
RA Ochs H.D., Notarangelo L.D., Duckett C.S.;
RT "Distinct interactions of the X-linked lymphoproliferative syndrome
RT gene product SAP with cytoplasmic domains of members of the CD2
RT receptor family.";
RL Clin. Immunol. 100:15-23(2001).
RN [22]
RP INTERACTION WITH SIT1.
RX PubMed=11433379;
RX DOI=10.1002/1521-4141(200106)31:6<1825::AID-IMMU1825>3.0.CO;2-V;
RA Pfrepper K.-I., Marie-Cardine A., Simeoni L., Kuramitsu Y., Leo A.,
RA Spicka J., Hilgert I., Scherer J., Schraven B.;
RT "Structural and functional dissection of the cytoplasmic domain of the
RT transmembrane adaptor protein SIT (SHP2-interacting transmembrane
RT adaptor protein).";
RL Eur. J. Immunol. 31:1825-1836(2001).
RN [23]
RP INTERACTION WITH FER AND PECAM1.
RX PubMed=12972546; DOI=10.1091/mbc.E03-02-0080;
RA Kogata N., Masuda M., Kamioka Y., Yamagishi A., Endo A., Okada M.,
RA Mochizuki N.;
RT "Identification of Fer tyrosine kinase localized on microtubules as a
RT platelet endothelial cell adhesion molecule-1 phosphorylating kinase
RT in vascular endothelial cells.";
RL Mol. Biol. Cell 14:3553-3564(2003).
RN [24]
RP INTERACTION WITH FCRL4.
RX PubMed=14597715; DOI=10.1073/pnas.1935944100;
RA Ehrhardt G.R.A., Davis R.S., Hsu J.T., Leu C.-M., Ehrhardt A.,
RA Cooper M.D.;
RT "The inhibitory potential of Fc receptor homolog 4 on memory B
RT cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:13489-13494(2003).
RN [25]
RP REVIEW ON ROLE IN KIT SIGNALING.
RX PubMed=15526160; DOI=10.1007/s00018-004-4189-6;
RA Ronnstrand L.;
RT "Signal transduction via the stem cell factor receptor/c-Kit.";
RL Cell. Mol. Life Sci. 61:2535-2548(2004).
RN [26]
RP INTERACTION WITH FLT4.
RX PubMed=15102829; DOI=10.1074/jbc.M314015200;
RA Wang J.F., Zhang X., Groopman J.E.;
RT "Activation of vascular endothelial growth factor receptor-3 and its
RT downstream signaling promote cell survival under oxidative stress.";
RL J. Biol. Chem. 279:27088-27097(2004).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [28]
RP INTERACTION WITH ANKHD1.
RX PubMed=16956752; DOI=10.1016/j.bbadis.2006.07.010;
RA Traina F., Favaro P.M.B., Medina Sde S., Duarte Ada S.,
RA Winnischofer S.M., Costa F.F., Saad S.T.O.;
RT "ANKHD1, ankyrin repeat and KH domain containing 1, is overexpressed
RT in acute leukemias and is associated with SHP2 in K562 cells.";
RL Biochim. Biophys. Acta 1762:828-834(2006).
RN [29]
RP INTERACTION WITH ROS1.
RX PubMed=16885344; DOI=10.1158/0008-5472.CAN-06-1193;
RA Charest A., Wilker E.W., McLaughlin M.E., Lane K., Gowda R., Coven S.,
RA McMahon K., Kovach S., Feng Y., Yaffe M.B., Jacks T., Housman D.;
RT "ROS fusion tyrosine kinase activates a SH2 domain-containing
RT phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of
RT rapamycin signaling axis to form glioblastoma in mice.";
RL Cancer Res. 66:7473-7481(2006).
RN [30]
RP INTERACTION WITH FCRL6.
RX PubMed=17213291; DOI=10.1182/blood-2006-06-030023;
RA Wilson T.J., Presti R.M., Tassi I., Overton E.T., Cella M.,
RA Colonna M.;
RT "FcRL6, a new ITIM-bearing receptor on cytolytic cells, is broadly
RT expressed by lymphocytes following HIV-1 infection.";
RL Blood 109:3786-3793(2007).
RN [31]
RP INTERACTION WITH TERT, AND FUNCTION.
RX PubMed=18829466; DOI=10.1074/jbc.M805138200;
RA Jakob S., Schroeder P., Lukosz M., Buchner N., Spyridopoulos I.,
RA Altschmied J., Haendeler J.;
RT "Nuclear protein tyrosine phosphatase Shp-2 is one important negative
RT regulator of nuclear export of telomerase reverse transcriptase.";
RL J. Biol. Chem. 283:33155-33161(2008).
RN [32]
RP FUNCTION.
RX PubMed=18559669; DOI=10.1083/jcb.200710187;
RA Lee H.H., Chang Z.F.;
RT "Regulation of RhoA-dependent ROCKII activation by Shp2.";
RL J. Cell Biol. 181:999-1012(2008).
RN [33]
RP INTERACTION WITH KIR2DL1.
RX PubMed=18604210; DOI=10.1038/ni.1635;
RA Yu M.-C., Su L.-L., Zou L., Liu Y., Wu N., Kong L., Zhuang Z.-H.,
RA Sun L., Liu H.P., Hu J.-H., Li D., Strominger J.L., Zang J.-W.,
RA Pei G., Ge B.-X.;
RT "An essential function for beta-arrestin 2 in the inhibitory signaling
RT of natural killer cells.";
RL Nat. Immunol. 9:898-907(2008).
RN [34]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [35]
RP INTERACTION WITH GAREM.
RX PubMed=19509291; DOI=10.1074/jbc.M109.021139;
RA Tashiro K., Tsunematsu T., Okubo H., Ohta T., Sano E., Yamauchi E.,
RA Taniguchi H., Konishi H.;
RT "GAREM, a novel adaptor protein for growth factor receptor-bound
RT protein 2, contributes to cellular transformation through the
RT activation of extracellular signal-regulated kinase signaling.";
RL J. Biol. Chem. 284:20206-20214(2009).
RN [36]
RP INTERACTION WITH PECAM1.
RX PubMed=19342684; DOI=10.4049/jimmunol.0803192;
RA Dasgupta B., Dufour E., Mamdouh Z., Muller W.A.;
RT "A novel and critical role for tyrosine 663 in platelet endothelial
RT cell adhesion molecule-1 trafficking and transendothelial migration.";
RL J. Immunol. 182:5041-5051(2009).
RN [37]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-62 AND TYR-584, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [38]
RP PHOSPHORYLATION, AND INTERACTION WITH PDGFRB.
RX PubMed=20494825; DOI=10.1016/j.cellsig.2010.05.004;
RA Wardega P., Heldin C.H., Lennartsson J.;
RT "Mutation of tyrosine residue 857 in the PDGF beta-receptor affects
RT cell proliferation but not migration.";
RL Cell. Signal. 22:1363-1368(2010).
RN [39]
RP INVOLVEMENT IN MC.
RX PubMed=20577567; DOI=10.1371/journal.pgen.1000991;
RA Sobreira N.L., Cirulli E.T., Avramopoulos D., Wohler E., Oswald G.L.,
RA Stevens E.L., Ge D., Shianna K.V., Smith J.P., Maia J.M., Gumbs C.E.,
RA Pevsner J., Thomas G., Valle D., Hoover-Fong J.E., Goldstein D.B.;
RT "Whole-genome sequencing of a single proband together with linkage
RT analysis identifies a Mendelian disease gene.";
RL PLoS Genet. 6:E1000991-E1000991(2010).
RN [40]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [41]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 3-530 (ISOFORM 2).
RX PubMed=9491886; DOI=10.1016/S0092-8674(00)80938-1;
RA Hof P., Pluskey S., Dhe-Paganon S., Eck M.J., Shoelson S.E.;
RT "Crystal structure of the tyrosine phosphatase SHP-2.";
RL Cell 92:441-450(1998).
RN [43]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 237-533.
RX PubMed=19167335; DOI=10.1016/j.cell.2008.11.038;
RA Barr A.J., Ugochukwu E., Lee W.H., King O.N.F., Filippakopoulos P.,
RA Alfano I., Savitsky P., Burgess-Brown N.A., Mueller S., Knapp S.;
RT "Large-scale structural analysis of the classical human protein
RT tyrosine phosphatome.";
RL Cell 136:352-363(2009).
RN [44]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 262-532 IN COMPLEX WITH
RP INHIBITOR, AND CATALYTIC ACTIVITY.
RX PubMed=20170098; DOI=10.1021/jm901645u;
RA Zhang X., He Y., Liu S., Yu Z., Jiang Z.X., Yang Z., Dong Y.,
RA Nabinger S.C., Wu L., Gunawan A.M., Wang L., Chan R.J., Zhang Z.Y.;
RT "Salicylic acid based small molecule inhibitor for the oncogenic Src
RT homology-2 domain containing protein tyrosine phosphatase-2 (SHP2).";
RL J. Med. Chem. 53:2482-2493(2010).
RN [45]
RP VARIANTS NS1 GLY-61; CYS-63; GLY-72; SER-72; ASP-76; ARG-79; VAL-282;
RP ASP-308 AND VAL-508.
RX PubMed=11704759; DOI=10.1038/ng772;
RA Tartaglia M., Mehler E.L., Goldberg R., Zampino G., Brunner H.G.,
RA Kremer H., van der Burgt I., Crosby A.H., Ion A., Jeffery S.,
RA Kalidas K., Patton M.A., Kucherlapati R.S., Gelb B.D.;
RT "Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2,
RT cause Noonan syndrome.";
RL Nat. Genet. 29:465-468(2001).
RN [46]
RP ERRATUM.
RA Tartaglia M., Mehler E.L., Goldberg R., Zampino G., Brunner H.G.,
RA Kremer H., van der Burgt I., Crosby A.H., Ion A., Jeffery S.,
RA Kalidas K., Patton M.A., Kucherlapati R.S., Gelb B.D.;
RL Nat. Genet. 29:491-491(2001).
RN [47]
RP ERRATUM.
RA Tartaglia M., Mehler E.L., Goldberg R., Zampino G., Brunner H.G.,
RA Kremer H., van der Burgt I., Crosby A.H., Ion A., Jeffery S.,
RA Kalidas K., Patton M.A., Kucherlapati R.S., Gelb B.D.;
RL Nat. Genet. 30:123-123(2001).
RN [48]
RP VARIANTS NS1 ALA-42; ALA-60; ASN-61; GLY-61; ASP-62; CYS-63; GLY-72;
RP ILE-73; ASP-76; ARG-79; ALA-106; ASP-139; CYS-279; VAL-282; LEU-285;
RP SER-285; ASP-308; SER-308; VAL-309; LYS-505 AND VAL-508.
RX PubMed=11992261; DOI=10.1086/340847;
RA Tartaglia M., Kalidas K., Shaw A., Song X., Musat D.L.,
RA van der Burgt I., Brunner H.G., Bertola D.R., Crosby A.H., Ion A.,
RA Kucherlapati R.S., Jeffery S., Patton M.A., Gelb B.D.;
RT "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-
RT phenotype correlation, and phenotypic heterogeneity.";
RL Am. J. Hum. Genet. 70:1555-1563(2002).
RN [49]
RP VARIANTS LEOPARD1 CYS-279 AND MET-472.
RX PubMed=12058348; DOI=10.1086/341528;
RA Digilio M.C., Conti E., Sarkozy A., Mingarelli R., Dottorini T.,
RA Marino B., Pizzuti A., Dallapiccola B.;
RT "Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the
RT PTPN11 gene.";
RL Am. J. Hum. Genet. 71:389-394(2002).
RN [50]
RP VARIANTS NS1 ASP-62; CYS-63 AND THR-506.
RX PubMed=12325025; DOI=10.1002/humu.10129;
RA Maheshwari M., Belmont J., Fernbach S., Ho T., Molinari L., Yakub I.,
RA Yu F., Combes A., Towbin J.A., Craigen W.J., Gibbs R.A.;
RT "PTPN11 mutations in Noonan syndrome type I: detection of recurrent
RT mutations in exons 3 and 13.";
RL Hum. Mutat. 20:298-304(2002).
RN [51]
RP VARIANTS NS1 GLY-61; CYS-63; SER-72; ILE-73; SER-285 AND ASP-308.
RX PubMed=12161469; DOI=10.1210/jc.87.8.3529;
RA Kosaki K., Suzuki T., Muroya K., Hasegawa T., Sato S., Matsuo N.,
RA Kosaki R., Nagai T., Hasegawa Y., Ogata T.;
RT "PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations
RT in seven Japanese patients with Noonan syndrome.";
RL J. Clin. Endocrinol. Metab. 87:3529-3533(2002).
RN [52]
RP VARIANT NS1 ARG-79.
RX PubMed=12529711; DOI=10.1038/sj.ejhg.5200915;
RA Schollen E., Matthijs G., Gewillig M., Fryns J.-P., Legius E.;
RT "PTPN11 mutation in a large family with Noonan syndrome and dizygous
RT twinning.";
RL Eur. J. Hum. Genet. 11:85-88(2003).
RN [53]
RP VARIANTS NS1 LYS-58; ASN-61; GLY-61; CYS-63; GLN-69; LEU-71; SER-72;
RP ILE-73; ASP-76; ARG-79; ASP-139; ARG-256; VAL-282 AND ASP-308.
RX PubMed=12634870; DOI=10.1038/sj.ejhg.5200935;
RA Musante L., Kehl H.G., Majewski F., Meinecke P., Schweiger S.,
RA Gillessen-Kaesbach G., Wieczorek D., Hinkel G.K., Tinschert S.,
RA Hoeltzenbein M., Ropers H.-H., Kalscheuer V.M.;
RT "Spectrum of mutations in PTPN11 and genotype-phenotype correlation in
RT 96 patients with Noonan syndrome and five patients with cardio-facio-
RT cutaneous syndrome.";
RL Eur. J. Hum. Genet. 11:201-206(2003).
RN [54]
RP ERRATUM.
RA Musante L., Kehl H.G., Majewski F., Meinecke P., Schweiger S.,
RA Gillessen-Kaesbach G., Wieczorek D., Hinkel G.K., Tinschert S.,
RA Hoeltzenbein M., Ropers H.-H., Kalscheuer V.M.;
RL Eur. J. Hum. Genet. 11:551-551(2003).
RN [55]
RP VARIANT NS1 THR-506.
RX PubMed=12739139; DOI=10.1007/s00431-003-1227-6;
RA Kondoh T., Ishii E., Aoki Y., Shimizu T., Zaitsu M., Matsubara Y.,
RA Moriuchi H.;
RT "Noonan syndrome with leukaemoid reaction and overproduction of
RT catecholamines: a case report.";
RL Eur. J. Pediatr. 162:548-549(2003).
RN [56]
RP VARIANT LEOPARD1 PRO-510.
RX PubMed=14961557; DOI=10.1002/humu.9149;
RA Conti E., Dottorini T., Sarkozy A., Tiller G.E., Esposito G.,
RA Pizzuti A., Dallapiccola B.;
RT "A novel PTPN11 mutation in LEOPARD syndrome.";
RL Hum. Mutat. 21:654-654(2003).
RN [57]
RP VARIANTS NS1 ILE-2; ALA-42; ASP-62; CYS-63; GLY-72; PRO-79; ALA-106;
RP CYS-279; ASP-308; SER-308; MET-472; ARG-507; VAL-508 AND PHE-564.
RX PubMed=12960218; DOI=10.1136/jmg.40.9.704;
RA Sarkozy A., Conti E., Seripa D., Digilio M.C., Grifone N., Tandoi C.,
RA Fazio V.M., Di Ciommo V., Marino B., Pizzuti A., Dallapiccola B.;
RT "Correlation between PTPN11 gene mutations and congenital heart
RT defects in Noonan and LEOPARD syndromes.";
RL J. Med. Genet. 40:704-708(2003).
RN [58]
RP VARIANTS JMML TYR-61; VAL-61; LYS-69; THR-72; VAL-72; ALA-76; GLY-76;
RP LYS-76; VAL-76; ALA-507 AND ARG-507, VARIANTS MYELODYSPLASTIC SYNDROME
RP VAL-60; VAL-61; LYS-69; LEU-71 AND ALA-76, VARIANTS NS1 ASP-62 AND
RP ILE-73, AND VARIANT ACUTE MYELOID LEUKEMIA LYS-71.
RX PubMed=12717436; DOI=10.1038/ng1156;
RA Tartaglia M., Niemeyer C.M., Fragale A., Song X., Buechner J.,
RA Jung A., Haehlen K., Hasle H., Licht J.D., Gelb B.D.;
RT "Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia,
RT myelodysplastic syndromes and acute myeloid leukemia.";
RL Nat. Genet. 34:148-150(2003).
RN [59]
RP VARIANT NS1 MET-415.
RX PubMed=15384080; DOI=10.1002/ajmg.a.30270;
RA Bertola D.R., Pereira A.C., de Oliveira P.S.L., Kim C.A.,
RA Krieger J.E.;
RT "Clinical variability in a Noonan syndrome family with a new PTPN11
RT gene mutation.";
RL Am. J. Med. Genet. A 130:378-383(2004).
RN [60]
RP VARIANTS LEOPARD1 THR-465 AND ALA-468.
RX PubMed=15389709; DOI=10.1002/ajmg.a.30281;
RA Yoshida R., Nagai T., Hasegawa T., Kinoshita E., Tanaka T., Ogata T.;
RT "Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome.";
RL Am. J. Med. Genet. A 130:432-434(2004).
RN [61]
RP VARIANTS LEOPARD1 CYS-279; SER-279; MET-472 AND PRO-514.
RX PubMed=15520399; DOI=10.1136/jmg.2004.021451;
RG French collaborative Noonan study group;
RA Keren B., Hadchouel A., Saba S., Sznajer Y., Bonneau D., Leheup B.,
RA Boute O., Gaillard D., Lacombe D., Layet V., Marlin S., Mortier G.,
RA Toutain A., Beylot C., Baumann C., Verloes A., Cave H.;
RT "PTPN11 mutations in patients with LEOPARD syndrome: a French
RT multicentric experience.";
RL J. Med. Genet. 41:E117-E117(2004).
RN [62]
RP VARIANTS LEOPARD1 CYS-279; SER-279; ALA-468; MET-472; TRP-502; LEU-502
RP AND PRO-510.
RX PubMed=15121796; DOI=10.1136/jmg.2003.013466;
RA Sarkozy A., Conti E., Digilio M.C., Marino B., Morini E., Pacileo G.,
RA Wilson M., Calabro R., Pizzuti A., Dallapiccola B.;
RT "Clinical and molecular analysis of 30 patients with multiple
RT lentigines LEOPARD syndrome.";
RL J. Med. Genet. 41:E68-E68(2004).
RN [63]
RP VARIANT NS1 ARG-510.
RX PubMed=15948193; DOI=10.1002/ajmg.a.30813;
RA Bertola D.R., Pereira A.C., Passetti F., de Oliveira P.S.L.,
RA Messiaen L., Gelb B.D., Kim C.A., Krieger J.E.;
RT "Neurofibromatosis-Noonan syndrome: molecular evidence of the
RT concurrence of both disorders in a patient.";
RL Am. J. Med. Genet. A 136:242-245(2005).
RN [64]
RP VARIANT LEOPARD1 PRO-510.
RX PubMed=15690106; DOI=10.1007/s10038-004-0212-x;
RA Kalidas K., Shaw A.C., Crosby A.H., Newbury-Ecob R., Greenhalgh L.,
RA Temple I.K., Law C., Patel A., Patton M.A., Jeffery S.;
RT "Genetic heterogeneity in LEOPARD syndrome: two families with no
RT mutations in PTPN11.";
RL J. Hum. Genet. 50:21-25(2005).
RN [65]
RP VARIANT LEOPARD1 CYS-279.
RX PubMed=16679933; DOI=10.1097/01.mph.0000199590.21797.0b;
RA Ucar C., Calyskan U., Martini S., Heinritz W.;
RT "Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11
RT gene mutation positive).";
RL J. Pediatr. Hematol. Oncol. 28:123-125(2006).
RN [66]
RP VARIANT NS1 ALA-59.
RX PubMed=19020799; DOI=10.1007/s10038-008-0343-6;
RA Ko J.M., Kim J.M., Kim G.H., Yoo H.W.;
RT "PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype
RT correlation in Korean patients with Noonan syndrome.";
RL J. Hum. Genet. 53:999-1006(2008).
CC -!- FUNCTION: Acts downstream of various receptor and cytoplasmic
CC protein tyrosine kinases to participate in the signal transduction
CC from the cell surface to the nucleus. Dephosphorylates ROCK2 at
CC Tyr-722 resulting in stimulatation of its RhoA binding activity.
CC -!- CATALYTIC ACTIVITY: Protein tyrosine phosphate + H(2)O = protein
CC tyrosine + phosphate.
CC -!- SUBUNIT: Interacts with phosphorylated LIME1 and BCAR3. Interacts
CC with SHB and INPP5D/SHIP1 (By similarity). Interacts with MILR1
CC (tyrosine-phosphorylated). Interacts with FLT1 (tyrosine-
CC phosphorylated), FLT3 (tyrosine-phosphorylated), FLT4 (tyrosine-
CC phosphorylated), KIT and GRB2. Interacts with PDGFRA (tyrosine
CC phosphorylated). Interacts (via SH2 domain) with TEK/TIE2
CC (tyrosine phosphorylated) (By similarity). Interacts with PTPNS1
CC and CD84. Interacts with phosphorylated SIT1 and MPZL1. Interacts
CC with FCRL3, FCRL4, FCRL6 and ANKHD1. Interacts with KIR2DL1; the
CC interaction is enhanced by ARRB2. Interacts with GAB2. Interacts
CC with TERT; the interaction retains TERT in the nucleus. Interacts
CC with PECAM1 and FER. Interacts with EPHA2 (activated);
CC participates in PTK2/FAK1 dephosphorylation in EPHA2 downstream
CC signaling. Interacts with ROS1; mediates PTPN11 phosphorylation.
CC Interacts with PDGFRB (tyrosine phosphorylated); this interaction
CC increases the PTPN11 phosphatase activity. Interacts with GAREM
CC isoform 1 (tyrosine phosphorylated); the interaction increases
CC MAPK/ERK activity and does not affect the GRB2/SOS complex
CC formation.
CC -!- INTERACTION:
CC P32239:CCKBR; NbExp=5; IntAct=EBI-297779, EBI-1753137;
CC P20138:CD33; NbExp=5; IntAct=EBI-297779, EBI-3906571;
CC Q08345:DDR1; NbExp=4; IntAct=EBI-297779, EBI-711879;
CC P68105:EEF1A1 (xeno); NbExp=2; IntAct=EBI-297779, EBI-7645934;
CC Q71V39:EEF1A2 (xeno); NbExp=2; IntAct=EBI-297779, EBI-7645815;
CC P04626:ERBB2; NbExp=2; IntAct=EBI-297779, EBI-641062;
CC P17948:FLT1; NbExp=2; IntAct=EBI-297779, EBI-1026718;
CC Q13480:GAB1; NbExp=21; IntAct=EBI-297779, EBI-517684;
CC Q9UQC2:GAB2; NbExp=4; IntAct=EBI-297779, EBI-975200;
CC P62993:GRB2; NbExp=6; IntAct=EBI-297779, EBI-401755;
CC P08069:IGF1R; NbExp=3; IntAct=EBI-297779, EBI-475981;
CC P06213:INSR; NbExp=2; IntAct=EBI-297779, EBI-475899;
CC P35568:IRS1; NbExp=3; IntAct=EBI-297779, EBI-517592;
CC P35570:Irs1 (xeno); NbExp=3; IntAct=EBI-297779, EBI-520230;
CC P43628:KIR2DL3; NbExp=4; IntAct=EBI-297779, EBI-8632435;
CC O95297:MPZL1; NbExp=4; IntAct=EBI-297779, EBI-963338;
CC P09619:PDGFRB; NbExp=8; IntAct=EBI-297779, EBI-641237;
CC P16284:PECAM1; NbExp=7; IntAct=EBI-297779, EBI-716404;
CC P49023:PXN; NbExp=3; IntAct=EBI-297779, EBI-702209;
CC P97710:Sirpa (xeno); NbExp=3; IntAct=EBI-297779, EBI-7945080;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=PTP2Ci;
CC IsoId=Q06124-1; Sequence=Displayed;
CC Name=2; Synonyms=PTP2C;
CC IsoId=Q06124-2; Sequence=VSP_016672;
CC Name=3;
CC IsoId=Q06124-3; Sequence=VSP_016672, VSP_016673, VSP_016674;
CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in
CC heart, brain, and skeletal muscle.
CC -!- DOMAIN: The SH2 domains repress phosphatase activity. Binding of
CC these domains to phosphotyrosine-containing proteins relieves this
CC auto-inhibition, possibly by inducing a conformational change in
CC the enzyme.
CC -!- PTM: Phosphorylated on Tyr-546 and Tyr-584 upon receptor protein
CC tyrosine kinase activation; which creates a binding site for GRB2
CC and other SH2-containing proteins. Phosphorylated upon activation
CC of the receptor-type kinase FLT3. Phosphorylated upon activation
CC of the receptor-type kinase PDGFRA (By similarity). Phosphorylated
CC by activated PDGFRB.
CC -!- DISEASE: LEOPARD syndrome 1 (LEOPARD1) [MIM:151100]: A disorder
CC characterized by lentigines, electrocardiographic conduction
CC abnormalities, ocular hypertelorism, pulmonic stenosis,
CC abnormalities of genitalia, retardation of growth, and
CC sensorineural deafness. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Noonan syndrome 1 (NS1) [MIM:163950]: A form of Noonan
CC syndrome, a disease characterized by short stature, facial
CC dysmorphic features such as hypertelorism, a downward eyeslant and
CC low-set posteriorly rotated ears, and a high incidence of
CC congenital heart defects and hypertrophic cardiomyopathy. Other
CC features can include a short neck with webbing or redundancy of
CC skin, deafness, motor delay, variable intellectual deficits,
CC multiple skeletal defects, cryptorchidism, and bleeding diathesis.
CC Individuals with Noonan syndrome are at risk of juvenile
CC myelomonocytic leukemia, a myeloproliferative disorder
CC characterized by excessive production of myelomonocytic cells.
CC Some patients with NS1 develop multiple giant cell lesions of the
CC jaw or other bony or soft tissues, which are classified as
CC pigmented villonodular synovitis (PVNS) when occurring in the jaw
CC or joints. Note=The disease is caused by mutations affecting the
CC gene represented in this entry. Mutations in PTPN11 account for
CC more than 50% of the cases.
CC -!- DISEASE: Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An
CC aggressive pediatric myelodysplastic syndrome/myeloproliferative
CC disorder characterized by malignant transformation in the
CC hematopoietic stem cell compartment with proliferation of
CC differentiated progeny. Patients have splenomegaly, enlarged lymph
CC nodes, rashes, and hemorrhages. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Metachondromatosis (MC) [MIM:156250]: A skeletal disorder
CC with radiologic features of both multiple exostoses and Ollier
CC disease, characterized by the presence of exostoses, commonly of
CC the bones of the hands and feet, and enchondromas of the
CC metaphyses of long bones and iliac crest. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
CC Non-receptor class 2 subfamily.
CC -!- SIMILARITY: Contains 2 SH2 domains.
CC -!- SIMILARITY: Contains 1 tyrosine-protein phosphatase domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PTPN11ID41910ch12q24.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PTPN11";
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DR EMBL; D13540; BAA02740.2; -; mRNA.
DR EMBL; L03535; AAA36611.1; -; mRNA.
DR EMBL; L07527; AAA17022.1; -; mRNA.
DR EMBL; L08807; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; X70766; CAA50045.1; -; mRNA.
DR EMBL; BT007106; AAP35770.1; -; mRNA.
DR EMBL; AK289854; BAF82543.1; -; mRNA.
DR EMBL; CH471054; EAW98012.1; -; Genomic_DNA.
DR EMBL; BC008692; AAH08692.1; -; mRNA.
DR PIR; JN0805; JN0805.
DR RefSeq; NP_002825.3; NM_002834.3.
DR RefSeq; NP_542168.1; NM_080601.1.
DR UniGene; Hs.506852; -.
DR PDB; 2SHP; X-ray; 2.00 A; A/B=3-529.
DR PDB; 3B7O; X-ray; 1.60 A; A=237-533.
DR PDB; 3MOW; X-ray; 2.30 A; A=262-532.
DR PDB; 3O5X; X-ray; 2.00 A; A=262-532.
DR PDB; 3TKZ; X-ray; 1.80 A; A=1-106.
DR PDB; 3TL0; X-ray; 2.05 A; A=1-106.
DR PDB; 4DGP; X-ray; 2.30 A; A=1-532.
DR PDB; 4DGX; X-ray; 2.30 A; A=1-532.
DR PDB; 4GWF; X-ray; 2.10 A; A/B=1-543.
DR PDB; 4H1O; X-ray; 2.20 A; A=1-543.
DR PDB; 4H34; X-ray; 2.70 A; A=1-543.
DR PDB; 4JE4; X-ray; 2.31 A; A=1-103.
DR PDB; 4JEG; X-ray; 2.30 A; A=97-217.
DR PDBsum; 2SHP; -.
DR PDBsum; 3B7O; -.
DR PDBsum; 3MOW; -.
DR PDBsum; 3O5X; -.
DR PDBsum; 3TKZ; -.
DR PDBsum; 3TL0; -.
DR PDBsum; 4DGP; -.
DR PDBsum; 4DGX; -.
DR PDBsum; 4GWF; -.
DR PDBsum; 4H1O; -.
DR PDBsum; 4H34; -.
DR PDBsum; 4JE4; -.
DR PDBsum; 4JEG; -.
DR ProteinModelPortal; Q06124; -.
DR SMR; Q06124; 3-595.
DR DIP; DIP-516N; -.
DR IntAct; Q06124; 58.
DR MINT; MINT-199832; -.
DR STRING; 9606.ENSP00000340944; -.
DR BindingDB; Q06124; -.
DR ChEMBL; CHEMBL3864; -.
DR PhosphoSite; Q06124; -.
DR DMDM; 84028248; -.
DR PaxDb; Q06124; -.
DR PRIDE; Q06124; -.
DR DNASU; 5781; -.
DR Ensembl; ENST00000351677; ENSP00000340944; ENSG00000179295.
DR Ensembl; ENST00000392597; ENSP00000376376; ENSG00000179295.
DR GeneID; 5781; -.
DR KEGG; hsa:5781; -.
DR CTD; 5781; -.
DR GeneCards; GC12P112856; -.
DR HGNC; HGNC:9644; PTPN11.
DR HPA; CAB005377; -.
DR MIM; 151100; phenotype.
DR MIM; 156250; phenotype.
DR MIM; 163950; phenotype.
DR MIM; 176876; gene.
DR MIM; 607785; phenotype.
DR neXtProt; NX_Q06124; -.
DR Orphanet; 86834; Juvenile myelomonocytic leukemia.
DR Orphanet; 500; LEOPARD syndrome.
DR Orphanet; 2499; Metachondromatosis.
DR Orphanet; 648; Noonan syndrome.
DR PharmGKB; PA33986; -.
DR eggNOG; COG5599; -.
DR HOGENOM; HOG000273907; -.
DR HOVERGEN; HBG000223; -.
DR InParanoid; Q06124; -.
DR KO; K07293; -.
DR OMA; KEYGAMR; -.
DR OrthoDB; EOG7NPFST; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q06124; -.
DR ChiTaRS; PTPN11; human.
DR EvolutionaryTrace; Q06124; -.
DR GeneWiki; PTPN11; -.
DR GenomeRNAi; 5781; -.
DR NextBio; 22484; -.
DR PRO; PR:Q06124; -.
DR ArrayExpress; Q06124; -.
DR Bgee; Q06124; -.
DR CleanEx; HS_PTPN11; -.
DR Genevestigator; Q06124; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; IEA:Ensembl.
DR GO; GO:0004726; F:non-membrane spanning protein tyrosine phosphatase activity; IMP:UniProtKB.
DR GO; GO:0005070; F:SH3/SH2 adaptor activity; IDA:BHF-UCL.
DR GO; GO:0000187; P:activation of MAPK activity; IEA:Ensembl.
DR GO; GO:0036302; P:atrioventricular canal development; IMP:BHF-UCL.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0007420; P:brain development; IMP:BHF-UCL.
DR GO; GO:0000077; P:DNA damage checkpoint; IEA:Ensembl.
DR GO; GO:0048013; P:ephrin receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0060325; P:face morphogenesis; IMP:BHF-UCL.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048806; P:genitalia development; IMP:BHF-UCL.
DR GO; GO:0042593; P:glucose homeostasis; IEA:Ensembl.
DR GO; GO:0042445; P:hormone metabolic process; IEA:Ensembl.
DR GO; GO:0009755; P:hormone-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0048839; P:inner ear development; IMP:BHF-UCL.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0060333; P:interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0048609; P:multicellular organismal reproductive process; IEA:Ensembl.
DR GO; GO:0051463; P:negative regulation of cortisol secretion; IEA:Ensembl.
DR GO; GO:0060125; P:negative regulation of growth hormone secretion; IEA:Ensembl.
DR GO; GO:0046676; P:negative regulation of insulin secretion; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0035265; P:organ growth; IEA:Ensembl.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
DR GO; GO:2001275; P:positive regulation of glucose import in response to insulin stimulus; IDA:BHF-UCL.
DR GO; GO:0046887; P:positive regulation of hormone secretion; IEA:Ensembl.
DR GO; GO:0033628; P:regulation of cell adhesion mediated by integrin; IMP:UniProtKB.
DR GO; GO:0060334; P:regulation of interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0046825; P:regulation of protein export from nucleus; IEA:Ensembl.
DR GO; GO:0060338; P:regulation of type I interferon-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0031295; P:T cell costimulation; TAS:Reactome.
DR GO; GO:0006641; P:triglyceride metabolic process; IEA:Ensembl.
DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; TAS:Reactome.
DR Gene3D; 3.30.505.10; -; 2.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR000387; Tyr/Dual-sp_Pase.
DR InterPro; IPR016130; Tyr_Pase_AS.
DR InterPro; IPR012152; Tyr_Pase_non-rcpt_typ-6/11.
DR InterPro; IPR000242; Tyr_Pase_rcpt/non-rcpt.
DR Pfam; PF00017; SH2; 2.
DR Pfam; PF00102; Y_phosphatase; 1.
DR PIRSF; PIRSF000929; Tyr-Ptase_nr_6; 1.
DR PRINTS; PR00700; PRTYPHPHTASE.
DR PRINTS; PR00401; SH2DOMAIN.
DR SMART; SM00194; PTPc; 1.
DR SMART; SM00252; SH2; 2.
DR PROSITE; PS50001; SH2; 2.
DR PROSITE; PS00383; TYR_PHOSPHATASE_1; 1.
DR PROSITE; PS50056; TYR_PHOSPHATASE_2; 1.
DR PROSITE; PS50055; TYR_PHOSPHATASE_PTP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Deafness; Disease mutation; Hydrolase; Phosphoprotein;
KW Protein phosphatase; Reference proteome; Repeat; SH2 domain.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 597 Tyrosine-protein phosphatase non-receptor
FT type 11.
FT /FTId=PRO_0000094767.
FT DOMAIN 6 102 SH2 1.
FT DOMAIN 112 216 SH2 2.
FT DOMAIN 247 521 Tyrosine-protein phosphatase.
FT REGION 463 469 Substrate binding (By similarity).
FT ACT_SITE 463 463 Phosphocysteine intermediate.
FT BINDING 429 429 Substrate (By similarity).
FT BINDING 510 510 Substrate (By similarity).
FT MOD_RES 2 2 N-acetylthreonine.
FT MOD_RES 62 62 Phosphotyrosine.
FT MOD_RES 63 63 Phosphotyrosine.
FT MOD_RES 66 66 Phosphotyrosine (By similarity).
FT MOD_RES 280 280 N6-acetyllysine.
FT MOD_RES 546 546 Phosphotyrosine; by PDGFR.
FT MOD_RES 562 562 Phosphoserine.
FT MOD_RES 584 584 Phosphotyrosine; by PDGFR.
FT MOD_RES 595 595 Phosphoserine.
FT VAR_SEQ 408 411 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_016672.
FT VAR_SEQ 464 464 S -> R (in isoform 3).
FT /FTId=VSP_016673.
FT VAR_SEQ 465 597 Missing (in isoform 3).
FT /FTId=VSP_016674.
FT VARIANT 2 2 T -> I (in NS1).
FT /FTId=VAR_027183.
FT VARIANT 42 42 T -> A (in NS1).
FT /FTId=VAR_015601.
FT VARIANT 58 58 N -> K (in NS1).
FT /FTId=VAR_027184.
FT VARIANT 59 59 T -> A (in NS1).
FT /FTId=VAR_066060.
FT VARIANT 60 60 G -> A (in NS1).
FT /FTId=VAR_015602.
FT VARIANT 60 60 G -> V (in myelodysplastic syndrome).
FT /FTId=VAR_015990.
FT VARIANT 61 61 D -> G (in NS1).
FT /FTId=VAR_015603.
FT VARIANT 61 61 D -> N (in NS1).
FT /FTId=VAR_015604.
FT VARIANT 61 61 D -> V (in JMML; also in myelodysplastic
FT syndrome).
FT /FTId=VAR_015991.
FT VARIANT 61 61 D -> Y (in JMML).
FT /FTId=VAR_015992.
FT VARIANT 62 62 Y -> D (in NS1; also in Noonan patients
FT manifesting juvenile myelomonocytic
FT leukemia).
FT /FTId=VAR_015605.
FT VARIANT 63 63 Y -> C (in NS1).
FT /FTId=VAR_015606.
FT VARIANT 69 69 E -> K (in JMML; also in myelodysplastic
FT syndrome).
FT /FTId=VAR_015993.
FT VARIANT 69 69 E -> Q (in NS1).
FT /FTId=VAR_027185.
FT VARIANT 71 71 F -> K (in acute myeloid leukemia;
FT requires 2 nucleotide substitutions).
FT /FTId=VAR_015994.
FT VARIANT 71 71 F -> L (in myelodysplastic syndrome).
FT /FTId=VAR_015995.
FT VARIANT 72 72 A -> G (in NS1).
FT /FTId=VAR_015607.
FT VARIANT 72 72 A -> S (in NS1).
FT /FTId=VAR_015608.
FT VARIANT 72 72 A -> T (in JMML).
FT /FTId=VAR_015996.
FT VARIANT 72 72 A -> V (in JMML).
FT /FTId=VAR_015997.
FT VARIANT 73 73 T -> I (in NS1; also in Noonan patients
FT manifesting juvenile myelomonocytic
FT leukemia; dbSNP:rs28933387).
FT /FTId=VAR_015609.
FT VARIANT 76 76 E -> A (in JMML; also in myelodysplastic
FT syndrome).
FT /FTId=VAR_015998.
FT VARIANT 76 76 E -> D (in NS1).
FT /FTId=VAR_015610.
FT VARIANT 76 76 E -> G (in JMML).
FT /FTId=VAR_015999.
FT VARIANT 76 76 E -> K (in JMML; dbSNP:rs28933388).
FT /FTId=VAR_016000.
FT VARIANT 76 76 E -> V (in JMML).
FT /FTId=VAR_016001.
FT VARIANT 79 79 Q -> P (in NS1).
FT /FTId=VAR_027186.
FT VARIANT 79 79 Q -> R (in NS1).
FT /FTId=VAR_015611.
FT VARIANT 106 106 D -> A (in NS1).
FT /FTId=VAR_015612.
FT VARIANT 139 139 E -> D (in NS1).
FT /FTId=VAR_015613.
FT VARIANT 256 256 Q -> R (in NS1).
FT /FTId=VAR_027187.
FT VARIANT 279 279 Y -> C (in NS1 and LEOPARD1).
FT /FTId=VAR_015614.
FT VARIANT 279 279 Y -> S (in LEOPARD1).
FT /FTId=VAR_027188.
FT VARIANT 282 282 I -> V (in NS1).
FT /FTId=VAR_015615.
FT VARIANT 285 285 F -> L (in NS1).
FT /FTId=VAR_015617.
FT VARIANT 285 285 F -> S (in NS1).
FT /FTId=VAR_015616.
FT VARIANT 308 308 N -> D (in NS1; common mutation).
FT /FTId=VAR_015619.
FT VARIANT 308 308 N -> S (in NS1; some patients also
FT manifest giant cell lesions of bone and
FT soft tissue).
FT /FTId=VAR_015618.
FT VARIANT 309 309 I -> V (in NS1).
FT /FTId=VAR_015620.
FT VARIANT 415 415 T -> M (in NS1).
FT /FTId=VAR_027189.
FT VARIANT 465 465 A -> T (in LEOPARD1).
FT /FTId=VAR_027190.
FT VARIANT 468 468 G -> A (in LEOPARD1).
FT /FTId=VAR_027191.
FT VARIANT 472 472 T -> M (in LEOPARD1).
FT /FTId=VAR_015621.
FT VARIANT 502 502 R -> L (in LEOPARD1).
FT /FTId=VAR_027192.
FT VARIANT 502 502 R -> W (in LEOPARD1).
FT /FTId=VAR_027193.
FT VARIANT 505 505 R -> K (in NS1).
FT /FTId=VAR_015622.
FT VARIANT 506 506 S -> T (in NS1).
FT /FTId=VAR_015623.
FT VARIANT 507 507 G -> A (in JMML).
FT /FTId=VAR_016002.
FT VARIANT 507 507 G -> R (in patients with growth
FT retardation, pulmonic stenosis and
FT juvenile myelomonocytic leukemia).
FT /FTId=VAR_016003.
FT VARIANT 508 508 M -> V (in NS1).
FT /FTId=VAR_015624.
FT VARIANT 510 510 Q -> P (in LEOPARD1).
FT /FTId=VAR_027194.
FT VARIANT 510 510 Q -> R (in NS1).
FT /FTId=VAR_027195.
FT VARIANT 514 514 Q -> P (in LEOPARD1).
FT /FTId=VAR_027196.
FT VARIANT 564 564 L -> F (in NS1).
FT /FTId=VAR_027197.
FT MUTAGEN 463 463 C->S: Abolishes phosphatase activity.
FT CONFLICT 539 539 S -> R (in Ref. 3; BAA02740).
FT CONFLICT 552 552 S -> P (in Ref. 3; BAA02740).
FT HELIX 13 23
FT STRAND 28 33
FT STRAND 35 37
FT STRAND 41 47
FT STRAND 50 58
FT STRAND 59 61
FT STRAND 63 68
FT STRAND 71 73
FT HELIX 74 83
FT STRAND 87 90
FT HELIX 107 109
FT STRAND 113 116
FT HELIX 119 128
FT STRAND 134 139
FT STRAND 141 143
FT STRAND 147 153
FT STRAND 166 175
FT STRAND 178 184
FT STRAND 187 189
FT HELIX 190 199
FT HELIX 223 225
FT HELIX 226 234
FT HELIX 247 258
FT HELIX 259 262
FT HELIX 267 269
FT HELIX 271 276
FT STRAND 277 279
FT TURN 286 288
FT STRAND 289 291
FT STRAND 303 310
FT STRAND 327 331
FT TURN 335 337
FT HELIX 338 347
FT STRAND 352 355
FT STRAND 359 361
FT STRAND 364 366
FT STRAND 377 380
FT STRAND 383 392
FT STRAND 394 405
FT STRAND 412 424
FT STRAND 429 431
FT STRAND 434 436
FT HELIX 437 451
FT STRAND 459 467
FT HELIX 468 486
FT STRAND 490 492
FT HELIX 494 502
FT HELIX 512 531
SQ SEQUENCE 597 AA; 68436 MW; 37E8BFC7ECA2D03F CRC64;
MTSRRWFHPN ITGVEAENLL LTRGVDGSFL ARPSKSNPGD FTLSVRRNGA VTHIKIQNTG
DYYDLYGGEK FATLAELVQY YMEHHGQLKE KNGDVIELKY PLNCADPTSE RWFHGHLSGK
EAEKLLTEKG KHGSFLVRES QSHPGDFVLS VRTGDDKGES NDGKSKVTHV MIRCQELKYD
VGGGERFDSL TDLVEHYKKN PMVETLGTVL QLKQPLNTTR INAAEIESRV RELSKLAETT
DKVKQGFWEE FETLQQQECK LLYSRKEGQR QENKNKNRYK NILPFDHTRV VLHDGDPNEP
VSDYINANII MPEFETKCNN SKPKKSYIAT QGCLQNTVND FWRMVFQENS RVIVMTTKEV
ERGKSKCVKY WPDEYALKEY GVMRVRNVKE SAAHDYTLRE LKLSKVGQAL LQGNTERTVW
QYHFRTWPDH GVPSDPGGVL DFLEEVHHKQ ESIMDAGPVV VHCSAGIGRT GTFIVIDILI
DIIREKGVDC DIDVPKTIQM VRSQRSGMVQ TEAQYRFIYM AVQHYIETLQ RRIEEEQKSK
RKGHEYTNIK YSLADQTSGD QSPLPPCTPT PPCAEMREDS ARVYENVGLM QQQKSFR
//
ID PTN11_HUMAN Reviewed; 597 AA.
AC Q06124; A8K1D9; Q96HD7;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 20-DEC-2005, sequence version 2.
DT 22-JAN-2014, entry version 172.
DE RecName: Full=Tyrosine-protein phosphatase non-receptor type 11;
DE EC=3.1.3.48;
DE AltName: Full=Protein-tyrosine phosphatase 1D;
DE Short=PTP-1D;
DE AltName: Full=Protein-tyrosine phosphatase 2C;
DE Short=PTP-2C;
DE AltName: Full=SH-PTP2;
DE Short=SHP-2;
DE Short=Shp2;
DE AltName: Full=SH-PTP3;
GN Name=PTPN11; Synonyms=PTP2C, SHPTP2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=T-cell;
RX PubMed=1281790; DOI=10.1016/0014-5793(92)81500-L;
RA Adachi M., Sekiya M., Miyachi T., Matsuno K., Hinoda Y., Imai K.,
RA Yachi A.;
RT "Molecular cloning of a novel protein-tyrosine phosphatase SH-PTP3
RT with sequence similarity to the src-homology region 2.";
RL FEBS Lett. 314:335-339(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY.
RX PubMed=1280823; DOI=10.1073/pnas.89.23.11239;
RA Freeman R.M. Jr., Plutzky J., Neel B.G.;
RT "Identification of a human src homology 2-containing protein-tyrosine-
RT phosphatase: a putative homolog of Drosophila corkscrew.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:11239-11243(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), MUTAGENESIS OF CYS-463, AND
RP TISSUE SPECIFICITY.
RX PubMed=8216283; DOI=10.1006/bbrc.1993.2224;
RA Bastien L., Ramachandran C., Liu S., Adam M.;
RT "Cloning, expression and mutational analysis of SH-PTP2, human
RT protein-tyrosine phosphatase.";
RL Biochem. Biophys. Res. Commun. 196:124-133(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY.
RC TISSUE=Umbilical cord;
RX PubMed=7681589; DOI=10.1073/pnas.90.6.2197;
RA Ahmad S., Banville D.L., Zhao Z., Fischer E.H., Shen S.H.;
RT "A widely expressed human protein-tyrosine phosphatase containing src
RT homology 2 domains.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:2197-2201(1993).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND PHOSPHORYLATION.
RX PubMed=7681217; DOI=10.1126/science.7681217;
RA Vogel W., Lammers R., Huang J., Ullrich A.;
RT "Activation of a phosphotyrosine phosphatase by tyrosine
RT phosphorylation.";
RL Science 259:1611-1614(1993).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP PHOSPHORYLATION, AND INTERACTION WITH PDGFRB.
RX PubMed=7691811;
RA Lechleider R.J., Sugimoto S., Bennett A.M., Kashishian A.S.,
RA Cooper J.A., Shoelson S.E., Walsh C.T., Neel B.G.;
RT "Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2
RT by its binding site, phosphotyrosine 1009, on the human platelet-
RT derived growth factor receptor.";
RL J. Biol. Chem. 268:21478-21481(1993).
RN [11]
RP PHOSPHORYLATION BY PDGFRB.
RX PubMed=8041791; DOI=10.1073/pnas.91.15.7335;
RA Bennett A.M., Tang T.L., Sugimoto S., Walsh C.T., Neel B.G.;
RT "Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth
RT factor receptor beta to Ras.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:7335-7339(1994).
RN [12]
RP INTERACTION WITH PTPNS1.
RX PubMed=8810330; DOI=10.1074/jbc.271.41.25569;
RA Ohnishi H., Kubota M., Ohtake A., Sato K., Sano S.;
RT "Activation of protein-tyrosine phosphatase SH-PTP2 by a tyrosine-
RT based activation motif of a novel brain molecule.";
RL J. Biol. Chem. 271:25569-25574(1996).
RN [13]
RP INTERACTION WITH PTPNS1.
RX PubMed=9062191; DOI=10.1038/386181a0;
RA Kharitonenkov A., Chen Z., Sures I., Wang H., Schilling J.,
RA Ullrich A.;
RT "A family of proteins that inhibit signalling through tyrosine kinase
RT receptors.";
RL Nature 386:181-186(1997).
RN [14]
RP INTERACTION WITH FLT1.
RX PubMed=9600074; DOI=10.1006/bbrc.1998.8578;
RA Igarashi K., Isohara T., Kato T., Shigeta K., Yamano T., Uno I.;
RT "Tyrosine 1213 of Flt-1 is a major binding site of Nck and SHP-2.";
RL Biochem. Biophys. Res. Commun. 246:95-99(1998).
RN [15]
RP INTERACTION WITH GAB2.
RX PubMed=10068651;
RA Nishida K., Yoshida Y., Itoh M., Fukada T., Ohtani T., Shirogane T.,
RA Atsumi T., Takahashi-Tezuka M., Ishihara K., Hibi M., Hirano T.;
RT "Gab-family adapter proteins act downstream of cytokine and growth
RT factor receptors and T- and B-cell antigen receptors.";
RL Blood 93:1809-1816(1999).
RN [16]
RP INTERACTION WITH SIT1.
RX PubMed=10209036; DOI=10.1084/jem.189.8.1181;
RA Marie-Cardine A., Kirchgessner H., Bruyns E., Shevchenko A., Mann M.,
RA Autschbach F., Ratnofsky S., Meuer S., Schraven B.;
RT "SHP2-interacting transmembrane adaptor protein (SIT), a novel
RT disulfide-linked dimer regulating human T-cell activation.";
RL J. Exp. Med. 189:1181-1194(1999).
RN [17]
RP FUNCTION, AND INTERACTION WITH EPHA2.
RX PubMed=10655584; DOI=10.1038/35000008;
RA Miao H., Burnett E., Kinch M., Simon E., Wang B.;
RT "Activation of EphA2 kinase suppresses integrin function and causes
RT focal-adhesion-kinase dephosphorylation.";
RL Nat. Cell Biol. 2:62-69(2000).
RN [18]
RP INTERACTION WITH MZPL1, AND DEPHOSPHORYLATION OF MZPL1.
RX PubMed=10681522; DOI=10.1074/jbc.275.8.5453;
RA Zhao R., Zhao Z.J.;
RT "Dissecting the interaction of SHP-2 with PZR, an immunoglobulin
RT family protein containing immunoreceptor tyrosine-based inhibitory
RT motifs.";
RL J. Biol. Chem. 275:5453-5459(2000).
RN [19]
RP INTERACTION WITH FCRL3.
RX PubMed=11162587; DOI=10.1006/bbrc.2000.4213;
RA Xu M.-J., Zhao R., Zhao Z.J.;
RT "Molecular cloning and characterization of SPAP1, an inhibitory
RT receptor.";
RL Biochem. Biophys. Res. Commun. 280:768-775(2001).
RN [20]
RP INTERACTION WITH CD84.
RX PubMed=11389028; DOI=10.1182/blood.V97.12.3867;
RA Sayos J., Martin M., Chen A., Simarro M., Howie D., Morra M.,
RA Engel P., Terhorst C.;
RT "Cell surface receptors Ly-9 and CD84 recruit the X-linked
RT lymphoproliferative disease gene product SAP.";
RL Blood 97:3867-3874(2001).
RN [21]
RP INTERACTION WITH CD84.
RX PubMed=11414741; DOI=10.1006/clim.2001.5035;
RA Lewis J., Eiben L.J., Nelson D.L., Cohen J.I., Nichols K.E.,
RA Ochs H.D., Notarangelo L.D., Duckett C.S.;
RT "Distinct interactions of the X-linked lymphoproliferative syndrome
RT gene product SAP with cytoplasmic domains of members of the CD2
RT receptor family.";
RL Clin. Immunol. 100:15-23(2001).
RN [22]
RP INTERACTION WITH SIT1.
RX PubMed=11433379;
RX DOI=10.1002/1521-4141(200106)31:6<1825::AID-IMMU1825>3.0.CO;2-V;
RA Pfrepper K.-I., Marie-Cardine A., Simeoni L., Kuramitsu Y., Leo A.,
RA Spicka J., Hilgert I., Scherer J., Schraven B.;
RT "Structural and functional dissection of the cytoplasmic domain of the
RT transmembrane adaptor protein SIT (SHP2-interacting transmembrane
RT adaptor protein).";
RL Eur. J. Immunol. 31:1825-1836(2001).
RN [23]
RP INTERACTION WITH FER AND PECAM1.
RX PubMed=12972546; DOI=10.1091/mbc.E03-02-0080;
RA Kogata N., Masuda M., Kamioka Y., Yamagishi A., Endo A., Okada M.,
RA Mochizuki N.;
RT "Identification of Fer tyrosine kinase localized on microtubules as a
RT platelet endothelial cell adhesion molecule-1 phosphorylating kinase
RT in vascular endothelial cells.";
RL Mol. Biol. Cell 14:3553-3564(2003).
RN [24]
RP INTERACTION WITH FCRL4.
RX PubMed=14597715; DOI=10.1073/pnas.1935944100;
RA Ehrhardt G.R.A., Davis R.S., Hsu J.T., Leu C.-M., Ehrhardt A.,
RA Cooper M.D.;
RT "The inhibitory potential of Fc receptor homolog 4 on memory B
RT cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:13489-13494(2003).
RN [25]
RP REVIEW ON ROLE IN KIT SIGNALING.
RX PubMed=15526160; DOI=10.1007/s00018-004-4189-6;
RA Ronnstrand L.;
RT "Signal transduction via the stem cell factor receptor/c-Kit.";
RL Cell. Mol. Life Sci. 61:2535-2548(2004).
RN [26]
RP INTERACTION WITH FLT4.
RX PubMed=15102829; DOI=10.1074/jbc.M314015200;
RA Wang J.F., Zhang X., Groopman J.E.;
RT "Activation of vascular endothelial growth factor receptor-3 and its
RT downstream signaling promote cell survival under oxidative stress.";
RL J. Biol. Chem. 279:27088-27097(2004).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [28]
RP INTERACTION WITH ANKHD1.
RX PubMed=16956752; DOI=10.1016/j.bbadis.2006.07.010;
RA Traina F., Favaro P.M.B., Medina Sde S., Duarte Ada S.,
RA Winnischofer S.M., Costa F.F., Saad S.T.O.;
RT "ANKHD1, ankyrin repeat and KH domain containing 1, is overexpressed
RT in acute leukemias and is associated with SHP2 in K562 cells.";
RL Biochim. Biophys. Acta 1762:828-834(2006).
RN [29]
RP INTERACTION WITH ROS1.
RX PubMed=16885344; DOI=10.1158/0008-5472.CAN-06-1193;
RA Charest A., Wilker E.W., McLaughlin M.E., Lane K., Gowda R., Coven S.,
RA McMahon K., Kovach S., Feng Y., Yaffe M.B., Jacks T., Housman D.;
RT "ROS fusion tyrosine kinase activates a SH2 domain-containing
RT phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of
RT rapamycin signaling axis to form glioblastoma in mice.";
RL Cancer Res. 66:7473-7481(2006).
RN [30]
RP INTERACTION WITH FCRL6.
RX PubMed=17213291; DOI=10.1182/blood-2006-06-030023;
RA Wilson T.J., Presti R.M., Tassi I., Overton E.T., Cella M.,
RA Colonna M.;
RT "FcRL6, a new ITIM-bearing receptor on cytolytic cells, is broadly
RT expressed by lymphocytes following HIV-1 infection.";
RL Blood 109:3786-3793(2007).
RN [31]
RP INTERACTION WITH TERT, AND FUNCTION.
RX PubMed=18829466; DOI=10.1074/jbc.M805138200;
RA Jakob S., Schroeder P., Lukosz M., Buchner N., Spyridopoulos I.,
RA Altschmied J., Haendeler J.;
RT "Nuclear protein tyrosine phosphatase Shp-2 is one important negative
RT regulator of nuclear export of telomerase reverse transcriptase.";
RL J. Biol. Chem. 283:33155-33161(2008).
RN [32]
RP FUNCTION.
RX PubMed=18559669; DOI=10.1083/jcb.200710187;
RA Lee H.H., Chang Z.F.;
RT "Regulation of RhoA-dependent ROCKII activation by Shp2.";
RL J. Cell Biol. 181:999-1012(2008).
RN [33]
RP INTERACTION WITH KIR2DL1.
RX PubMed=18604210; DOI=10.1038/ni.1635;
RA Yu M.-C., Su L.-L., Zou L., Liu Y., Wu N., Kong L., Zhuang Z.-H.,
RA Sun L., Liu H.P., Hu J.-H., Li D., Strominger J.L., Zang J.-W.,
RA Pei G., Ge B.-X.;
RT "An essential function for beta-arrestin 2 in the inhibitory signaling
RT of natural killer cells.";
RL Nat. Immunol. 9:898-907(2008).
RN [34]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [35]
RP INTERACTION WITH GAREM.
RX PubMed=19509291; DOI=10.1074/jbc.M109.021139;
RA Tashiro K., Tsunematsu T., Okubo H., Ohta T., Sano E., Yamauchi E.,
RA Taniguchi H., Konishi H.;
RT "GAREM, a novel adaptor protein for growth factor receptor-bound
RT protein 2, contributes to cellular transformation through the
RT activation of extracellular signal-regulated kinase signaling.";
RL J. Biol. Chem. 284:20206-20214(2009).
RN [36]
RP INTERACTION WITH PECAM1.
RX PubMed=19342684; DOI=10.4049/jimmunol.0803192;
RA Dasgupta B., Dufour E., Mamdouh Z., Muller W.A.;
RT "A novel and critical role for tyrosine 663 in platelet endothelial
RT cell adhesion molecule-1 trafficking and transendothelial migration.";
RL J. Immunol. 182:5041-5051(2009).
RN [37]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-62 AND TYR-584, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [38]
RP PHOSPHORYLATION, AND INTERACTION WITH PDGFRB.
RX PubMed=20494825; DOI=10.1016/j.cellsig.2010.05.004;
RA Wardega P., Heldin C.H., Lennartsson J.;
RT "Mutation of tyrosine residue 857 in the PDGF beta-receptor affects
RT cell proliferation but not migration.";
RL Cell. Signal. 22:1363-1368(2010).
RN [39]
RP INVOLVEMENT IN MC.
RX PubMed=20577567; DOI=10.1371/journal.pgen.1000991;
RA Sobreira N.L., Cirulli E.T., Avramopoulos D., Wohler E., Oswald G.L.,
RA Stevens E.L., Ge D., Shianna K.V., Smith J.P., Maia J.M., Gumbs C.E.,
RA Pevsner J., Thomas G., Valle D., Hoover-Fong J.E., Goldstein D.B.;
RT "Whole-genome sequencing of a single proband together with linkage
RT analysis identifies a Mendelian disease gene.";
RL PLoS Genet. 6:E1000991-E1000991(2010).
RN [40]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [41]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 3-530 (ISOFORM 2).
RX PubMed=9491886; DOI=10.1016/S0092-8674(00)80938-1;
RA Hof P., Pluskey S., Dhe-Paganon S., Eck M.J., Shoelson S.E.;
RT "Crystal structure of the tyrosine phosphatase SHP-2.";
RL Cell 92:441-450(1998).
RN [43]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 237-533.
RX PubMed=19167335; DOI=10.1016/j.cell.2008.11.038;
RA Barr A.J., Ugochukwu E., Lee W.H., King O.N.F., Filippakopoulos P.,
RA Alfano I., Savitsky P., Burgess-Brown N.A., Mueller S., Knapp S.;
RT "Large-scale structural analysis of the classical human protein
RT tyrosine phosphatome.";
RL Cell 136:352-363(2009).
RN [44]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 262-532 IN COMPLEX WITH
RP INHIBITOR, AND CATALYTIC ACTIVITY.
RX PubMed=20170098; DOI=10.1021/jm901645u;
RA Zhang X., He Y., Liu S., Yu Z., Jiang Z.X., Yang Z., Dong Y.,
RA Nabinger S.C., Wu L., Gunawan A.M., Wang L., Chan R.J., Zhang Z.Y.;
RT "Salicylic acid based small molecule inhibitor for the oncogenic Src
RT homology-2 domain containing protein tyrosine phosphatase-2 (SHP2).";
RL J. Med. Chem. 53:2482-2493(2010).
RN [45]
RP VARIANTS NS1 GLY-61; CYS-63; GLY-72; SER-72; ASP-76; ARG-79; VAL-282;
RP ASP-308 AND VAL-508.
RX PubMed=11704759; DOI=10.1038/ng772;
RA Tartaglia M., Mehler E.L., Goldberg R., Zampino G., Brunner H.G.,
RA Kremer H., van der Burgt I., Crosby A.H., Ion A., Jeffery S.,
RA Kalidas K., Patton M.A., Kucherlapati R.S., Gelb B.D.;
RT "Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2,
RT cause Noonan syndrome.";
RL Nat. Genet. 29:465-468(2001).
RN [46]
RP ERRATUM.
RA Tartaglia M., Mehler E.L., Goldberg R., Zampino G., Brunner H.G.,
RA Kremer H., van der Burgt I., Crosby A.H., Ion A., Jeffery S.,
RA Kalidas K., Patton M.A., Kucherlapati R.S., Gelb B.D.;
RL Nat. Genet. 29:491-491(2001).
RN [47]
RP ERRATUM.
RA Tartaglia M., Mehler E.L., Goldberg R., Zampino G., Brunner H.G.,
RA Kremer H., van der Burgt I., Crosby A.H., Ion A., Jeffery S.,
RA Kalidas K., Patton M.A., Kucherlapati R.S., Gelb B.D.;
RL Nat. Genet. 30:123-123(2001).
RN [48]
RP VARIANTS NS1 ALA-42; ALA-60; ASN-61; GLY-61; ASP-62; CYS-63; GLY-72;
RP ILE-73; ASP-76; ARG-79; ALA-106; ASP-139; CYS-279; VAL-282; LEU-285;
RP SER-285; ASP-308; SER-308; VAL-309; LYS-505 AND VAL-508.
RX PubMed=11992261; DOI=10.1086/340847;
RA Tartaglia M., Kalidas K., Shaw A., Song X., Musat D.L.,
RA van der Burgt I., Brunner H.G., Bertola D.R., Crosby A.H., Ion A.,
RA Kucherlapati R.S., Jeffery S., Patton M.A., Gelb B.D.;
RT "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-
RT phenotype correlation, and phenotypic heterogeneity.";
RL Am. J. Hum. Genet. 70:1555-1563(2002).
RN [49]
RP VARIANTS LEOPARD1 CYS-279 AND MET-472.
RX PubMed=12058348; DOI=10.1086/341528;
RA Digilio M.C., Conti E., Sarkozy A., Mingarelli R., Dottorini T.,
RA Marino B., Pizzuti A., Dallapiccola B.;
RT "Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the
RT PTPN11 gene.";
RL Am. J. Hum. Genet. 71:389-394(2002).
RN [50]
RP VARIANTS NS1 ASP-62; CYS-63 AND THR-506.
RX PubMed=12325025; DOI=10.1002/humu.10129;
RA Maheshwari M., Belmont J., Fernbach S., Ho T., Molinari L., Yakub I.,
RA Yu F., Combes A., Towbin J.A., Craigen W.J., Gibbs R.A.;
RT "PTPN11 mutations in Noonan syndrome type I: detection of recurrent
RT mutations in exons 3 and 13.";
RL Hum. Mutat. 20:298-304(2002).
RN [51]
RP VARIANTS NS1 GLY-61; CYS-63; SER-72; ILE-73; SER-285 AND ASP-308.
RX PubMed=12161469; DOI=10.1210/jc.87.8.3529;
RA Kosaki K., Suzuki T., Muroya K., Hasegawa T., Sato S., Matsuo N.,
RA Kosaki R., Nagai T., Hasegawa Y., Ogata T.;
RT "PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations
RT in seven Japanese patients with Noonan syndrome.";
RL J. Clin. Endocrinol. Metab. 87:3529-3533(2002).
RN [52]
RP VARIANT NS1 ARG-79.
RX PubMed=12529711; DOI=10.1038/sj.ejhg.5200915;
RA Schollen E., Matthijs G., Gewillig M., Fryns J.-P., Legius E.;
RT "PTPN11 mutation in a large family with Noonan syndrome and dizygous
RT twinning.";
RL Eur. J. Hum. Genet. 11:85-88(2003).
RN [53]
RP VARIANTS NS1 LYS-58; ASN-61; GLY-61; CYS-63; GLN-69; LEU-71; SER-72;
RP ILE-73; ASP-76; ARG-79; ASP-139; ARG-256; VAL-282 AND ASP-308.
RX PubMed=12634870; DOI=10.1038/sj.ejhg.5200935;
RA Musante L., Kehl H.G., Majewski F., Meinecke P., Schweiger S.,
RA Gillessen-Kaesbach G., Wieczorek D., Hinkel G.K., Tinschert S.,
RA Hoeltzenbein M., Ropers H.-H., Kalscheuer V.M.;
RT "Spectrum of mutations in PTPN11 and genotype-phenotype correlation in
RT 96 patients with Noonan syndrome and five patients with cardio-facio-
RT cutaneous syndrome.";
RL Eur. J. Hum. Genet. 11:201-206(2003).
RN [54]
RP ERRATUM.
RA Musante L., Kehl H.G., Majewski F., Meinecke P., Schweiger S.,
RA Gillessen-Kaesbach G., Wieczorek D., Hinkel G.K., Tinschert S.,
RA Hoeltzenbein M., Ropers H.-H., Kalscheuer V.M.;
RL Eur. J. Hum. Genet. 11:551-551(2003).
RN [55]
RP VARIANT NS1 THR-506.
RX PubMed=12739139; DOI=10.1007/s00431-003-1227-6;
RA Kondoh T., Ishii E., Aoki Y., Shimizu T., Zaitsu M., Matsubara Y.,
RA Moriuchi H.;
RT "Noonan syndrome with leukaemoid reaction and overproduction of
RT catecholamines: a case report.";
RL Eur. J. Pediatr. 162:548-549(2003).
RN [56]
RP VARIANT LEOPARD1 PRO-510.
RX PubMed=14961557; DOI=10.1002/humu.9149;
RA Conti E., Dottorini T., Sarkozy A., Tiller G.E., Esposito G.,
RA Pizzuti A., Dallapiccola B.;
RT "A novel PTPN11 mutation in LEOPARD syndrome.";
RL Hum. Mutat. 21:654-654(2003).
RN [57]
RP VARIANTS NS1 ILE-2; ALA-42; ASP-62; CYS-63; GLY-72; PRO-79; ALA-106;
RP CYS-279; ASP-308; SER-308; MET-472; ARG-507; VAL-508 AND PHE-564.
RX PubMed=12960218; DOI=10.1136/jmg.40.9.704;
RA Sarkozy A., Conti E., Seripa D., Digilio M.C., Grifone N., Tandoi C.,
RA Fazio V.M., Di Ciommo V., Marino B., Pizzuti A., Dallapiccola B.;
RT "Correlation between PTPN11 gene mutations and congenital heart
RT defects in Noonan and LEOPARD syndromes.";
RL J. Med. Genet. 40:704-708(2003).
RN [58]
RP VARIANTS JMML TYR-61; VAL-61; LYS-69; THR-72; VAL-72; ALA-76; GLY-76;
RP LYS-76; VAL-76; ALA-507 AND ARG-507, VARIANTS MYELODYSPLASTIC SYNDROME
RP VAL-60; VAL-61; LYS-69; LEU-71 AND ALA-76, VARIANTS NS1 ASP-62 AND
RP ILE-73, AND VARIANT ACUTE MYELOID LEUKEMIA LYS-71.
RX PubMed=12717436; DOI=10.1038/ng1156;
RA Tartaglia M., Niemeyer C.M., Fragale A., Song X., Buechner J.,
RA Jung A., Haehlen K., Hasle H., Licht J.D., Gelb B.D.;
RT "Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia,
RT myelodysplastic syndromes and acute myeloid leukemia.";
RL Nat. Genet. 34:148-150(2003).
RN [59]
RP VARIANT NS1 MET-415.
RX PubMed=15384080; DOI=10.1002/ajmg.a.30270;
RA Bertola D.R., Pereira A.C., de Oliveira P.S.L., Kim C.A.,
RA Krieger J.E.;
RT "Clinical variability in a Noonan syndrome family with a new PTPN11
RT gene mutation.";
RL Am. J. Med. Genet. A 130:378-383(2004).
RN [60]
RP VARIANTS LEOPARD1 THR-465 AND ALA-468.
RX PubMed=15389709; DOI=10.1002/ajmg.a.30281;
RA Yoshida R., Nagai T., Hasegawa T., Kinoshita E., Tanaka T., Ogata T.;
RT "Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome.";
RL Am. J. Med. Genet. A 130:432-434(2004).
RN [61]
RP VARIANTS LEOPARD1 CYS-279; SER-279; MET-472 AND PRO-514.
RX PubMed=15520399; DOI=10.1136/jmg.2004.021451;
RG French collaborative Noonan study group;
RA Keren B., Hadchouel A., Saba S., Sznajer Y., Bonneau D., Leheup B.,
RA Boute O., Gaillard D., Lacombe D., Layet V., Marlin S., Mortier G.,
RA Toutain A., Beylot C., Baumann C., Verloes A., Cave H.;
RT "PTPN11 mutations in patients with LEOPARD syndrome: a French
RT multicentric experience.";
RL J. Med. Genet. 41:E117-E117(2004).
RN [62]
RP VARIANTS LEOPARD1 CYS-279; SER-279; ALA-468; MET-472; TRP-502; LEU-502
RP AND PRO-510.
RX PubMed=15121796; DOI=10.1136/jmg.2003.013466;
RA Sarkozy A., Conti E., Digilio M.C., Marino B., Morini E., Pacileo G.,
RA Wilson M., Calabro R., Pizzuti A., Dallapiccola B.;
RT "Clinical and molecular analysis of 30 patients with multiple
RT lentigines LEOPARD syndrome.";
RL J. Med. Genet. 41:E68-E68(2004).
RN [63]
RP VARIANT NS1 ARG-510.
RX PubMed=15948193; DOI=10.1002/ajmg.a.30813;
RA Bertola D.R., Pereira A.C., Passetti F., de Oliveira P.S.L.,
RA Messiaen L., Gelb B.D., Kim C.A., Krieger J.E.;
RT "Neurofibromatosis-Noonan syndrome: molecular evidence of the
RT concurrence of both disorders in a patient.";
RL Am. J. Med. Genet. A 136:242-245(2005).
RN [64]
RP VARIANT LEOPARD1 PRO-510.
RX PubMed=15690106; DOI=10.1007/s10038-004-0212-x;
RA Kalidas K., Shaw A.C., Crosby A.H., Newbury-Ecob R., Greenhalgh L.,
RA Temple I.K., Law C., Patel A., Patton M.A., Jeffery S.;
RT "Genetic heterogeneity in LEOPARD syndrome: two families with no
RT mutations in PTPN11.";
RL J. Hum. Genet. 50:21-25(2005).
RN [65]
RP VARIANT LEOPARD1 CYS-279.
RX PubMed=16679933; DOI=10.1097/01.mph.0000199590.21797.0b;
RA Ucar C., Calyskan U., Martini S., Heinritz W.;
RT "Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11
RT gene mutation positive).";
RL J. Pediatr. Hematol. Oncol. 28:123-125(2006).
RN [66]
RP VARIANT NS1 ALA-59.
RX PubMed=19020799; DOI=10.1007/s10038-008-0343-6;
RA Ko J.M., Kim J.M., Kim G.H., Yoo H.W.;
RT "PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype
RT correlation in Korean patients with Noonan syndrome.";
RL J. Hum. Genet. 53:999-1006(2008).
CC -!- FUNCTION: Acts downstream of various receptor and cytoplasmic
CC protein tyrosine kinases to participate in the signal transduction
CC from the cell surface to the nucleus. Dephosphorylates ROCK2 at
CC Tyr-722 resulting in stimulatation of its RhoA binding activity.
CC -!- CATALYTIC ACTIVITY: Protein tyrosine phosphate + H(2)O = protein
CC tyrosine + phosphate.
CC -!- SUBUNIT: Interacts with phosphorylated LIME1 and BCAR3. Interacts
CC with SHB and INPP5D/SHIP1 (By similarity). Interacts with MILR1
CC (tyrosine-phosphorylated). Interacts with FLT1 (tyrosine-
CC phosphorylated), FLT3 (tyrosine-phosphorylated), FLT4 (tyrosine-
CC phosphorylated), KIT and GRB2. Interacts with PDGFRA (tyrosine
CC phosphorylated). Interacts (via SH2 domain) with TEK/TIE2
CC (tyrosine phosphorylated) (By similarity). Interacts with PTPNS1
CC and CD84. Interacts with phosphorylated SIT1 and MPZL1. Interacts
CC with FCRL3, FCRL4, FCRL6 and ANKHD1. Interacts with KIR2DL1; the
CC interaction is enhanced by ARRB2. Interacts with GAB2. Interacts
CC with TERT; the interaction retains TERT in the nucleus. Interacts
CC with PECAM1 and FER. Interacts with EPHA2 (activated);
CC participates in PTK2/FAK1 dephosphorylation in EPHA2 downstream
CC signaling. Interacts with ROS1; mediates PTPN11 phosphorylation.
CC Interacts with PDGFRB (tyrosine phosphorylated); this interaction
CC increases the PTPN11 phosphatase activity. Interacts with GAREM
CC isoform 1 (tyrosine phosphorylated); the interaction increases
CC MAPK/ERK activity and does not affect the GRB2/SOS complex
CC formation.
CC -!- INTERACTION:
CC P32239:CCKBR; NbExp=5; IntAct=EBI-297779, EBI-1753137;
CC P20138:CD33; NbExp=5; IntAct=EBI-297779, EBI-3906571;
CC Q08345:DDR1; NbExp=4; IntAct=EBI-297779, EBI-711879;
CC P68105:EEF1A1 (xeno); NbExp=2; IntAct=EBI-297779, EBI-7645934;
CC Q71V39:EEF1A2 (xeno); NbExp=2; IntAct=EBI-297779, EBI-7645815;
CC P04626:ERBB2; NbExp=2; IntAct=EBI-297779, EBI-641062;
CC P17948:FLT1; NbExp=2; IntAct=EBI-297779, EBI-1026718;
CC Q13480:GAB1; NbExp=21; IntAct=EBI-297779, EBI-517684;
CC Q9UQC2:GAB2; NbExp=4; IntAct=EBI-297779, EBI-975200;
CC P62993:GRB2; NbExp=6; IntAct=EBI-297779, EBI-401755;
CC P08069:IGF1R; NbExp=3; IntAct=EBI-297779, EBI-475981;
CC P06213:INSR; NbExp=2; IntAct=EBI-297779, EBI-475899;
CC P35568:IRS1; NbExp=3; IntAct=EBI-297779, EBI-517592;
CC P35570:Irs1 (xeno); NbExp=3; IntAct=EBI-297779, EBI-520230;
CC P43628:KIR2DL3; NbExp=4; IntAct=EBI-297779, EBI-8632435;
CC O95297:MPZL1; NbExp=4; IntAct=EBI-297779, EBI-963338;
CC P09619:PDGFRB; NbExp=8; IntAct=EBI-297779, EBI-641237;
CC P16284:PECAM1; NbExp=7; IntAct=EBI-297779, EBI-716404;
CC P49023:PXN; NbExp=3; IntAct=EBI-297779, EBI-702209;
CC P97710:Sirpa (xeno); NbExp=3; IntAct=EBI-297779, EBI-7945080;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=PTP2Ci;
CC IsoId=Q06124-1; Sequence=Displayed;
CC Name=2; Synonyms=PTP2C;
CC IsoId=Q06124-2; Sequence=VSP_016672;
CC Name=3;
CC IsoId=Q06124-3; Sequence=VSP_016672, VSP_016673, VSP_016674;
CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in
CC heart, brain, and skeletal muscle.
CC -!- DOMAIN: The SH2 domains repress phosphatase activity. Binding of
CC these domains to phosphotyrosine-containing proteins relieves this
CC auto-inhibition, possibly by inducing a conformational change in
CC the enzyme.
CC -!- PTM: Phosphorylated on Tyr-546 and Tyr-584 upon receptor protein
CC tyrosine kinase activation; which creates a binding site for GRB2
CC and other SH2-containing proteins. Phosphorylated upon activation
CC of the receptor-type kinase FLT3. Phosphorylated upon activation
CC of the receptor-type kinase PDGFRA (By similarity). Phosphorylated
CC by activated PDGFRB.
CC -!- DISEASE: LEOPARD syndrome 1 (LEOPARD1) [MIM:151100]: A disorder
CC characterized by lentigines, electrocardiographic conduction
CC abnormalities, ocular hypertelorism, pulmonic stenosis,
CC abnormalities of genitalia, retardation of growth, and
CC sensorineural deafness. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Noonan syndrome 1 (NS1) [MIM:163950]: A form of Noonan
CC syndrome, a disease characterized by short stature, facial
CC dysmorphic features such as hypertelorism, a downward eyeslant and
CC low-set posteriorly rotated ears, and a high incidence of
CC congenital heart defects and hypertrophic cardiomyopathy. Other
CC features can include a short neck with webbing or redundancy of
CC skin, deafness, motor delay, variable intellectual deficits,
CC multiple skeletal defects, cryptorchidism, and bleeding diathesis.
CC Individuals with Noonan syndrome are at risk of juvenile
CC myelomonocytic leukemia, a myeloproliferative disorder
CC characterized by excessive production of myelomonocytic cells.
CC Some patients with NS1 develop multiple giant cell lesions of the
CC jaw or other bony or soft tissues, which are classified as
CC pigmented villonodular synovitis (PVNS) when occurring in the jaw
CC or joints. Note=The disease is caused by mutations affecting the
CC gene represented in this entry. Mutations in PTPN11 account for
CC more than 50% of the cases.
CC -!- DISEASE: Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An
CC aggressive pediatric myelodysplastic syndrome/myeloproliferative
CC disorder characterized by malignant transformation in the
CC hematopoietic stem cell compartment with proliferation of
CC differentiated progeny. Patients have splenomegaly, enlarged lymph
CC nodes, rashes, and hemorrhages. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Metachondromatosis (MC) [MIM:156250]: A skeletal disorder
CC with radiologic features of both multiple exostoses and Ollier
CC disease, characterized by the presence of exostoses, commonly of
CC the bones of the hands and feet, and enchondromas of the
CC metaphyses of long bones and iliac crest. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
CC Non-receptor class 2 subfamily.
CC -!- SIMILARITY: Contains 2 SH2 domains.
CC -!- SIMILARITY: Contains 1 tyrosine-protein phosphatase domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PTPN11ID41910ch12q24.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PTPN11";
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DR EMBL; D13540; BAA02740.2; -; mRNA.
DR EMBL; L03535; AAA36611.1; -; mRNA.
DR EMBL; L07527; AAA17022.1; -; mRNA.
DR EMBL; L08807; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; X70766; CAA50045.1; -; mRNA.
DR EMBL; BT007106; AAP35770.1; -; mRNA.
DR EMBL; AK289854; BAF82543.1; -; mRNA.
DR EMBL; CH471054; EAW98012.1; -; Genomic_DNA.
DR EMBL; BC008692; AAH08692.1; -; mRNA.
DR PIR; JN0805; JN0805.
DR RefSeq; NP_002825.3; NM_002834.3.
DR RefSeq; NP_542168.1; NM_080601.1.
DR UniGene; Hs.506852; -.
DR PDB; 2SHP; X-ray; 2.00 A; A/B=3-529.
DR PDB; 3B7O; X-ray; 1.60 A; A=237-533.
DR PDB; 3MOW; X-ray; 2.30 A; A=262-532.
DR PDB; 3O5X; X-ray; 2.00 A; A=262-532.
DR PDB; 3TKZ; X-ray; 1.80 A; A=1-106.
DR PDB; 3TL0; X-ray; 2.05 A; A=1-106.
DR PDB; 4DGP; X-ray; 2.30 A; A=1-532.
DR PDB; 4DGX; X-ray; 2.30 A; A=1-532.
DR PDB; 4GWF; X-ray; 2.10 A; A/B=1-543.
DR PDB; 4H1O; X-ray; 2.20 A; A=1-543.
DR PDB; 4H34; X-ray; 2.70 A; A=1-543.
DR PDB; 4JE4; X-ray; 2.31 A; A=1-103.
DR PDB; 4JEG; X-ray; 2.30 A; A=97-217.
DR PDBsum; 2SHP; -.
DR PDBsum; 3B7O; -.
DR PDBsum; 3MOW; -.
DR PDBsum; 3O5X; -.
DR PDBsum; 3TKZ; -.
DR PDBsum; 3TL0; -.
DR PDBsum; 4DGP; -.
DR PDBsum; 4DGX; -.
DR PDBsum; 4GWF; -.
DR PDBsum; 4H1O; -.
DR PDBsum; 4H34; -.
DR PDBsum; 4JE4; -.
DR PDBsum; 4JEG; -.
DR ProteinModelPortal; Q06124; -.
DR SMR; Q06124; 3-595.
DR DIP; DIP-516N; -.
DR IntAct; Q06124; 58.
DR MINT; MINT-199832; -.
DR STRING; 9606.ENSP00000340944; -.
DR BindingDB; Q06124; -.
DR ChEMBL; CHEMBL3864; -.
DR PhosphoSite; Q06124; -.
DR DMDM; 84028248; -.
DR PaxDb; Q06124; -.
DR PRIDE; Q06124; -.
DR DNASU; 5781; -.
DR Ensembl; ENST00000351677; ENSP00000340944; ENSG00000179295.
DR Ensembl; ENST00000392597; ENSP00000376376; ENSG00000179295.
DR GeneID; 5781; -.
DR KEGG; hsa:5781; -.
DR CTD; 5781; -.
DR GeneCards; GC12P112856; -.
DR HGNC; HGNC:9644; PTPN11.
DR HPA; CAB005377; -.
DR MIM; 151100; phenotype.
DR MIM; 156250; phenotype.
DR MIM; 163950; phenotype.
DR MIM; 176876; gene.
DR MIM; 607785; phenotype.
DR neXtProt; NX_Q06124; -.
DR Orphanet; 86834; Juvenile myelomonocytic leukemia.
DR Orphanet; 500; LEOPARD syndrome.
DR Orphanet; 2499; Metachondromatosis.
DR Orphanet; 648; Noonan syndrome.
DR PharmGKB; PA33986; -.
DR eggNOG; COG5599; -.
DR HOGENOM; HOG000273907; -.
DR HOVERGEN; HBG000223; -.
DR InParanoid; Q06124; -.
DR KO; K07293; -.
DR OMA; KEYGAMR; -.
DR OrthoDB; EOG7NPFST; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q06124; -.
DR ChiTaRS; PTPN11; human.
DR EvolutionaryTrace; Q06124; -.
DR GeneWiki; PTPN11; -.
DR GenomeRNAi; 5781; -.
DR NextBio; 22484; -.
DR PRO; PR:Q06124; -.
DR ArrayExpress; Q06124; -.
DR Bgee; Q06124; -.
DR CleanEx; HS_PTPN11; -.
DR Genevestigator; Q06124; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; IEA:Ensembl.
DR GO; GO:0004726; F:non-membrane spanning protein tyrosine phosphatase activity; IMP:UniProtKB.
DR GO; GO:0005070; F:SH3/SH2 adaptor activity; IDA:BHF-UCL.
DR GO; GO:0000187; P:activation of MAPK activity; IEA:Ensembl.
DR GO; GO:0036302; P:atrioventricular canal development; IMP:BHF-UCL.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0007420; P:brain development; IMP:BHF-UCL.
DR GO; GO:0000077; P:DNA damage checkpoint; IEA:Ensembl.
DR GO; GO:0048013; P:ephrin receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0060325; P:face morphogenesis; IMP:BHF-UCL.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048806; P:genitalia development; IMP:BHF-UCL.
DR GO; GO:0042593; P:glucose homeostasis; IEA:Ensembl.
DR GO; GO:0042445; P:hormone metabolic process; IEA:Ensembl.
DR GO; GO:0009755; P:hormone-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0048839; P:inner ear development; IMP:BHF-UCL.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0060333; P:interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0048609; P:multicellular organismal reproductive process; IEA:Ensembl.
DR GO; GO:0051463; P:negative regulation of cortisol secretion; IEA:Ensembl.
DR GO; GO:0060125; P:negative regulation of growth hormone secretion; IEA:Ensembl.
DR GO; GO:0046676; P:negative regulation of insulin secretion; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0035265; P:organ growth; IEA:Ensembl.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
DR GO; GO:2001275; P:positive regulation of glucose import in response to insulin stimulus; IDA:BHF-UCL.
DR GO; GO:0046887; P:positive regulation of hormone secretion; IEA:Ensembl.
DR GO; GO:0033628; P:regulation of cell adhesion mediated by integrin; IMP:UniProtKB.
DR GO; GO:0060334; P:regulation of interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0046825; P:regulation of protein export from nucleus; IEA:Ensembl.
DR GO; GO:0060338; P:regulation of type I interferon-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0031295; P:T cell costimulation; TAS:Reactome.
DR GO; GO:0006641; P:triglyceride metabolic process; IEA:Ensembl.
DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; TAS:Reactome.
DR Gene3D; 3.30.505.10; -; 2.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR000387; Tyr/Dual-sp_Pase.
DR InterPro; IPR016130; Tyr_Pase_AS.
DR InterPro; IPR012152; Tyr_Pase_non-rcpt_typ-6/11.
DR InterPro; IPR000242; Tyr_Pase_rcpt/non-rcpt.
DR Pfam; PF00017; SH2; 2.
DR Pfam; PF00102; Y_phosphatase; 1.
DR PIRSF; PIRSF000929; Tyr-Ptase_nr_6; 1.
DR PRINTS; PR00700; PRTYPHPHTASE.
DR PRINTS; PR00401; SH2DOMAIN.
DR SMART; SM00194; PTPc; 1.
DR SMART; SM00252; SH2; 2.
DR PROSITE; PS50001; SH2; 2.
DR PROSITE; PS00383; TYR_PHOSPHATASE_1; 1.
DR PROSITE; PS50056; TYR_PHOSPHATASE_2; 1.
DR PROSITE; PS50055; TYR_PHOSPHATASE_PTP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Deafness; Disease mutation; Hydrolase; Phosphoprotein;
KW Protein phosphatase; Reference proteome; Repeat; SH2 domain.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 597 Tyrosine-protein phosphatase non-receptor
FT type 11.
FT /FTId=PRO_0000094767.
FT DOMAIN 6 102 SH2 1.
FT DOMAIN 112 216 SH2 2.
FT DOMAIN 247 521 Tyrosine-protein phosphatase.
FT REGION 463 469 Substrate binding (By similarity).
FT ACT_SITE 463 463 Phosphocysteine intermediate.
FT BINDING 429 429 Substrate (By similarity).
FT BINDING 510 510 Substrate (By similarity).
FT MOD_RES 2 2 N-acetylthreonine.
FT MOD_RES 62 62 Phosphotyrosine.
FT MOD_RES 63 63 Phosphotyrosine.
FT MOD_RES 66 66 Phosphotyrosine (By similarity).
FT MOD_RES 280 280 N6-acetyllysine.
FT MOD_RES 546 546 Phosphotyrosine; by PDGFR.
FT MOD_RES 562 562 Phosphoserine.
FT MOD_RES 584 584 Phosphotyrosine; by PDGFR.
FT MOD_RES 595 595 Phosphoserine.
FT VAR_SEQ 408 411 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_016672.
FT VAR_SEQ 464 464 S -> R (in isoform 3).
FT /FTId=VSP_016673.
FT VAR_SEQ 465 597 Missing (in isoform 3).
FT /FTId=VSP_016674.
FT VARIANT 2 2 T -> I (in NS1).
FT /FTId=VAR_027183.
FT VARIANT 42 42 T -> A (in NS1).
FT /FTId=VAR_015601.
FT VARIANT 58 58 N -> K (in NS1).
FT /FTId=VAR_027184.
FT VARIANT 59 59 T -> A (in NS1).
FT /FTId=VAR_066060.
FT VARIANT 60 60 G -> A (in NS1).
FT /FTId=VAR_015602.
FT VARIANT 60 60 G -> V (in myelodysplastic syndrome).
FT /FTId=VAR_015990.
FT VARIANT 61 61 D -> G (in NS1).
FT /FTId=VAR_015603.
FT VARIANT 61 61 D -> N (in NS1).
FT /FTId=VAR_015604.
FT VARIANT 61 61 D -> V (in JMML; also in myelodysplastic
FT syndrome).
FT /FTId=VAR_015991.
FT VARIANT 61 61 D -> Y (in JMML).
FT /FTId=VAR_015992.
FT VARIANT 62 62 Y -> D (in NS1; also in Noonan patients
FT manifesting juvenile myelomonocytic
FT leukemia).
FT /FTId=VAR_015605.
FT VARIANT 63 63 Y -> C (in NS1).
FT /FTId=VAR_015606.
FT VARIANT 69 69 E -> K (in JMML; also in myelodysplastic
FT syndrome).
FT /FTId=VAR_015993.
FT VARIANT 69 69 E -> Q (in NS1).
FT /FTId=VAR_027185.
FT VARIANT 71 71 F -> K (in acute myeloid leukemia;
FT requires 2 nucleotide substitutions).
FT /FTId=VAR_015994.
FT VARIANT 71 71 F -> L (in myelodysplastic syndrome).
FT /FTId=VAR_015995.
FT VARIANT 72 72 A -> G (in NS1).
FT /FTId=VAR_015607.
FT VARIANT 72 72 A -> S (in NS1).
FT /FTId=VAR_015608.
FT VARIANT 72 72 A -> T (in JMML).
FT /FTId=VAR_015996.
FT VARIANT 72 72 A -> V (in JMML).
FT /FTId=VAR_015997.
FT VARIANT 73 73 T -> I (in NS1; also in Noonan patients
FT manifesting juvenile myelomonocytic
FT leukemia; dbSNP:rs28933387).
FT /FTId=VAR_015609.
FT VARIANT 76 76 E -> A (in JMML; also in myelodysplastic
FT syndrome).
FT /FTId=VAR_015998.
FT VARIANT 76 76 E -> D (in NS1).
FT /FTId=VAR_015610.
FT VARIANT 76 76 E -> G (in JMML).
FT /FTId=VAR_015999.
FT VARIANT 76 76 E -> K (in JMML; dbSNP:rs28933388).
FT /FTId=VAR_016000.
FT VARIANT 76 76 E -> V (in JMML).
FT /FTId=VAR_016001.
FT VARIANT 79 79 Q -> P (in NS1).
FT /FTId=VAR_027186.
FT VARIANT 79 79 Q -> R (in NS1).
FT /FTId=VAR_015611.
FT VARIANT 106 106 D -> A (in NS1).
FT /FTId=VAR_015612.
FT VARIANT 139 139 E -> D (in NS1).
FT /FTId=VAR_015613.
FT VARIANT 256 256 Q -> R (in NS1).
FT /FTId=VAR_027187.
FT VARIANT 279 279 Y -> C (in NS1 and LEOPARD1).
FT /FTId=VAR_015614.
FT VARIANT 279 279 Y -> S (in LEOPARD1).
FT /FTId=VAR_027188.
FT VARIANT 282 282 I -> V (in NS1).
FT /FTId=VAR_015615.
FT VARIANT 285 285 F -> L (in NS1).
FT /FTId=VAR_015617.
FT VARIANT 285 285 F -> S (in NS1).
FT /FTId=VAR_015616.
FT VARIANT 308 308 N -> D (in NS1; common mutation).
FT /FTId=VAR_015619.
FT VARIANT 308 308 N -> S (in NS1; some patients also
FT manifest giant cell lesions of bone and
FT soft tissue).
FT /FTId=VAR_015618.
FT VARIANT 309 309 I -> V (in NS1).
FT /FTId=VAR_015620.
FT VARIANT 415 415 T -> M (in NS1).
FT /FTId=VAR_027189.
FT VARIANT 465 465 A -> T (in LEOPARD1).
FT /FTId=VAR_027190.
FT VARIANT 468 468 G -> A (in LEOPARD1).
FT /FTId=VAR_027191.
FT VARIANT 472 472 T -> M (in LEOPARD1).
FT /FTId=VAR_015621.
FT VARIANT 502 502 R -> L (in LEOPARD1).
FT /FTId=VAR_027192.
FT VARIANT 502 502 R -> W (in LEOPARD1).
FT /FTId=VAR_027193.
FT VARIANT 505 505 R -> K (in NS1).
FT /FTId=VAR_015622.
FT VARIANT 506 506 S -> T (in NS1).
FT /FTId=VAR_015623.
FT VARIANT 507 507 G -> A (in JMML).
FT /FTId=VAR_016002.
FT VARIANT 507 507 G -> R (in patients with growth
FT retardation, pulmonic stenosis and
FT juvenile myelomonocytic leukemia).
FT /FTId=VAR_016003.
FT VARIANT 508 508 M -> V (in NS1).
FT /FTId=VAR_015624.
FT VARIANT 510 510 Q -> P (in LEOPARD1).
FT /FTId=VAR_027194.
FT VARIANT 510 510 Q -> R (in NS1).
FT /FTId=VAR_027195.
FT VARIANT 514 514 Q -> P (in LEOPARD1).
FT /FTId=VAR_027196.
FT VARIANT 564 564 L -> F (in NS1).
FT /FTId=VAR_027197.
FT MUTAGEN 463 463 C->S: Abolishes phosphatase activity.
FT CONFLICT 539 539 S -> R (in Ref. 3; BAA02740).
FT CONFLICT 552 552 S -> P (in Ref. 3; BAA02740).
FT HELIX 13 23
FT STRAND 28 33
FT STRAND 35 37
FT STRAND 41 47
FT STRAND 50 58
FT STRAND 59 61
FT STRAND 63 68
FT STRAND 71 73
FT HELIX 74 83
FT STRAND 87 90
FT HELIX 107 109
FT STRAND 113 116
FT HELIX 119 128
FT STRAND 134 139
FT STRAND 141 143
FT STRAND 147 153
FT STRAND 166 175
FT STRAND 178 184
FT STRAND 187 189
FT HELIX 190 199
FT HELIX 223 225
FT HELIX 226 234
FT HELIX 247 258
FT HELIX 259 262
FT HELIX 267 269
FT HELIX 271 276
FT STRAND 277 279
FT TURN 286 288
FT STRAND 289 291
FT STRAND 303 310
FT STRAND 327 331
FT TURN 335 337
FT HELIX 338 347
FT STRAND 352 355
FT STRAND 359 361
FT STRAND 364 366
FT STRAND 377 380
FT STRAND 383 392
FT STRAND 394 405
FT STRAND 412 424
FT STRAND 429 431
FT STRAND 434 436
FT HELIX 437 451
FT STRAND 459 467
FT HELIX 468 486
FT STRAND 490 492
FT HELIX 494 502
FT HELIX 512 531
SQ SEQUENCE 597 AA; 68436 MW; 37E8BFC7ECA2D03F CRC64;
MTSRRWFHPN ITGVEAENLL LTRGVDGSFL ARPSKSNPGD FTLSVRRNGA VTHIKIQNTG
DYYDLYGGEK FATLAELVQY YMEHHGQLKE KNGDVIELKY PLNCADPTSE RWFHGHLSGK
EAEKLLTEKG KHGSFLVRES QSHPGDFVLS VRTGDDKGES NDGKSKVTHV MIRCQELKYD
VGGGERFDSL TDLVEHYKKN PMVETLGTVL QLKQPLNTTR INAAEIESRV RELSKLAETT
DKVKQGFWEE FETLQQQECK LLYSRKEGQR QENKNKNRYK NILPFDHTRV VLHDGDPNEP
VSDYINANII MPEFETKCNN SKPKKSYIAT QGCLQNTVND FWRMVFQENS RVIVMTTKEV
ERGKSKCVKY WPDEYALKEY GVMRVRNVKE SAAHDYTLRE LKLSKVGQAL LQGNTERTVW
QYHFRTWPDH GVPSDPGGVL DFLEEVHHKQ ESIMDAGPVV VHCSAGIGRT GTFIVIDILI
DIIREKGVDC DIDVPKTIQM VRSQRSGMVQ TEAQYRFIYM AVQHYIETLQ RRIEEEQKSK
RKGHEYTNIK YSLADQTSGD QSPLPPCTPT PPCAEMREDS ARVYENVGLM QQQKSFR
//
MIM
151100
*RECORD*
*FIELD* NO
151100
*FIELD* TI
#151100 LEOPARD SYNDROME 1
;;LENTIGINOSIS, CARDIOMYOPATHIC;;
MULTIPLE LENTIGINES SYNDROME
read more*FIELD* TX
A number sign (#) is used with this entry because LEOPARD syndrome can
be caused by mutations in the PTPN11 gene (176876) on chromosome 12q24.
The disorder is allelic to Noonan syndrome-1 (NS1; 163950).
DESCRIPTION
LEOPARD is an acronym for the manifestations of this syndrome as listed
by Gorlin et al. (1969): multiple lentigines, electrocardiographic
conduction abnormalities, ocular hypertelorism, pulmonic stenosis,
abnormal genitalia, retardation of growth, and sensorineural deafness.
- Genetic Heterogeneity of LEOPARD Syndrome
LEOPARD syndrome is a genetically heterogeneous disorder. See also
LEOPARD syndrome-2 (611554), caused by mutation in the RAF1 gene
(164760), and LEOPARD syndrome-3 (613707), caused by mutation in the
BRAF gene (164757).
CLINICAL FEATURES
Walther et al. (1966) found asymptomatic cardiac changes associated with
generalized lentigo in a mother and her son and daughter. The
electrocardiogram in the son suggested myocardial infarction. The mother
was shown by cardiac catheterization to have mild pulmonary stenosis.
Similar generalized lentigines were described by Moynahan (1962) in 3
unrelated patients (2 females, 1 male). Growth was stunted. In 1 girl,
one ovary was absent and the other hypoplastic. The boy had hypospadias
and undescended testes. Endocardial and myocardial fibroelastosis may
have been present. Intelligence was normal but behavior childish.
Matthews (1968) reported mother and 2 half-sib children with generalized
lentigines, electrocardiographic changes and murmurs. A history of
male-to-male transmission was recorded. Lentigines were also present in
the cardiac syndrome reported by Forney et al. (see mitral
regurgitation, conductive deafness, etc.; 157800).
Polani and Moynahan (1972) gave a full report of 8 patients and their
families. They were impressed with the occurrence of left-sided
obstructive cardiomyopathy and none of their patients was deaf. They
proposed the designation 'progressive cardiomyopathic lentiginosis' for
this disorder. St. John Sutton et al. (1981) reported 11 patients, 10 of
them male, with classic hypertrophic obstructive cardiomyopathy and
lentiginosis. All were sporadic. Mental retardation, deafness, and
gonadal and somatic infantilism were uncommon in this series. The
21-year-old patient of Senn et al. (1984) had severe hypertrophic
obstructive cardiomyopathy for which surgery was performed on the left
ventricle to relieve severe obstruction. Both parents were unaffected;
both were 40 years old at the birth of the patient. Peter and Kemp
(1990) described a 19-year-old woman who died as a result of respiratory
insufficiency secondary to thoracic deformities which, together with a
congenital heart defect, led to pulmonary hypertension. The syndrome of
cafe-au-lait spots and pulmonic stenosis, described by Watson (1967), is
distinct (193520).
Coppin and Temple (1997) provided a review of the condition and added 5
cases, including relatives of one of the cases described by Polani and
Moynahan (1972). Coppin and Temple (1997) pointed out the difficulty of
differentiating LEOPARD syndrome from Noonan syndrome (163950) given
previous reports of lentiginosis without lentigines.
Shamsadini et al. (1999) described an 18-year-old Iranian girl with
LEOPARD syndrome. Clinical manifestations included lentigines, ocular
hypertelorism, mental and growth retardation, deaf mutism, and several
patches of hair loss on her scalp. There was no family history of
lentiginosis or any other inherited condition.
Schrader et al. (2009) reported a patient with LEOPARD syndrome,
confirmed by genetic analysis (176876.0006), who developed multiple
granular cell tumors of the skin and subcutaneous tissues during
adolescence. Studies of tumor tissue did not reveal loss of
heterozygosity at the PTPN11 or NF1 (613113) genes. A review of the
literature on multiple granular cell tumors associated with other
syndromic features indicated that many reported cases also exhibited
features of neuro-cardio-facial-cutaneous syndromes, such as
lentiginosis, cryptorchidism, pulmonary stenosis, ptosis, and short
stature.
Lehmann et al. (2009) reported a 37-year-old woman with genetically
confirmed LEOPARD syndrome who had hypertrophic cardiomyopathy, multiple
lentigines, deafness, growth retardation, hypertelorism, and strabismus.
Extensive cardiac workup showed biventricular apical hypertrophy, right
ventricular fibrosis, and coronary artery dilatation. Pulmonary stenosis
was not a feature.
DIAGNOSIS
Digilio et al. (2006) confirmed the diagnosis of LEOPARD syndrome by
molecular analysis in 8 (80%) of 10 infants clinically suspected to have
the disorder in the first year of life. One additional patient was
subsequently found to have neurofibromatosis type I (NF1; 162200)
following evaluation of the mother. Review of the clinical
characteristics of the 8 LS patients with PTPN11 mutations demonstrated
characteristic facial features in 100%, hypertrophic cardiomyopathy in
87%, and cafe-au-lait spots in 75%. Common facial features included
hypertelorism (100%), malformed ears (87%), and low-set ears with
overfolded helix (50%). Six (75%) patients had skeletal thorax
anomalies.
INHERITANCE
Gorlin et al. (1969) presented evidence for dominant inheritance.
MOLECULAR GENETICS
Digilio et al. (2002) screened for mutations in the PTPN11 gene, known
to be mutated in Noonan syndrome, in 9 patients with LEOPARD syndrome
(including a mother-daughter pair) and 2 children with Noonan syndrome
who had multiple cafe-au-lait spots. In 10 of the 11 patients, they
found 1 of 2 mutations: tyr279 to cys (Y279C; 176876.0005) or thr468 to
met (T468M; 176876.0006).
In 4 of 6 Japanese patients with LEOPARD syndrome, Yoshida et al. (2004)
identified 1 of 3 heterozygous missense mutations: Y279C, ala461 to thr
(A461T; 176876.0020), or gly464 to ala (G464A; 176876.0021).
Kalidas et al. (2005) performed mutation screening and linkage analysis
of PTPN11 in 3 families in each of which LEOPARD syndrome occurred in 3
generations. One family was found to carry a novel mutation (Q510P;
176876.0022). No variations in sequence were observed in the other 2
families, and negative lod scores excluded linkage to the PTPN11 locus,
showing that LEOPARD syndrome is genetically heterogeneous.
Tartaglia et al. (2006) showed that the recurrent LEOPARD
syndrome-causing Y279C (176876.0005) and T468M (176876.0006) amino acid
substitutions engender loss of SHP2 catalytic activity, thus identifying
a previously unrecognized behavior for this class of missense PTPN11
mutations.
Kontaridis et al. (2006) examined the enzymatic properties of mutations
in PTPN11 causing LEOPARD syndrome and found that, in contrast to the
activating mutations that cause Noonan syndrome and neoplasia, LEOPARD
syndrome mutants are catalytically defective and act as
dominant-negative mutations that interfere with growth factor/ERK-MAPK
(see 176948)-mediated signaling. Molecular modeling and biochemical
studies suggested that LEOPARD syndrome mutations control the SHP2
catalytic domain and result in open, inactive forms of SHP2. Kontaridis
et al. (2006) concluded that the pathogenesis of LEOPARD syndrome is
distinct from that of Noonan syndrome and suggested that these disorders
should be distinguished by mutation analysis rather than clinical
presentation.
Carvajal-Vergara et al. (2010) generated induced pluripotent stem cells
(iPSCs) derived from 2 unrelated LEOPARD patients who were heterozygous
for the T468M mutation in PTPN11 (176876.0006). The iPSCs were
extensively characterized and produced multiple differentiated cell
lineages. A major disease phenotype in patients with LEOPARD syndrome is
hypertrophic cardiomyopathy. Carvajal-Vergara et al. (2010) showed that
in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger,
have a higher degree of sarcomeric organization, and have preferential
localization of NFATC4 (602699) in the nucleus when compared with
cardiomyocytes derived from human embryonic stem cells or wildtype iPSCs
derived from a healthy brother of one of the LEOPARD syndrome patients.
These features correlate with a potential hypertrophic state.
Carvajal-Vergara et al. (2010) also provided molecular insights into
signaling pathways that may promote the disease phenotype.
Carvajal-Vergara et al. (2010) showed that basic fibroblast growth
factor treatment increased the phosphorylation of ERK1/2 levels over
time in several cell lines but did not have a similar effect in the
LEOPARD syndrome iPSCs despite higher basal phosphorylated ERK levels in
the LEOPARD syndrome iPSCs compared with the other cell lines.
GENOTYPE/PHENOTYPE CORRELATIONS
Limongelli et al. (2008) studied 24 LEOPARD syndrome patients, 16 with
mutations in the PTPN11 gene, 2 with mutations in the RAF1 gene, and 6
in whom no mutation had been found. Patients without PTPN11 mutations
showed a significantly higher frequency of family history of sudden
death, increased left atrial dimensions, and cardiac arrhythmias, and
seemed to be at higher risk for adverse cardiac events. Three patients
with mutations in exon 13 of the PTPN11 gene had a severe form of
biventricular obstructive LVH with early onset of heart failure
symptoms, consistent with previous observations.
HISTORY
In a family in which the mother and 2 daughters had the multiple
lentigines syndrome, Edman Ahlbom et al. (1995) demonstrated that the
gene is not linked to the neurofibromatosis type 1 locus (NF1; 613113).
Wu et al. (1996) described a de novo missense mutation (M1035R) in exon
18 of the NF1 gene in a 32-year-old woman with a prior mistaken
diagnosis of LEOPARD syndrome.
*FIELD* SA
Bhawan et al. (1976); Capute et al. (1969); Pickering et al. (1971);
Selmanowitz et al. (1971); Seuanez et al. (1976); Sommer et al. (1971);
Swanson et al. (1971); Voron et al. (1976); Weiss and Zelickson (1977)
*FIELD* RF
1. Bhawan, J.; Purtilo, D. T.; Riordan, J. A.; Saxena, V. K.; Edelstein,
L.: Giant and 'granular melanosomes' in Leopard syndrome: an ultrastructural
study. J. Cutan. Path. 3: 207-216, 1976.
2. Capute, A. J.; Rimoin, D. L.; Konigsmark, B. W.; Esterly, N. B.;
Richardson, F.: Congenital deafness and multiple lentigines. A report
of cases in a mother and daughter. Arch. Derm. 100: 207-213, 1969.
3. Carvajal-Vergara, X.; Sevilla, A.; D'Souza, S. L.; Ang, Y.-S.;
Schaniel, C.; Lee, D.-F.; Yang, L.; Kaplan, A. D.; Adler, E. D.; Rozov,
R.; Ge, Y.; Cohen, N.; and 9 others: Patient-specific induced pluripotent
stem-cell-derived models of LEOPARD syndrome. Nature 465: 808-812,
2010.
4. Coppin, B. D.; Temple, I. K.: Multiple lentigines syndrome (LEOPARD
syndrome or progressive cardiomyopathic lentiginosis). J. Med. Genet. 34:
582-586, 1997.
5. Digilio, M. C.; Conti, E.; Sarkozy, A.; Mingarelli, R.; Dottorini,
T.; Marino, B.; Pizzuti, A.; Dallapiccola, B.: Grouping of multiple-lentigines/LEOPARD
and Noonan syndromes on the PTPN11 gene. Am. J. Hum. Genet. 71:
389-394, 2002.
6. Digilio, M. C.; Sarkozy, A.; de Zorzi, A.; Pacileo, G.; Limongelli,
G.; Mingarelli, R.; Calabro, R.; Marino, B.; Dallapiccola, B.: LEOPARD
syndrome: clinical diagnosis in the first year of life. Am. J. Med.
Genet. 140A: 740-746, 2006.
7. Edman Ahlbom, B.; Dahl, N.; Zetterqvist, P.; Anneren, G.: Noonan
syndrome with cafe-au-lait spots and multiple lentigines syndrome
are not linked to the neurofibromatosis type 1 locus. Clin. Genet. 48:
85-89, 1995.
8. Gorlin, R. J.; Anderson, R. C.; Blaw, M. E.: Multiple lentigines
syndrome: complex comprising multiple lentigines, electrocardiographic
conduction abnormalities, ocular hypertelorism, pulmonary stenosis,
abnormalities of genitalia, retardation of growth, sensorineural deafness,
and autosomal dominant hereditary pattern. Am. J. Dis. Child. 117:
652-662, 1969.
9. Kalidas, K.; Shaw, A. C.; Crosby, A. H.; Newbury-Ecob, R.; Greenhalgh,
L.; Temple, I. K.; Law, C.; Patel, A.; Patton, M. A.; Jeffery, S.
: Genetic heterogeneity in LEOPARD syndrome: two families with no
mutations in PTPN11. J. Hum. Genet. 50: 21-25, 2005.
10. Kontaridis, M. I.; Swanson, K. D.; David, F. S.; Barford, D.;
Neel, B. G.: PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant
negative, not activating, effects. J. Biol. Chem. 281: 6785-6792,
2006.
11. Lehmann, L. H.; Schaeufele, T.; Buss, S. J.; Balanova, M.; Hartschuh,
W.; Ehlermann, P.; Katus, H. A.: A patient with LEOPARD syndrome
and PTPN11 mutation. Circulation 119: 1328-1329, 2009.
12. Limongelli, G.; Sarkozy, A.; Pacileo, G.; Calabro, P.; Digilio,
M. C.; Maddaloni, V.; Gagliardi, G.; Di Salvo, G.; Iacomino, M.; Marino,
B.; Dallapiccola, B.; Calabro, R.: Genotype-phenotype analysis and
natural history of left ventricular hypertrophy in LEOPARD syndrome. Am.
J. Med. Genet. 146A: 620-628, 2008.
13. Matthews, N. L.: Lentigo and electrocardiographic changes. New
Eng. J. Med. 278: 780-781, 1968.
14. Moynahan, E. J.: Multiple symmetrical moles, with psychic and
somatic infantilism and genital hypoplasia: first male case of a new
syndrome. Proc. Roy. Soc. Med. 55: 959-960, 1962.
15. Peter, J. R.; Kemp, J. S.: LEOPARD syndrome: death because of
chronic respiratory insufficiency. Am. J. Med. Genet. 37: 340-341,
1990.
16. Pickering, D.; Laski, B.; MacMillan, D. C.; Rose, V.: 'Little
leopard' syndrome. Arch. Dis. Child. 46: 85-90, 1971.
17. Polani, P. E.; Moynahan, E. J.: Progressive cardiomyopathic lentiginosis. Quart.
J. Med. 41: 205-225, 1972.
18. Schrader, K. A.; Nelson, T. N.; De Luca, A.; Huntsman, D. G.;
McGillivray, B. C.: Multiple granular cell tumors are an associated
feature of LEOPARD syndrome caused by mutation in PTPN11. Clin. Genet. 75:
185-189, 2009.
19. Selmanowitz, V. J.; Orentreich, N.; Felsenstein, J. M.: Lentiginosis
profusa syndrome (multiple lentigines syndrome). Arch. Derm. 104:
393-401, 1971.
20. Senn, M.; Hess, O. M.; Krayenbuhl, H. P.: Hypertrophe Kardiomyopathie
und Lentiginose. Schweiz. Med. Wschr. 114: 838-841, 1984.
21. Seuanez, H.; Mane-Garzon, F.; Kolski, R.: Cardio-cutaneous syndrome
(the 'LEOPARD' syndrome). Review of the literature and a new family. Clin.
Genet. 9: 266-276, 1976.
22. Shamsadini, S.; Abazardi, H.; Shamsadini, F.: Leopard syndrome.
(Letter) Lancet 354: 1530 only, 1999.
23. Sommer, A.; Contras, S. B.; Craenen, J. M.; Hosier, D. M.: A
family study of the leopard syndrome. Am. J. Dis. Child. 121: 520-523,
1971.
24. St. John Sutton, M. G.; Tajik, A. J.; Giuliani, E. R.; Gordon,
H.; Su, W. P. D.: Hypertrophic obstructive cardiomyopathy and lentiginosis:
a little known neural ectodermal syndrome. Am. J. Cardiol. 47: 214-217,
1981.
25. Swanson, S. L.; Santen, R. J.; Smith, D. W.: Multiple lentigines
syndrome: new findings of hypogonadotrophism, hyposmia, and unilateral
renal agenesis. J. Pediat. 78: 1037-1039, 1971.
26. Tartaglia, M.; Martinelli, S.; Stella, L.; Bocchinfuso, G.; Flex,
E.; Cordeddu, V.; Zampino, G.; van der Burgt, I.; Palleschi, A.; Petrucci,
T. C.; Sorcini, M.; Schoch, C.; Foa, R.; Emanuel, P. D.; Gelb, B.
D.: Diversity and functional consequences of germline and somatic
PTPN11 mutations in human disease. Am. J. Hum. Genet. 78: 279-290,
2006.
27. Voron, D. A.; Hatfield, H. H.; Kalkhoff, R. K.: Multiple lentigines
syndrome: case report and review of the literature. Am. J. Med. 60:
447-456, 1976.
28. Walther, R. J.; Polansky, B.; Grots, I. A.: Electrocardiographic
abnormalities in a family with generalized lentigo. New Eng. J. Med. 275:
1220-1225, 1966.
29. Watson, G. H.: Pulmonary stenosis, cafe-au-lait spots, and dull
intelligence. Arch. Dis. Child. 42: 303-307, 1967.
30. Weiss, L. W.; Zelickson, A. S.: Giant melanosomes in multiple
lentigines syndrome. Arch. Derm. 113: 491-494, 1977.
31. Wu, R.; Legius, E.; Robberecht, W.; Dumoulin, M.; Cassiman, J.-J.;
Fryns, J.-P.: Neurofibromatosis type I gene mutation in a patient
with features of LEOPARD syndrome. Hum. Mutat. 8: 51-56, 1996.
32. Yoshida, R.; Nagai, T.; Hasegawa, T.; Kinoshita, E.; Tanaka, T.;
Ogata, T.: Two novel and one recurrent PTPN11 mutations in LEOPARD
syndrome. (Letter) Am. J. Med. Genet. 130A: 432-434, 2004.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
[Weight];
Short stature;
[Other];
Growth retardation
HEAD AND NECK:
[Face];
Prognathism;
Triangular face;
Biparietal bossing;
[Ears];
Prominent ears;
Sensorineural hearing loss;
Low-set ears;
Posteriorly rotated ears;
[Eyes];
Hypertelorism;
Ptosis;
Epicanthal folds;
Strabismus;
[Nose];
Hyposmia;
Broad, flat nose;
[Mouth];
Cleft palate;
[Neck];
Pterygium colli;
Short neck
CARDIOVASCULAR:
[Heart];
Pulmonic stenosis (40%);
Superior EKG axis (-60 degrees to -120 degrees);
Hypertrophic cardiomyopathy (20%);
Subaortic stenosis;
Complete heart block;
Bundle branch block
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Winged scapulae;
Pectus excavatum;
Pectus carinatum;
Absent ribs
GENITOURINARY:
[External genitalia, male];
Hypospadias (50%);
Small penis;
[Internal genitalia, male];
Cryptorchidism (unilateral or bilateral);
[Internal genitalia, female];
Absent ovary;
Hypoplastic ovary;
[Kidneys];
Unilateral renal agenesis
SKELETAL:
[Spine];
Kyphoscoliosis;
Spina bifida occulta;
[Limbs];
Cubitus valgus;
Limited elbow mobility
SKIN, NAILS, HAIR:
[Skin];
1-5mm dark lentigines (especially neck and trunk);
Lentigines may be absent;
Lentigines may be congenital or develop in first months to years of
life;
Cafe-au-lait spots;
cafe-noir spots (trunk)
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild
ENDOCRINE FEATURES:
Late menarche;
Delayed puberty
MISCELLANEOUS:
LEOPARD is an acronym: lentigines, EKG abnormalities, ocular hypertelorism,
obstructive cardiomyopathy, pulmonic stenosis, abnormalities of genitalia,
retardation of growth, and deafness;
Allelic to Noonan syndrome (163950)
MOLECULAR BASIS:
Caused by mutation in the protein-tyrosine phosphatase, nonreceptor-type,
11 (PTPN11, 176876.0005)
*FIELD* CN
Kelly A. Przylepa - revised: 3/11/2003
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
terry: 02/12/2009
joanna: 12/5/2008
joanna: 3/11/2003
*FIELD* CN
Ada Hamosh - updated: 8/20/2010
Cassandra L. Kniffin - updated: 6/23/2009
Cassandra L. Kniffin - updated: 3/4/2009
Marla J. F. O'Neill - updated: 4/9/2008
Marla J. F. O'Neill - updated: 10/24/2007
Marla J. F. O'Neill - updated: 3/9/2007
Cassandra L. Kniffin - updated: 8/14/2006
Victor A. McKusick - updated: 1/24/2006
Victor A. McKusick - updated: 3/7/2005
Marla J. F. O'Neill - updated: 1/4/2005
Victor A. McKusick - updated: 8/16/2002
Victor A. McKusick - updated: 12/22/1999
Michael J. Wright - updated: 12/18/1997
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 11/28/2012
wwang: 2/7/2011
ckniffin: 1/21/2011
alopez: 8/30/2010
terry: 8/20/2010
carol: 11/23/2009
wwang: 7/20/2009
ckniffin: 6/23/2009
wwang: 3/16/2009
ckniffin: 3/4/2009
wwang: 4/9/2008
wwang: 10/25/2007
terry: 10/24/2007
wwang: 4/19/2007
wwang: 3/12/2007
terry: 3/9/2007
wwang: 8/21/2006
ckniffin: 8/14/2006
alopez: 5/4/2006
terry: 1/24/2006
wwang: 3/10/2005
wwang: 3/9/2005
terry: 3/7/2005
carol: 1/5/2005
terry: 1/4/2005
carol: 2/27/2003
tkritzer: 8/23/2002
tkritzer: 8/21/2002
terry: 8/16/2002
mcapotos: 1/10/2000
terry: 12/22/1999
alopez: 1/15/1998
terry: 12/18/1997
terry: 7/8/1997
alopez: 6/2/1997
terry: 8/22/1996
pfoster: 10/12/1995
mark: 9/19/1995
mimadm: 11/5/1994
warfield: 3/31/1994
carol: 6/24/1993
carol: 6/22/1993
*RECORD*
*FIELD* NO
151100
*FIELD* TI
#151100 LEOPARD SYNDROME 1
;;LENTIGINOSIS, CARDIOMYOPATHIC;;
MULTIPLE LENTIGINES SYNDROME
read more*FIELD* TX
A number sign (#) is used with this entry because LEOPARD syndrome can
be caused by mutations in the PTPN11 gene (176876) on chromosome 12q24.
The disorder is allelic to Noonan syndrome-1 (NS1; 163950).
DESCRIPTION
LEOPARD is an acronym for the manifestations of this syndrome as listed
by Gorlin et al. (1969): multiple lentigines, electrocardiographic
conduction abnormalities, ocular hypertelorism, pulmonic stenosis,
abnormal genitalia, retardation of growth, and sensorineural deafness.
- Genetic Heterogeneity of LEOPARD Syndrome
LEOPARD syndrome is a genetically heterogeneous disorder. See also
LEOPARD syndrome-2 (611554), caused by mutation in the RAF1 gene
(164760), and LEOPARD syndrome-3 (613707), caused by mutation in the
BRAF gene (164757).
CLINICAL FEATURES
Walther et al. (1966) found asymptomatic cardiac changes associated with
generalized lentigo in a mother and her son and daughter. The
electrocardiogram in the son suggested myocardial infarction. The mother
was shown by cardiac catheterization to have mild pulmonary stenosis.
Similar generalized lentigines were described by Moynahan (1962) in 3
unrelated patients (2 females, 1 male). Growth was stunted. In 1 girl,
one ovary was absent and the other hypoplastic. The boy had hypospadias
and undescended testes. Endocardial and myocardial fibroelastosis may
have been present. Intelligence was normal but behavior childish.
Matthews (1968) reported mother and 2 half-sib children with generalized
lentigines, electrocardiographic changes and murmurs. A history of
male-to-male transmission was recorded. Lentigines were also present in
the cardiac syndrome reported by Forney et al. (see mitral
regurgitation, conductive deafness, etc.; 157800).
Polani and Moynahan (1972) gave a full report of 8 patients and their
families. They were impressed with the occurrence of left-sided
obstructive cardiomyopathy and none of their patients was deaf. They
proposed the designation 'progressive cardiomyopathic lentiginosis' for
this disorder. St. John Sutton et al. (1981) reported 11 patients, 10 of
them male, with classic hypertrophic obstructive cardiomyopathy and
lentiginosis. All were sporadic. Mental retardation, deafness, and
gonadal and somatic infantilism were uncommon in this series. The
21-year-old patient of Senn et al. (1984) had severe hypertrophic
obstructive cardiomyopathy for which surgery was performed on the left
ventricle to relieve severe obstruction. Both parents were unaffected;
both were 40 years old at the birth of the patient. Peter and Kemp
(1990) described a 19-year-old woman who died as a result of respiratory
insufficiency secondary to thoracic deformities which, together with a
congenital heart defect, led to pulmonary hypertension. The syndrome of
cafe-au-lait spots and pulmonic stenosis, described by Watson (1967), is
distinct (193520).
Coppin and Temple (1997) provided a review of the condition and added 5
cases, including relatives of one of the cases described by Polani and
Moynahan (1972). Coppin and Temple (1997) pointed out the difficulty of
differentiating LEOPARD syndrome from Noonan syndrome (163950) given
previous reports of lentiginosis without lentigines.
Shamsadini et al. (1999) described an 18-year-old Iranian girl with
LEOPARD syndrome. Clinical manifestations included lentigines, ocular
hypertelorism, mental and growth retardation, deaf mutism, and several
patches of hair loss on her scalp. There was no family history of
lentiginosis or any other inherited condition.
Schrader et al. (2009) reported a patient with LEOPARD syndrome,
confirmed by genetic analysis (176876.0006), who developed multiple
granular cell tumors of the skin and subcutaneous tissues during
adolescence. Studies of tumor tissue did not reveal loss of
heterozygosity at the PTPN11 or NF1 (613113) genes. A review of the
literature on multiple granular cell tumors associated with other
syndromic features indicated that many reported cases also exhibited
features of neuro-cardio-facial-cutaneous syndromes, such as
lentiginosis, cryptorchidism, pulmonary stenosis, ptosis, and short
stature.
Lehmann et al. (2009) reported a 37-year-old woman with genetically
confirmed LEOPARD syndrome who had hypertrophic cardiomyopathy, multiple
lentigines, deafness, growth retardation, hypertelorism, and strabismus.
Extensive cardiac workup showed biventricular apical hypertrophy, right
ventricular fibrosis, and coronary artery dilatation. Pulmonary stenosis
was not a feature.
DIAGNOSIS
Digilio et al. (2006) confirmed the diagnosis of LEOPARD syndrome by
molecular analysis in 8 (80%) of 10 infants clinically suspected to have
the disorder in the first year of life. One additional patient was
subsequently found to have neurofibromatosis type I (NF1; 162200)
following evaluation of the mother. Review of the clinical
characteristics of the 8 LS patients with PTPN11 mutations demonstrated
characteristic facial features in 100%, hypertrophic cardiomyopathy in
87%, and cafe-au-lait spots in 75%. Common facial features included
hypertelorism (100%), malformed ears (87%), and low-set ears with
overfolded helix (50%). Six (75%) patients had skeletal thorax
anomalies.
INHERITANCE
Gorlin et al. (1969) presented evidence for dominant inheritance.
MOLECULAR GENETICS
Digilio et al. (2002) screened for mutations in the PTPN11 gene, known
to be mutated in Noonan syndrome, in 9 patients with LEOPARD syndrome
(including a mother-daughter pair) and 2 children with Noonan syndrome
who had multiple cafe-au-lait spots. In 10 of the 11 patients, they
found 1 of 2 mutations: tyr279 to cys (Y279C; 176876.0005) or thr468 to
met (T468M; 176876.0006).
In 4 of 6 Japanese patients with LEOPARD syndrome, Yoshida et al. (2004)
identified 1 of 3 heterozygous missense mutations: Y279C, ala461 to thr
(A461T; 176876.0020), or gly464 to ala (G464A; 176876.0021).
Kalidas et al. (2005) performed mutation screening and linkage analysis
of PTPN11 in 3 families in each of which LEOPARD syndrome occurred in 3
generations. One family was found to carry a novel mutation (Q510P;
176876.0022). No variations in sequence were observed in the other 2
families, and negative lod scores excluded linkage to the PTPN11 locus,
showing that LEOPARD syndrome is genetically heterogeneous.
Tartaglia et al. (2006) showed that the recurrent LEOPARD
syndrome-causing Y279C (176876.0005) and T468M (176876.0006) amino acid
substitutions engender loss of SHP2 catalytic activity, thus identifying
a previously unrecognized behavior for this class of missense PTPN11
mutations.
Kontaridis et al. (2006) examined the enzymatic properties of mutations
in PTPN11 causing LEOPARD syndrome and found that, in contrast to the
activating mutations that cause Noonan syndrome and neoplasia, LEOPARD
syndrome mutants are catalytically defective and act as
dominant-negative mutations that interfere with growth factor/ERK-MAPK
(see 176948)-mediated signaling. Molecular modeling and biochemical
studies suggested that LEOPARD syndrome mutations control the SHP2
catalytic domain and result in open, inactive forms of SHP2. Kontaridis
et al. (2006) concluded that the pathogenesis of LEOPARD syndrome is
distinct from that of Noonan syndrome and suggested that these disorders
should be distinguished by mutation analysis rather than clinical
presentation.
Carvajal-Vergara et al. (2010) generated induced pluripotent stem cells
(iPSCs) derived from 2 unrelated LEOPARD patients who were heterozygous
for the T468M mutation in PTPN11 (176876.0006). The iPSCs were
extensively characterized and produced multiple differentiated cell
lineages. A major disease phenotype in patients with LEOPARD syndrome is
hypertrophic cardiomyopathy. Carvajal-Vergara et al. (2010) showed that
in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger,
have a higher degree of sarcomeric organization, and have preferential
localization of NFATC4 (602699) in the nucleus when compared with
cardiomyocytes derived from human embryonic stem cells or wildtype iPSCs
derived from a healthy brother of one of the LEOPARD syndrome patients.
These features correlate with a potential hypertrophic state.
Carvajal-Vergara et al. (2010) also provided molecular insights into
signaling pathways that may promote the disease phenotype.
Carvajal-Vergara et al. (2010) showed that basic fibroblast growth
factor treatment increased the phosphorylation of ERK1/2 levels over
time in several cell lines but did not have a similar effect in the
LEOPARD syndrome iPSCs despite higher basal phosphorylated ERK levels in
the LEOPARD syndrome iPSCs compared with the other cell lines.
GENOTYPE/PHENOTYPE CORRELATIONS
Limongelli et al. (2008) studied 24 LEOPARD syndrome patients, 16 with
mutations in the PTPN11 gene, 2 with mutations in the RAF1 gene, and 6
in whom no mutation had been found. Patients without PTPN11 mutations
showed a significantly higher frequency of family history of sudden
death, increased left atrial dimensions, and cardiac arrhythmias, and
seemed to be at higher risk for adverse cardiac events. Three patients
with mutations in exon 13 of the PTPN11 gene had a severe form of
biventricular obstructive LVH with early onset of heart failure
symptoms, consistent with previous observations.
HISTORY
In a family in which the mother and 2 daughters had the multiple
lentigines syndrome, Edman Ahlbom et al. (1995) demonstrated that the
gene is not linked to the neurofibromatosis type 1 locus (NF1; 613113).
Wu et al. (1996) described a de novo missense mutation (M1035R) in exon
18 of the NF1 gene in a 32-year-old woman with a prior mistaken
diagnosis of LEOPARD syndrome.
*FIELD* SA
Bhawan et al. (1976); Capute et al. (1969); Pickering et al. (1971);
Selmanowitz et al. (1971); Seuanez et al. (1976); Sommer et al. (1971);
Swanson et al. (1971); Voron et al. (1976); Weiss and Zelickson (1977)
*FIELD* RF
1. Bhawan, J.; Purtilo, D. T.; Riordan, J. A.; Saxena, V. K.; Edelstein,
L.: Giant and 'granular melanosomes' in Leopard syndrome: an ultrastructural
study. J. Cutan. Path. 3: 207-216, 1976.
2. Capute, A. J.; Rimoin, D. L.; Konigsmark, B. W.; Esterly, N. B.;
Richardson, F.: Congenital deafness and multiple lentigines. A report
of cases in a mother and daughter. Arch. Derm. 100: 207-213, 1969.
3. Carvajal-Vergara, X.; Sevilla, A.; D'Souza, S. L.; Ang, Y.-S.;
Schaniel, C.; Lee, D.-F.; Yang, L.; Kaplan, A. D.; Adler, E. D.; Rozov,
R.; Ge, Y.; Cohen, N.; and 9 others: Patient-specific induced pluripotent
stem-cell-derived models of LEOPARD syndrome. Nature 465: 808-812,
2010.
4. Coppin, B. D.; Temple, I. K.: Multiple lentigines syndrome (LEOPARD
syndrome or progressive cardiomyopathic lentiginosis). J. Med. Genet. 34:
582-586, 1997.
5. Digilio, M. C.; Conti, E.; Sarkozy, A.; Mingarelli, R.; Dottorini,
T.; Marino, B.; Pizzuti, A.; Dallapiccola, B.: Grouping of multiple-lentigines/LEOPARD
and Noonan syndromes on the PTPN11 gene. Am. J. Hum. Genet. 71:
389-394, 2002.
6. Digilio, M. C.; Sarkozy, A.; de Zorzi, A.; Pacileo, G.; Limongelli,
G.; Mingarelli, R.; Calabro, R.; Marino, B.; Dallapiccola, B.: LEOPARD
syndrome: clinical diagnosis in the first year of life. Am. J. Med.
Genet. 140A: 740-746, 2006.
7. Edman Ahlbom, B.; Dahl, N.; Zetterqvist, P.; Anneren, G.: Noonan
syndrome with cafe-au-lait spots and multiple lentigines syndrome
are not linked to the neurofibromatosis type 1 locus. Clin. Genet. 48:
85-89, 1995.
8. Gorlin, R. J.; Anderson, R. C.; Blaw, M. E.: Multiple lentigines
syndrome: complex comprising multiple lentigines, electrocardiographic
conduction abnormalities, ocular hypertelorism, pulmonary stenosis,
abnormalities of genitalia, retardation of growth, sensorineural deafness,
and autosomal dominant hereditary pattern. Am. J. Dis. Child. 117:
652-662, 1969.
9. Kalidas, K.; Shaw, A. C.; Crosby, A. H.; Newbury-Ecob, R.; Greenhalgh,
L.; Temple, I. K.; Law, C.; Patel, A.; Patton, M. A.; Jeffery, S.
: Genetic heterogeneity in LEOPARD syndrome: two families with no
mutations in PTPN11. J. Hum. Genet. 50: 21-25, 2005.
10. Kontaridis, M. I.; Swanson, K. D.; David, F. S.; Barford, D.;
Neel, B. G.: PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant
negative, not activating, effects. J. Biol. Chem. 281: 6785-6792,
2006.
11. Lehmann, L. H.; Schaeufele, T.; Buss, S. J.; Balanova, M.; Hartschuh,
W.; Ehlermann, P.; Katus, H. A.: A patient with LEOPARD syndrome
and PTPN11 mutation. Circulation 119: 1328-1329, 2009.
12. Limongelli, G.; Sarkozy, A.; Pacileo, G.; Calabro, P.; Digilio,
M. C.; Maddaloni, V.; Gagliardi, G.; Di Salvo, G.; Iacomino, M.; Marino,
B.; Dallapiccola, B.; Calabro, R.: Genotype-phenotype analysis and
natural history of left ventricular hypertrophy in LEOPARD syndrome. Am.
J. Med. Genet. 146A: 620-628, 2008.
13. Matthews, N. L.: Lentigo and electrocardiographic changes. New
Eng. J. Med. 278: 780-781, 1968.
14. Moynahan, E. J.: Multiple symmetrical moles, with psychic and
somatic infantilism and genital hypoplasia: first male case of a new
syndrome. Proc. Roy. Soc. Med. 55: 959-960, 1962.
15. Peter, J. R.; Kemp, J. S.: LEOPARD syndrome: death because of
chronic respiratory insufficiency. Am. J. Med. Genet. 37: 340-341,
1990.
16. Pickering, D.; Laski, B.; MacMillan, D. C.; Rose, V.: 'Little
leopard' syndrome. Arch. Dis. Child. 46: 85-90, 1971.
17. Polani, P. E.; Moynahan, E. J.: Progressive cardiomyopathic lentiginosis. Quart.
J. Med. 41: 205-225, 1972.
18. Schrader, K. A.; Nelson, T. N.; De Luca, A.; Huntsman, D. G.;
McGillivray, B. C.: Multiple granular cell tumors are an associated
feature of LEOPARD syndrome caused by mutation in PTPN11. Clin. Genet. 75:
185-189, 2009.
19. Selmanowitz, V. J.; Orentreich, N.; Felsenstein, J. M.: Lentiginosis
profusa syndrome (multiple lentigines syndrome). Arch. Derm. 104:
393-401, 1971.
20. Senn, M.; Hess, O. M.; Krayenbuhl, H. P.: Hypertrophe Kardiomyopathie
und Lentiginose. Schweiz. Med. Wschr. 114: 838-841, 1984.
21. Seuanez, H.; Mane-Garzon, F.; Kolski, R.: Cardio-cutaneous syndrome
(the 'LEOPARD' syndrome). Review of the literature and a new family. Clin.
Genet. 9: 266-276, 1976.
22. Shamsadini, S.; Abazardi, H.; Shamsadini, F.: Leopard syndrome.
(Letter) Lancet 354: 1530 only, 1999.
23. Sommer, A.; Contras, S. B.; Craenen, J. M.; Hosier, D. M.: A
family study of the leopard syndrome. Am. J. Dis. Child. 121: 520-523,
1971.
24. St. John Sutton, M. G.; Tajik, A. J.; Giuliani, E. R.; Gordon,
H.; Su, W. P. D.: Hypertrophic obstructive cardiomyopathy and lentiginosis:
a little known neural ectodermal syndrome. Am. J. Cardiol. 47: 214-217,
1981.
25. Swanson, S. L.; Santen, R. J.; Smith, D. W.: Multiple lentigines
syndrome: new findings of hypogonadotrophism, hyposmia, and unilateral
renal agenesis. J. Pediat. 78: 1037-1039, 1971.
26. Tartaglia, M.; Martinelli, S.; Stella, L.; Bocchinfuso, G.; Flex,
E.; Cordeddu, V.; Zampino, G.; van der Burgt, I.; Palleschi, A.; Petrucci,
T. C.; Sorcini, M.; Schoch, C.; Foa, R.; Emanuel, P. D.; Gelb, B.
D.: Diversity and functional consequences of germline and somatic
PTPN11 mutations in human disease. Am. J. Hum. Genet. 78: 279-290,
2006.
27. Voron, D. A.; Hatfield, H. H.; Kalkhoff, R. K.: Multiple lentigines
syndrome: case report and review of the literature. Am. J. Med. 60:
447-456, 1976.
28. Walther, R. J.; Polansky, B.; Grots, I. A.: Electrocardiographic
abnormalities in a family with generalized lentigo. New Eng. J. Med. 275:
1220-1225, 1966.
29. Watson, G. H.: Pulmonary stenosis, cafe-au-lait spots, and dull
intelligence. Arch. Dis. Child. 42: 303-307, 1967.
30. Weiss, L. W.; Zelickson, A. S.: Giant melanosomes in multiple
lentigines syndrome. Arch. Derm. 113: 491-494, 1977.
31. Wu, R.; Legius, E.; Robberecht, W.; Dumoulin, M.; Cassiman, J.-J.;
Fryns, J.-P.: Neurofibromatosis type I gene mutation in a patient
with features of LEOPARD syndrome. Hum. Mutat. 8: 51-56, 1996.
32. Yoshida, R.; Nagai, T.; Hasegawa, T.; Kinoshita, E.; Tanaka, T.;
Ogata, T.: Two novel and one recurrent PTPN11 mutations in LEOPARD
syndrome. (Letter) Am. J. Med. Genet. 130A: 432-434, 2004.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
[Weight];
Short stature;
[Other];
Growth retardation
HEAD AND NECK:
[Face];
Prognathism;
Triangular face;
Biparietal bossing;
[Ears];
Prominent ears;
Sensorineural hearing loss;
Low-set ears;
Posteriorly rotated ears;
[Eyes];
Hypertelorism;
Ptosis;
Epicanthal folds;
Strabismus;
[Nose];
Hyposmia;
Broad, flat nose;
[Mouth];
Cleft palate;
[Neck];
Pterygium colli;
Short neck
CARDIOVASCULAR:
[Heart];
Pulmonic stenosis (40%);
Superior EKG axis (-60 degrees to -120 degrees);
Hypertrophic cardiomyopathy (20%);
Subaortic stenosis;
Complete heart block;
Bundle branch block
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Winged scapulae;
Pectus excavatum;
Pectus carinatum;
Absent ribs
GENITOURINARY:
[External genitalia, male];
Hypospadias (50%);
Small penis;
[Internal genitalia, male];
Cryptorchidism (unilateral or bilateral);
[Internal genitalia, female];
Absent ovary;
Hypoplastic ovary;
[Kidneys];
Unilateral renal agenesis
SKELETAL:
[Spine];
Kyphoscoliosis;
Spina bifida occulta;
[Limbs];
Cubitus valgus;
Limited elbow mobility
SKIN, NAILS, HAIR:
[Skin];
1-5mm dark lentigines (especially neck and trunk);
Lentigines may be absent;
Lentigines may be congenital or develop in first months to years of
life;
Cafe-au-lait spots;
cafe-noir spots (trunk)
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild
ENDOCRINE FEATURES:
Late menarche;
Delayed puberty
MISCELLANEOUS:
LEOPARD is an acronym: lentigines, EKG abnormalities, ocular hypertelorism,
obstructive cardiomyopathy, pulmonic stenosis, abnormalities of genitalia,
retardation of growth, and deafness;
Allelic to Noonan syndrome (163950)
MOLECULAR BASIS:
Caused by mutation in the protein-tyrosine phosphatase, nonreceptor-type,
11 (PTPN11, 176876.0005)
*FIELD* CN
Kelly A. Przylepa - revised: 3/11/2003
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
terry: 02/12/2009
joanna: 12/5/2008
joanna: 3/11/2003
*FIELD* CN
Ada Hamosh - updated: 8/20/2010
Cassandra L. Kniffin - updated: 6/23/2009
Cassandra L. Kniffin - updated: 3/4/2009
Marla J. F. O'Neill - updated: 4/9/2008
Marla J. F. O'Neill - updated: 10/24/2007
Marla J. F. O'Neill - updated: 3/9/2007
Cassandra L. Kniffin - updated: 8/14/2006
Victor A. McKusick - updated: 1/24/2006
Victor A. McKusick - updated: 3/7/2005
Marla J. F. O'Neill - updated: 1/4/2005
Victor A. McKusick - updated: 8/16/2002
Victor A. McKusick - updated: 12/22/1999
Michael J. Wright - updated: 12/18/1997
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 11/28/2012
wwang: 2/7/2011
ckniffin: 1/21/2011
alopez: 8/30/2010
terry: 8/20/2010
carol: 11/23/2009
wwang: 7/20/2009
ckniffin: 6/23/2009
wwang: 3/16/2009
ckniffin: 3/4/2009
wwang: 4/9/2008
wwang: 10/25/2007
terry: 10/24/2007
wwang: 4/19/2007
wwang: 3/12/2007
terry: 3/9/2007
wwang: 8/21/2006
ckniffin: 8/14/2006
alopez: 5/4/2006
terry: 1/24/2006
wwang: 3/10/2005
wwang: 3/9/2005
terry: 3/7/2005
carol: 1/5/2005
terry: 1/4/2005
carol: 2/27/2003
tkritzer: 8/23/2002
tkritzer: 8/21/2002
terry: 8/16/2002
mcapotos: 1/10/2000
terry: 12/22/1999
alopez: 1/15/1998
terry: 12/18/1997
terry: 7/8/1997
alopez: 6/2/1997
terry: 8/22/1996
pfoster: 10/12/1995
mark: 9/19/1995
mimadm: 11/5/1994
warfield: 3/31/1994
carol: 6/24/1993
carol: 6/22/1993
MIM
156250
*RECORD*
*FIELD* NO
156250
*FIELD* TI
#156250 METACHONDROMATOSIS; METCDS
*FIELD* TX
A number sign (#) is used with this entry because metachondromatosis
read more(METCDS) is caused by heterozygous mutation in the PTPN11 gene (176876)
on chromosome 12q24.
CLINICAL FEATURES
Maroteaux (1971) described 2 families with skeletal radiologic features
of both multiple exostoses (133700) and Ollier disease (166000). He
called the disorder metachondromatosis and suggested autosomal dominant
inheritance on the basis of 1 family with 5 affected persons.
Lachman et al. (1974) reported a case. Kennedy (1983) presented the case
of a 9.5-year-old boy in whom 'bumps' on the hands, feet and knees had
been noted at age 5. In the next few years, some of these enlarged, new
ones appeared, and others regressed. Peculiar striations were noted
radiologically in the metaphyses of the long bones and iliac crests. The
mother had a similar although milder history; x-ray showed a single
exostosis in the wrist. The maternal grandfather had had lesions of the
hands, feet, and knees, but none was evident at the time of radiologic
study. Two cousins were said to have similar lesions. Differentiation
from multiple exostoses of the classic type (133700) is important
because of the usual regression with little or minimal residual
deformity. Involvement of the hands and feet is the rule in
metachondromatosis but is said by Kennedy (1983) to be unusual in
classic multiple exostoses. Furthermore, in metachondromatosis, the
exostoses point toward the epiphysis.
Dorst (1983) observed metachondromatosis in a brother and sister of
Korean extraction. The radiologic findings combined those of multiple
exostoses, multiple enchondromatosis (Ollier disease), and dysplasia
epiphysealis hemimelica (127800). No other affected relatives were known
but the parents were not available for study.
In the family studied by Vanek (1982), the mother of 2 of the affected
persons had a history of exostoses as a child, which regressed as she
grew older. X-ray studies showed no peripheral exostoses but the
proximal end of one humerus was wide and a first metatarsal was
abnormally thin. A brother was said also to have had nodular growths
near joints as a child.
Bassett and Cowell (1985) studied 4 members of a kindred that had at
least 8 cases in all. They pointed out that the enchondromatous lesions
involve the iliac crest and metaphyseal region of the long bones of the
lower extremities as in Ollier disease. The exostoses of
metachondromatosis, unlike those of hereditary multiple exostosis, point
toward the nearby joint and do not cause shortening or bowing of the
long bone, joint deformity, or subluxation. They affect particularly the
digits and may resolve spontaneously.
MAPPING
Sobreira et al. (2010) performed a genomewide scan in a 5-generation
family segregating autosomal dominant metachondromatosis and identified
6 regions showing suggestive evidence for linkage, including chromosome
7p14.1 (maximum lod score, 2.5), 8q24.1, and 12q23 (lod score of 1.8 for
both), and 2p25, 5q12.1, and 9q31.1-q33.1 (lod scores between 1.0 and
1.5).
Bowen et al. (2011) performed linkage analysis with high-density SNP
arrays in a family with metachondromatosis and identified an 8.6-Mb
interval on chromosome 12 that attained a maximum lod score of 2.7.
MOLECULAR GENETICS
Sobreira et al. (2010) performed whole-genome sequencing in 1 affected
individual from a 5-generation family with metachondromatosis and
identified a heterozygous 11-bp deletion in the PTPN11 gene
(176876.0025); analysis of family members confirmed that the deletion
segregated with the disease. Sequencing of the PTPN11 gene in another
3-generation family with autosomal dominant metachondromatosis revealed
a heterozygous nonsense mutation (176876.0026) in affected individuals.
Neither mutation was detected in 469 controls.
Bowen et al. (2011) used a targeted array to capture exons and promoter
sequences from an 8.6-Mb linked interval in 16 participants from 11
metachondromatosis families, and sequenced the captured DNA using
high-throughput parallel sequencing technologies. They identified
heterozygous putative loss-of-function mutations in the PTPN11 gene in 4
of the 11 families (176876.0028-176876.0031). Sanger sequence analysis
of PTPN11 coding regions in the 7 remaining families and in 6 additional
metachondromatosis families identified novel heterozygous mutations in 4
families (176876.0032-176876.0035). Copy number analysis of sequencing
reads from a second targeted capture that included the entire PTPN11
gene identified an metachondromatosis patient with a 15-kb deletion
spanning exon 7 of PTPN11 (176876.0036). In total, of 17
metachondromatosis families, Bowen et al. (2011) identified mutations in
11 (5 frameshift, 2 nonsense, 3 splice site, and 1 large deletion). Each
family had a different mutation, and the mutations were scattered across
the gene. Microdissected metachondromatosis lesions from 2 patients with
PTPN11 mutations demonstrated loss of heterozygosity for the wildtype
allele. Bowen et al. (2011) suggested that metachondromatosis may be
genetically heterogeneous because 1 familial and 5 sporadically
occurring cases lacked obvious disease-causing PTPN11 mutations.
*FIELD* SA
De la Cruz and Garcia-Castro (1976); Giedion et al. (1975)
*FIELD* RF
1. Bassett, G. S.; Cowell, H. R.: Metachondromatosis: report of four
cases. J. Bone Joint Surg. Am. 67: 811-814, 1985.
2. Bowen, M. E.; Boyden, E. D.; Holm, I. A.; Campos-Xavier, B.; Bonafe,
L.; Superti-Furga, A.; Ikegawa, S.; Cormier-Daire, V.; Bovee, J. V.;
Pansuriya, T. C.; de Sousa, S. B.; Savarirayan, R.; and 16 others
: Loss-of-function mutations in PTPN11 cause metachondromatosis, but
not Ollier disease or Maffucci syndrome. PLoS Genet. 7: e1002050,
2011. Note: Electronic Article.
3. De la Cruz, J.; Garcia-Castro, J. M.: Metachondromatosis: a diagnostic
dilemma: apropos of studies in a Puerto Rican family. Bol. Assoc.
Med. PR 68: 340-344, 1976.
4. Dorst, J. P.: Personal Communication. Baltimore, Md. 6/14/1983.
5. Giedion, A.; Kesztler, R.; Muggiasca, F.: The widened spectrum
of multiple cartilaginous exostosis (MCE). Pediat. Radiol. 3: 93-100,
1975.
6. Kennedy, L. A.: Metachondromatosis. Radiology 148: 117-118,
1983.
7. Lachman, R. S.; Cohen, A.; Hollister, D. W.; Rimoin, D. L.: Metachondromatosis. Birth
Defects Orig. Art. Ser. X(9): 171-178, 1974.
8. Maroteaux, P.: La metachondromatose. Z. Kinderheilk. 109: 246-261,
1971.
9. Sobreira, N. L. M.; Cirulli, E. T.; Avramopoulos, D.; Wohler, E.;
Oswald, G. L.; Stevens, E. L.; Ge, D.; Shianna, K. V.; Smith, J. P.;
Maia, J. M.; Gumbs, C. E.; Pevsner, J.; Thomas, G.; Valle, D.; Hoover-Fong,
J. E.; Goldstein, D. B.: Whole-genome sequencing of a single proband
together with linkage analysis identifies a mendelian disease gene. PLoS
Genet. 6: e1000991, 2010. Note: Electronic Article.
10. Vanek, V. J.: Metachondromatose: 3 Beobachtungen mit erblichen
Vorkommen. Beitr. Orthop. Traumatol. 29: 103-107, 1982.
*FIELD* CS
Skel:
Multiple exostoses, esp. digits;
Multiple enchondromatosis
Joints:
No joint deformity, or subluxation
Misc:
Exostoses point toward nearby joint;
Exostoses may resolve spontaneously;
No shortening or bowing of long bones
Radiology:
Striations in metaphyses of long bones and iliac crests
Inheritance:
Autosomal dominant
*FIELD* CN
Nara Sobreira - updated: 5/15/2012
Marla J. F. O'Neill - updated: 6/28/2010
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 05/25/2012
carol: 5/15/2012
terry: 1/13/2011
carol: 6/28/2010
terry: 6/28/2010
carol: 9/2/2009
mimadm: 11/6/1994
warfield: 4/12/1994
supermim: 3/16/1992
carol: 3/3/1992
supermim: 3/20/1990
ddp: 10/27/1989
*RECORD*
*FIELD* NO
156250
*FIELD* TI
#156250 METACHONDROMATOSIS; METCDS
*FIELD* TX
A number sign (#) is used with this entry because metachondromatosis
read more(METCDS) is caused by heterozygous mutation in the PTPN11 gene (176876)
on chromosome 12q24.
CLINICAL FEATURES
Maroteaux (1971) described 2 families with skeletal radiologic features
of both multiple exostoses (133700) and Ollier disease (166000). He
called the disorder metachondromatosis and suggested autosomal dominant
inheritance on the basis of 1 family with 5 affected persons.
Lachman et al. (1974) reported a case. Kennedy (1983) presented the case
of a 9.5-year-old boy in whom 'bumps' on the hands, feet and knees had
been noted at age 5. In the next few years, some of these enlarged, new
ones appeared, and others regressed. Peculiar striations were noted
radiologically in the metaphyses of the long bones and iliac crests. The
mother had a similar although milder history; x-ray showed a single
exostosis in the wrist. The maternal grandfather had had lesions of the
hands, feet, and knees, but none was evident at the time of radiologic
study. Two cousins were said to have similar lesions. Differentiation
from multiple exostoses of the classic type (133700) is important
because of the usual regression with little or minimal residual
deformity. Involvement of the hands and feet is the rule in
metachondromatosis but is said by Kennedy (1983) to be unusual in
classic multiple exostoses. Furthermore, in metachondromatosis, the
exostoses point toward the epiphysis.
Dorst (1983) observed metachondromatosis in a brother and sister of
Korean extraction. The radiologic findings combined those of multiple
exostoses, multiple enchondromatosis (Ollier disease), and dysplasia
epiphysealis hemimelica (127800). No other affected relatives were known
but the parents were not available for study.
In the family studied by Vanek (1982), the mother of 2 of the affected
persons had a history of exostoses as a child, which regressed as she
grew older. X-ray studies showed no peripheral exostoses but the
proximal end of one humerus was wide and a first metatarsal was
abnormally thin. A brother was said also to have had nodular growths
near joints as a child.
Bassett and Cowell (1985) studied 4 members of a kindred that had at
least 8 cases in all. They pointed out that the enchondromatous lesions
involve the iliac crest and metaphyseal region of the long bones of the
lower extremities as in Ollier disease. The exostoses of
metachondromatosis, unlike those of hereditary multiple exostosis, point
toward the nearby joint and do not cause shortening or bowing of the
long bone, joint deformity, or subluxation. They affect particularly the
digits and may resolve spontaneously.
MAPPING
Sobreira et al. (2010) performed a genomewide scan in a 5-generation
family segregating autosomal dominant metachondromatosis and identified
6 regions showing suggestive evidence for linkage, including chromosome
7p14.1 (maximum lod score, 2.5), 8q24.1, and 12q23 (lod score of 1.8 for
both), and 2p25, 5q12.1, and 9q31.1-q33.1 (lod scores between 1.0 and
1.5).
Bowen et al. (2011) performed linkage analysis with high-density SNP
arrays in a family with metachondromatosis and identified an 8.6-Mb
interval on chromosome 12 that attained a maximum lod score of 2.7.
MOLECULAR GENETICS
Sobreira et al. (2010) performed whole-genome sequencing in 1 affected
individual from a 5-generation family with metachondromatosis and
identified a heterozygous 11-bp deletion in the PTPN11 gene
(176876.0025); analysis of family members confirmed that the deletion
segregated with the disease. Sequencing of the PTPN11 gene in another
3-generation family with autosomal dominant metachondromatosis revealed
a heterozygous nonsense mutation (176876.0026) in affected individuals.
Neither mutation was detected in 469 controls.
Bowen et al. (2011) used a targeted array to capture exons and promoter
sequences from an 8.6-Mb linked interval in 16 participants from 11
metachondromatosis families, and sequenced the captured DNA using
high-throughput parallel sequencing technologies. They identified
heterozygous putative loss-of-function mutations in the PTPN11 gene in 4
of the 11 families (176876.0028-176876.0031). Sanger sequence analysis
of PTPN11 coding regions in the 7 remaining families and in 6 additional
metachondromatosis families identified novel heterozygous mutations in 4
families (176876.0032-176876.0035). Copy number analysis of sequencing
reads from a second targeted capture that included the entire PTPN11
gene identified an metachondromatosis patient with a 15-kb deletion
spanning exon 7 of PTPN11 (176876.0036). In total, of 17
metachondromatosis families, Bowen et al. (2011) identified mutations in
11 (5 frameshift, 2 nonsense, 3 splice site, and 1 large deletion). Each
family had a different mutation, and the mutations were scattered across
the gene. Microdissected metachondromatosis lesions from 2 patients with
PTPN11 mutations demonstrated loss of heterozygosity for the wildtype
allele. Bowen et al. (2011) suggested that metachondromatosis may be
genetically heterogeneous because 1 familial and 5 sporadically
occurring cases lacked obvious disease-causing PTPN11 mutations.
*FIELD* SA
De la Cruz and Garcia-Castro (1976); Giedion et al. (1975)
*FIELD* RF
1. Bassett, G. S.; Cowell, H. R.: Metachondromatosis: report of four
cases. J. Bone Joint Surg. Am. 67: 811-814, 1985.
2. Bowen, M. E.; Boyden, E. D.; Holm, I. A.; Campos-Xavier, B.; Bonafe,
L.; Superti-Furga, A.; Ikegawa, S.; Cormier-Daire, V.; Bovee, J. V.;
Pansuriya, T. C.; de Sousa, S. B.; Savarirayan, R.; and 16 others
: Loss-of-function mutations in PTPN11 cause metachondromatosis, but
not Ollier disease or Maffucci syndrome. PLoS Genet. 7: e1002050,
2011. Note: Electronic Article.
3. De la Cruz, J.; Garcia-Castro, J. M.: Metachondromatosis: a diagnostic
dilemma: apropos of studies in a Puerto Rican family. Bol. Assoc.
Med. PR 68: 340-344, 1976.
4. Dorst, J. P.: Personal Communication. Baltimore, Md. 6/14/1983.
5. Giedion, A.; Kesztler, R.; Muggiasca, F.: The widened spectrum
of multiple cartilaginous exostosis (MCE). Pediat. Radiol. 3: 93-100,
1975.
6. Kennedy, L. A.: Metachondromatosis. Radiology 148: 117-118,
1983.
7. Lachman, R. S.; Cohen, A.; Hollister, D. W.; Rimoin, D. L.: Metachondromatosis. Birth
Defects Orig. Art. Ser. X(9): 171-178, 1974.
8. Maroteaux, P.: La metachondromatose. Z. Kinderheilk. 109: 246-261,
1971.
9. Sobreira, N. L. M.; Cirulli, E. T.; Avramopoulos, D.; Wohler, E.;
Oswald, G. L.; Stevens, E. L.; Ge, D.; Shianna, K. V.; Smith, J. P.;
Maia, J. M.; Gumbs, C. E.; Pevsner, J.; Thomas, G.; Valle, D.; Hoover-Fong,
J. E.; Goldstein, D. B.: Whole-genome sequencing of a single proband
together with linkage analysis identifies a mendelian disease gene. PLoS
Genet. 6: e1000991, 2010. Note: Electronic Article.
10. Vanek, V. J.: Metachondromatose: 3 Beobachtungen mit erblichen
Vorkommen. Beitr. Orthop. Traumatol. 29: 103-107, 1982.
*FIELD* CS
Skel:
Multiple exostoses, esp. digits;
Multiple enchondromatosis
Joints:
No joint deformity, or subluxation
Misc:
Exostoses point toward nearby joint;
Exostoses may resolve spontaneously;
No shortening or bowing of long bones
Radiology:
Striations in metaphyses of long bones and iliac crests
Inheritance:
Autosomal dominant
*FIELD* CN
Nara Sobreira - updated: 5/15/2012
Marla J. F. O'Neill - updated: 6/28/2010
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 05/25/2012
carol: 5/15/2012
terry: 1/13/2011
carol: 6/28/2010
terry: 6/28/2010
carol: 9/2/2009
mimadm: 11/6/1994
warfield: 4/12/1994
supermim: 3/16/1992
carol: 3/3/1992
supermim: 3/20/1990
ddp: 10/27/1989
MIM
163950
*RECORD*
*FIELD* NO
163950
*FIELD* TI
#163950 NOONAN SYNDROME 1; NS1
;;NOONAN SYNDROME;;
MALE TURNER SYNDROME;;
FEMALE PSEUDO-TURNER SYNDROME;;
read moreTURNER PHENOTYPE WITH NORMAL KARYOTYPE
PTERYGIUM COLLI SYNDROME, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because Noonan syndrome-1
(NS1) is caused by heterozygous mutation in the PTPN11 gene (176876) on
chromosome 12q24.1.
DESCRIPTION
Noonan syndrome (NS) is an autosomal dominant disorder characterized by
short stature, facial dysmorphism, and a wide spectrum of congenital
heart defects. The distinctive facial features consist of a broad
forehead, hypertelorism, downslanting palpebral fissures, a high-arched
palate, and low-set, posteriorly rotated ears. Cardiac involvement is
present in up to 90% of patients. Pulmonic stenosis and hypertrophic
cardiomyopathy are the most common forms of cardiac disease, but a
variety of other lesions are also observed. Additional relatively
frequent features include multiple skeletal defects (chest and spine
deformities), webbed neck, mental retardation, cryptorchidism, and
bleeding diathesis (summary by Tartaglia et al., 2002).
- Genetic Heterogeneity of Noonan Syndrome
See also NS3 (609942), caused by mutation in the KRAS gene (190070); NS4
(610733), caused by mutation in the SOS1 gene (182530); NS5 (611553),
caused by mutation in the RAF1 gene (164760); NS6 (613224), caused by
mutation in the NRAS gene (164790); NS7 (613706), caused by mutation in
the BRAF gene (164757); and NS8 (615355), caused by mutation in the RIT1
gene (609591).
See also NS2 (605275) for a possible autosomal recessive form of NS;
Noonan syndrome-like disorder with loose anagen hair (NSLH; 607721),
caused by mutation in the SHOC2 gene (602775); and Noonan syndrome-like
disorder with or without juvenile myelomonocytic leukemia (NSLL;
613563), caused by mutation in the CBL gene (165360).
Mutations in the neurofibromin gene (NF1; 613113), which is the site of
mutations causing classic neurofibromatosis type I (NF1; 162200), have
been found in neurofibromatosis-Noonan syndrome (NFNS; 601321).
CLINICAL FEATURES
The disorder now known as Noonan syndrome bears similarities to the
disorder described by Turner (1938) and shown by Ford et al. (1959) to
have its basis in a 45,X chromosomal aberration called Turner syndrome,
Ullrich-Turner syndrome (Wiedemann and Glatzl, 1991), or monosomy X.
Migeon and Whitehouse (1967) described 2 families, each with 2 sibs with
somatic features of the Turner phenotype. In 1 family, 2 brothers had
webbing of the neck, coarctation of the aorta, and cryptorchidism. In
the second, a brother and sister were affected.
Diekmann et al. (1967) described 2 brothers and a sister, with normal
and unrelated parents, who had somatic characteristics of the Turner
syndrome, particularly pterygium colli and deformed sternum, and had
myocardiopathy leading to death at ages 12 and 10 years in 2 of them.
Noonan (1968) reported 19 patients of whom 17 had pulmonary stenosis and
2 had patent ductus arteriosus (see 607411). Twelve were males and 7
were females. Deformity of the sternum with precocious closure of
sutures was a frequent feature.
Among 95 male patients with pulmonary stenosis, Celermajer et al. (1968)
found the Turner phenotype in 8. In 5 of these, karyotyping was
performed. In 4 the chromosomes were normal; in 1, an extra acrocentric
chromosome was present.
Kaplan et al. (1968) described 2 brothers with Noonan syndrome and
elevated alkaline phosphatase levels, one of whom also had malignant
schwannoma of the forearm.
Nora and Sinha (1968) observed mother-to-offspring transmission in 3
families; in 1 family, transmission was through 3 generations.
Baird and De Jong (1972) described 7 cases in 3 generations. One
affected woman had 5 affected children (out of 6) with 2 different
husbands. Seizures and anomalous upper lateral incisors may have been
coincidental.
Simpson et al. (1969) reported experiences suggesting that rubella
embryopathy may result in the Turner phenotype, thereby accounting for
either the male Turner syndrome or the female pseudo-Turner syndrome. A
particularly convincing pedigree for autosomal dominant inheritance was
reported by Bolton et al. (1974), who found the condition in a man and 4
sons (in a sibship of 10). Four of the 5 affected persons had pulmonic
stenosis. Father-to-son transmission was reported by Qazi et al. (1974).
Koretzky et al. (1969) described an unusual type of pulmonary valvular
dysplasia which showed a familial tendency with either affected parent
and offspring or affected sibs. Although some relatives had pulmonary
valvular stenosis of the standard dome-shaped variety, the valvular
dysplasia in others was characterized by the presence of three distinct
cusps and no commissural fusion. The obstructive mechanism was related
to markedly thickened, immobile cusps, with disorganized myxomatous
tissue. Other features were retarded growth, abnormal facies (triangular
face, hypertelorism, low-set ears and ptosis of the eyelids), absence of
ejection click, and unusually marked right axis deviation by
electrocardiogram. It now seems clear that the patients of Koretzky et
al. (1969) had Noonan syndrome.
Mendez and Opitz (1985) stated that the Watson syndrome (193520) and the
LEOPARD syndrome (151100) 'are essentially indistinguishable from the
Noonan syndrome.' Witt et al. (1987) reviewed the occurrence of
lymphedema in Noonan syndrome. When it does occur, it opens the
possibility of prenatal diagnosis by imaging methods or by AFP level.
Noonan syndrome was one of the causes found for posterior cervical
hygroma in a series of previable fetuses studied by Kalousek and Seller
(1987). The authors found, furthermore, that 45,X Turner syndrome lethal
in the fetal period showed a constant association of 3 defects,
posterior cervical cystic hygroma, generalized subcutaneous edema, and
preductal aortic coarctation.
Evans et al. (1991) found a large cutaneous lymphangioma of the right
cheek and amegakaryocytic thrombocytopenia in a male infant with Noonan
syndrome.
Donnenfeld et al. (1991) presented a case of Noonan syndrome in which
posterior nuchal cystic hygroma was diagnosed at 13 to 14 weeks of
gestation by ultrasonography. The hygroma had regressed by the time of
birth leaving nuchal skin fold redundancy and pterygium colli.
On the basis of studies of genital tract function in 11 adult males with
Noonan syndrome, Elsawi et al. (1994) concluded that bilateral
testicular maldescent was a main factor in contributing to impairment of
fertility. Four of the 11 men had fathered children.
Lee et al. (1992) reviewed the ophthalmologic and orthoptic findings in
58 patients with Noonan syndrome. External features were hypertelorism
(74%), downward sloping palpebral apertures (38%), epicanthal folds
(39%), and ptosis (48%). Orthoptic examination revealed strabismus in
48%, refractive errors in 61%, amblyopia in 33%, and nystagmus in 9% of
cases. Anterior segment changes, found in 63% of patients, included
prominent corneal nerves (46%), anterior stromal dystrophy (4%),
cataracts (8%), and panuveitis (2%). Fundal changes occurred in 20% of
patients and included optic nerve head drusen, optic disc hypoplasia,
colobomas, and myelinated nerve fiber layer. Lee et al. (1992)
recommended early ophthalmic examination of children with Noonan
syndrome.
Allanson et al. (1985) studied the changes in facial appearance with
age. They pointed out that the manifestations may be subtle in adults.
Ranke et al. (1988) analyzed the clinical features of 144 patients from
2 West German centers. The size at birth was normal in both sexes. In
both males and females, the mean height followed along the 3rd
percentile until puberty, but decreased transiently due to an
approximately 2-year delay in onset of puberty. Final height approaches
the lower limits of normal at the end of the second decade of life. The
mean adult height was 162.5 cm in males and 152.7 cm in females,
respectively. Allanson (1987) provided a useful review. The fetal
primidone syndrome, occurring in the offspring of mothers taking this
anticonvulsant, closely simulates the Noonan syndrome.
Baraitser and Patton (1986) reported 4 unrelated children (2 boys, 2
girls) with a Noonan-like syndrome associated with sparse hair as a
conspicuous feature. See 115150.
Leichtman (1996) reported a family suggesting that cardiofaciocutaneous
syndrome (CFC; 115150) is a variable expression of Noonan syndrome. He
described a 4-year-old girl who had all of the manifestations of CFC
syndrome (characteristic facial and cardiac anomalies, developmental
delay, hypotrichosis, eczematic eruption with resistance to treatment),
whose mother had typical characteristics of Noonan syndrome. Lorenzetti
and Fryns (1996) reported a 13-year-old boy with Noonan syndrome and
retinitis pigmentosa. Because similar eye defects are found in CFC
syndrome, the authors suggested that CFC and Noonan syndromes might be
variable manifestations of the same entity. However, Neri and Zollino
(1996) noted distinctions between the patient reported by Lorenzetti and
Fryns (1996) and CFC syndrome, and stated that similarity of eye defects
is not enough to conclude that CFC and Noonan syndromes are the same
condition.
Early feeding difficulties are common in Noonan syndrome but often go
unrecognized. Shah et al. (1999) studied a consecutive series of
children with Noonan syndrome whose diagnosis had been confirmed by a
clinical geneticist. Sixteen had poor feeding (poor suck or refusal to
take solids or liquids) and symptoms of gastrointestinal dysfunction
(vomiting, constipation, abdominal pain, and bloating). All 16 had
required nasogastric tube feeding. Seven of the 25 had foregut
dysmotility and gastroesophageal reflux. In 4 of these,
electrogastrography and antroduodenal manometry demonstrated immature
gastric motility reminiscent of that of a preterm infant of 32 to 35
weeks' gestation. Other children had less severe forms of gastric
dysmotility. The authors highlighted the importance of recognizing this
common, treatable feature of Noonan syndrome.
Lemire (2002) described a father, son, and daughter with an apparently
autosomal dominant disorder characterized by craniofacial anomalies,
coarctation of the aorta, hypertrophic cardiomyopathy, and other
structural heart defects with normal psychomotor development. Some
clinical features such as webbed neck, low-set ears, low posterior
hairline, and widely spaced nipples suggested Noonan syndrome.
Alternatively, a previously unrecognized disorder was considered. The
paternal age at the father's birth was 50 years. The father presented at
age 13 years when postductal coarctation of the aorta was discovered
during routine physical examination. Preoperative evaluation showed
hypertrophied interventricular septum with pulmonic stenosis and
bicuspid aortic valve in addition to the aortic coarctation. At age 22
years, echocardiogram showed marked systolic thickening of
interventricular septum and posterior wall of the left ventricle and
concentric left ventricular hypertrophy. He later developed atrial
flutter and congestive heart failure. His son was recognized at birth to
have 2 small ventricular septal defects, mildly hypoplastic aortic arch,
and coarctation of the aorta. The coarctation was repaired at age 14
days and bilateral inguinal hernias at age 5 weeks. At age 9 months, he
was found to have congestive heart failure due to a restrictive
cardiomyopathy. At age 10 months, studies confirmed the presence of
spongy myocardium with much impaired diastolic function. He died of
early acute graft failure at age 14 months after heart transplantation.
Autopsy showed restrictive cardiomyopathy with generalized myocardium
hypertrophy. The daughter was found at birth to have a small ventricular
septal defect, small patent ductus arteriosus, aneurysm of the atrial
septum, and coarctation of the aorta. Cardiomyopathy was suspected on
the basis of excessive thickening of the lower two-thirds of the
interventricular septum and of the free wall of the right ventricle.
Coarctation of the aorta was repaired surgically at age 19 days. At age
10.5 months, she was noted to have plagiocephaly, facial asymmetry with
left side smaller than the right, webbed neck, asymmetric chest with
widely spaced nipples, and edema of the dorsum of the feet. At age 2
years, bicuspid aortic valve and diffuse concentric hypertrophy of the
left ventricle were noted.
Juvenile myelomonocytic leukemia (JMML; 607785) has been observed in
some cases of Noonan syndrome (Bader-Meunier et al., 1997; Fukuda et
al., 1997; Choong et al., 1999).
Holder-Espinasse and Winter (2003) described a 6-year-old girl with
clinical features of Noonan syndrome, short stature, and headache who
was noted to have Arnold-Chiari malformation (207950) on MRI. They cited
3 previous reports of Noonan syndrome and Chiari malformation and/or
syringomelia (Ball and Peiris, 1982; Gabrielli et al., 1990; Colli et
al., 2001). Holder-Espinasse and Winter (2003) concluded that Chiari
malformation should be considered part of the Noonan syndrome spectrum
and that brain and cervical spine MRI should be required in patients
with Noonan syndrome, particularly if headaches or neurologic symptoms
are present.
For a comprehensive review of Turner syndrome, including clinical
management, see Ranke and Saenger (2001).
Kondoh et al. (2003) described a transient leukemoid reaction and an
apparently spontaneously regressing neuroblastoma in a 3-month-old
Japanese patient with Noonan syndrome and a de novo missense mutation in
the PTPN11 gene (176876.0007).
Noonan et al. (2003) reported their findings in 73 adults over 21 years
of age with Noonan syndrome. In 30%, adult height was in the normal
range between the 10th and 90th percentiles. More than half of the
females and nearly 40% of males had an adult height below the third
percentile. The presence or severity of heart disease was not a factor,
and none of the adults with normal height had been treated with growth
hormone. Serial measurements of height over many years through childhood
to adulthood were available in only a few patients, but their pattern of
growth suggested that catch up may occur in late adolescence. The
possible benefit of growth hormone therapy could not be evaluated.
Croonen et al. (2008) evaluated ECG findings and cardiographic
abnormalities in 84 patients with Noonan syndrome, 54 (67%) of whom were
positive for a mutation in the PTPN11 gene. As reported previously,
pulmonary stenosis was the most common cardiac abnormality, followed by
atrial septal defect and hypertrophic cardiomyopathy. ECG showed at
least 1 characteristic finding in 50% of cases, including left axis
deviation in 38 (45%), small R waves in the left precordial leads in 20
(24%), and an abnormal Q wave in 5 (6%) Noonan patients; however, these
ECG findings were not associated with a PTPN11 mutation or with a
specific cardiac anomaly.
Among 40 Italian patients with Noonan syndrome, Ferrero et al. (2008)
found short stature in 92%, congenital heart defect in 82.5%, isolated
pulmonic stenosis in 60.6%, and hypertrophic obstructive cardiomyopathy
in 12.2%. Prenatal anomalies were observed in 25% of cases, with
polyhydramnios being the most common. PTPN11 mutations were detected in
11 sporadic patients and 1 family, totaling 12 (31.5%) of 38 cases. One
patient without a detectable mutation had a Chiari I malformation with
seizures. Another of the remaining patients had a mutation in the SOS1
gene.
OTHER FEATURES
- Giant Cell Lesions
Some patients with Noonan syndrome develop multiple giant cell lesions
of the jaw or other bony or soft tissues, which are classified as
pigmented villonodular synovitis (PVNS) when occurring in the jaw or
joints. Early reports described this as a separate disorder (Leszczynski
et al., 1975; Lindenbaum and Hunt, 1977; Wagner et al., 1981); however,
it is now considered part of the phenotypic spectrum of Noonan syndrome
(Tartaglia et al., 2010).
Cohen et al. (1974) described a patient with short stature, ocular
hypertelorism, prominent posteriorly angulated ears, short webbed neck,
cubitus valgus, pulmonic stenosis, multiple lentigines, and giant cell
lesions of both bone and soft tissue. Cohen (1982) presented a
photographic montage of the patient. Cohen and Gorlin (1991) reviewed
further known cases to a total of 14. Chuong et al. (1986) studied
central giant cell lesions of the jaw in 17 patients and noted that 2 of
these occurred in patients with Noonan syndrome.
Ucar et al. (1998) described a patient with Noonan syndrome and PVNS. As
indicated by the photographs provided, the patient showed facies and
sternal configuration typical of Noonan syndrome. Cubitus valgus,
pulmonary valve stenosis, and patent foramen ovale, as well as
cryptorchidism, were also present. A central giant cell granuloma was
found originating from the lateral wall of the right maxillary sinus and
caused the presenting complaint of proptosis of the right eye. (Giant
cell granulomas in the head and neck region are called central when they
occur in bone and peripheral when they occur in gingiva or alveolar
mucosa.) In this family the patient's father also had the phenotype of
Noonan syndrome, suggesting autosomal dominant inheritance.
Bertola et al. (2001) described a family with typical clinical findings
of Noonan syndrome associated with giant cell lesions in maxilla and
mandible. The authors raised the possibility that Noonan syndrome and
Noonan syndrome-like disorder with multiple giant cell lesions might be
allelic disorders. This was indeed demonstrated to be the case by
Tartaglia et al. (2002), who found a mutation in the PTPN11 gene
(176876.0004), which is the site of mutation in about half of unrelated
individuals with sporadic or familial Noonan syndrome.
- Hematologic Abnormalities
Thrombocytopenia occurs in some cases of the Noonan syndrome (Goldstein,
1979). Partial deficiency of factor XI was described by Kitchens and
Alexander (1983). Out of 9 patients with Noonan syndrome, de Haan et al.
(1988) found 4 with partial deficiency of factor XI (30-65% of normal).
They reviewed the other reports of bleeding tendency associated with
thrombocytopenia or with abnormal platelet function.
Witt et al. (1988) described bleeding diathesis in 19 patients with
Noonan syndrome. Several different defects were identified in the
coagulation and platelet systems, occurring singly or in combination;
for example, 2 patients had factor XI deficiency, 3 had presumptive von
Willebrand disease, and 1 had thrombocytopenia. In 5 of the patients an
unusually pungent odor of urine and sweat was noted by parents. One of
these patients was reported by Humbert et al. (1970) as a case of
trimethylaminuria (136131) and another patient was suspected of having
this condition. Sharland et al. (1990) also described a variety of
coagulation factor deficiencies. The most common abnormality was a
partial factor XI deficiency in the heterozygote range, found in 21 of
31 patients. Of 72 patients studied (37 male, 35 female, mean age 11.4
years) by Sharland et al. (1992), 47 (65%) had a history of abnormal
bruising or bleeding. In 29 patients (40%), prolonged activated partial
thromboplastin time was found. In 36 patients (50%) specific
abnormalities were found in the intrinsic pathway of coagulation, i.e.,
partial deficiency of factor XI:C, XII:C, and VIII:C. Multiple
abnormalities among these 36 patients included combined deficiencies of
factors XI and XII (4 patients), of factors XI and VIII (4 patients),
and of factors VIII, XI, and XII (1 patient). In 5 families, similar
coagulation-factor deficiencies were present in first-degree relatives.
Sharland et al. (1992) suggested that because of the involvement of
several factors, either singly or in combination, there are likely to be
regulatory factors that control the intrinsic (contact activation)
system; that these factors are under chromosomal genetic control; and
that abnormalities of this regulation occur in Noonan syndrome.
Derbent et al. (2011) examined the hematologic profile of 30 patients
with Noonan syndrome, of whom 11 (36.7%) had proven PTPN11 mutations.
There were no statistically significant differences between the
mutation-positive and mutation-negative groups with respect to any of
the hematology results or the presence of moderate mental retardation,
pulmonic stenosis, chest deformity, genitourinary anomalies, or
sensorineural hearing loss. However, short stature and mild mental
retardation were more common in PTPN11 carriers. Only 1 of the patients
had a history of easy bruising; however, his hematologic and coagulation
tests were normal. None of the other patients had clinical coagulation
problems. Noonan syndrome patients had significantly lower values for
platelet count, activity of factors XI, XII, and protein C (612283)
compared to controls. Patient values for PT, aPTT, INR, and bleeding
time were also statistically different from the corresponding control
findings, but the absence of clinical problems rendered the tests
diagnostically inconclusive. Two patients had low protein C activity
(about 50% of normal), but neither had a thrombotic event or any
complication during about 3 years of follow-up. Derbent et al. (2011)
concluded that patients with Noonan syndrome should have a thorough
coagulation evaluation, but complications related to coagulation are
unlikely and extensive testing is unnecessary.
INHERITANCE
Noonan syndrome is inherited in an autosomal dominant pattern (Tartaglia
et al., 2010).
Wendt et al. (1986) reported a man with polyarticular pigmented
villonodular synovitis who had an affected son and daughter. Dunlap et
al. (1989) made reference to the fact that the father of one of his
cases was affected with Noonan syndrome and PVNS.
Elalaoui et al. (2010) reported 2 sibs, born of unrelated Moroccan
parents, with Noonan syndrome resulting from the same heterozygous
mutation in the PTPN11 gene (176876.0003). Both had characteristic
features of Noonan syndrome, including pulmonic stenosis and facial
anomalies, but neither parent showed any signs of the disorder.
Molecular analysis did not detect the mutation in multiple tissues of
either parent, excluding somatic mosaicism. Both affected children
inherited the same haplotypes from their mother and father, whereas
their unaffected brother inherited distinct haplotypes. This suggested
that a common somatic germ cell event in 1 of the parents was
responsible for the mutation, likely the father as he was 45 years of
age, but the parental origin could not be definitively determined.
Elalaoui et al. (2010) suggested an empirical recurrence rate of less
than 1% in this family.
POPULATION GENETICS
Noonan syndrome has an estimated incidence of 1 in 1,000 to 2,500 live
births (Tartaglia et al., 2001).
MAPPING
By means of a genomewide linkage analysis in a large Dutch kindred with
autosomal dominant Noonan syndrome, Jamieson et al. (1994) localized the
gene to chromosome 12; maximum lod = 4.04 at theta = 0.0. Linkage
analysis using chromosome 12 markers in 20 smaller, 2-generation
families gave a maximum lod of 2.89 at theta = 0.07, but haplotype
analysis showed nonlinkage in 1 family. These data suggested that a gene
for Noonan syndrome is located in the 12q22-qter region between markers
D12S84 and D12S366. Clinical studies in this kindred were reported by
van der Burgt et al. (1994).
Brady et al. (1997) further analyzed the 3-generation Dutch family
studied by Jamieson et al. (1994) using newly isolated CA-repeat markers
derived from the interval between D12S84 and D12S366. In this way they
were able to reduce the localization to an interval bounded by markers
D12S105 and NOS1 (163731), which has been mapped to 12q24.2-q24.31.
Legius et al. (1998) performed linkage analysis in a 4-generation
Belgian family with Noonan syndrome in some individuals and CFC syndrome
in others. Clinical and linkage data in this family indicated that the 2
syndromes result from variable expression of the same genetic defect.
They found a maximum lod score of 4.43 at zero recombination for marker
D12S84 in 12q24. A crossover in this pedigree narrowed the candidate
gene region to a 5-cM interval between D12S84 and D12S1341. A remarkable
feature of the family studied by Legius et al. (1998) was the presence
of 3 dizygotic twins in the offspring of 2 affected females. A dizygotic
twin pair was observed in the offspring of an affected female in the
family in which linkage was studied by Jamieson et al. (1994). It is
possible that an increased frequency of dizygotic twinning is associated
with NS1/CFC linked to 12q24. The fragile X syndrome (300624) is another
mendelian disorder with a possibly increased frequency of dizygotic
twinning (Partington et al., 1996; Schwartz et al., 1994).
- Exclusion Studies
Using a number of probes at the neurofibromatosis type I locus in the
study of 11 families with Noonan syndrome in 2 or 3 generations,
Sharland et al. (1992) excluded proximal 17q as the location of the
gene. Studying six 2-generation families with classic Noonan syndrome,
Flintoff et al. (1993) could find no evidence of linkage of this
disorder to NF1 on 17q or to NF2 (101000) on 22q.
In a study of candidate genes, Ion et al. (2000) excluded the genes EPS8
(600206) and DCN (125255) from the critical region by FISH analysis.
They also excluded the MYL2 (160781) and RPL6 (603703) genes by mutation
analysis.
CYTOGENETICS
Robin et al. (1995) described 6 patients with Noonan syndrome who
underwent molecular evaluation for submicroscopic deletion of chromosome
22q11. None of these patients presented with conotruncal heart defects.
Evidence for 22q11 hemizygosity was demonstrated in only 1 patient. This
patient had Noonan-like manifestations without clinical manifestations
of DiGeorge (188400) or velocardiofacial (192430) syndromes. Digilio et
al. (1996) studied 4 patients with Noonan syndrome and tetralogy of
Fallot. Chromosome analysis was normal in all 4 patients. DNA analysis
showed no hemizygosity for the 22q11 region in any of the patients.
- Duplication of Chromosome 12q24.13
Shchelochkov et al. (2008) described a 3-year-old girl with clinical
features consistent with Noonan syndrome. She presented with
postnatal-onset failure to thrive, microcephaly, velopalatal
incompetence, pectus excavatum, aortic coarctation, and atrial and
ventricular septal defects. Facial features included ptosis,
hypertelorism, epicanthal folds, cupped simple ears, and wide mouth with
downturned corners. Speech and fine and gross motor development were at
the level of a 12- to 18-month-old child, atypical for a child with
Noonan syndrome. Array CGH showed an interstitial 10-Mb duplication,
12q24.11-q24.23, that includes the genes PTPN11 (176876), TBX5 (601620),
and TBX3 (601621). This was confirmed by FISH analysis and chromosome
analysis. Sequencing of PTPN11, KRAS (190070), SOS1 (182530), and the
coding region of RAF1 (164760) did not reveal any pathogenic mutations.
Shchelochkov et al. (2008) proposed that duplications of the region
containing PTPN11 may result in a Noonan syndrome phenotype and may
account for the basis of Noonan syndrome in some of the 15 to 30% of
patients for whom no mutations can be detected by sequencing of
components of the RAS/MAPK signaling pathway.
Graham et al. (2009) reported another patient with Noonan syndrome
caused by an 8.98-Mb duplication on chromosome 12q24.13 encompassing the
PTPN11 gene, which was confirmed by FISH analysis. However, duplications
were not observed in a screening of more than 250 Noonan syndrome cases
without mutations in known disease-causing genes. Changes affecting the
3-prime untranslated region of the PTPN11 transcript were also not found
in 36 patients without disease-causing mutations. In contrast to
Shchelochkov et al. (2008), Graham et al. (2009) concluded that
duplication of PTPN11 represents an uncommon cause of Noonan syndrome.
However, the rare observation of NS in individuals with duplications
involving the PTPN11 locus suggested that increased dosage of this gene
may have dysregulating effects on intracellular signaling.
DIAGNOSIS
Butler et al. (2000) used metacarpophalangeal pattern profile (MCPP)
analysis to evaluate 15 individuals with Noonan syndrome. Discriminant
analysis resulted in the correct classification of 93% of Noonan
syndrome patients based on 2 MCPP variables (metacarpal 1 and middle
phalanx 3). The authors suggested that MCPP analysis may be useful as a
diagnostic tool in screening subjects for Noonan syndrome.
CLINICAL MANAGEMENT
MacFarlane et al. (2001) reported growth data from the first 3 years of
a multicenter study examining the efficacy and safety of recombinant
human GH in 23 children with Noonan syndrome. Sixteen male and 7 female
patients (aged 9.3 +/- 2.6 years at onset of GH therapy, mean +/- SD;
range 4.8-13.7) were each assessed at 1, 2, and 3 years after starting
treatment. Comparisons were made with a group of 8 subjects (6 males and
2 females, aged 9.0 +/- 4.1 years; range 4.1-14.8) with Noonan syndrome
and not treated with recombinant GH, and measured over the same period.
All treated subjects underwent annual cardiac assessment. Height SD
score increased from -2.7 +/- 0.4 at the start of GH therapy to -1.9 +/-
0.9 three years later. This corresponded to an increase in height from
116.1 +/- 13.2 to 137.3 +/- 14.0 cm. Height velocity increased from 4.4
+/- 1.7 cm/year in the year before treatment to 8.4 +/- 1.7, 6.2 +/-
1.7, and 5.8 +/- 1.8 during the first, second, and third years of GH
treatment, respectively. Height acceleration was not significant during
the second or third years when pubertal subjects were excluded. The
authors concluded that the increase in growth rate in Noonan syndrome
resulting from 1 year of GH therapy seems to be maintained during the
second year, although height velocity shows a less significant increase
over pretherapy values. Possible abnormal anabolic effects of
recombinant GH on myocardial thickness were not confirmed, and no
treated patient developed features of hypertrophic cardiomyopathy.
Kirk et al. (2001) presented data on 66 Noonan syndrome patients (54
males) treated with growth hormone. Treatment improved height velocity
in the short term, but longer-term therapy resulted in a waning of
effect. The study indicated that final height is not substantially
improved in most patients.
From a study of 14 children with Noonan syndrome who were treated with
human growth hormone, half of whom had a missense mutation in the PTPN11
gene, Ferreira et al. (2005) found that those with a PTPN11 mutation had
a lower increase in IGF-I (147440) levels during treatment and a
significantly lower gain in height SD score after 3 years of treatment
compared with those without mutations.
Binder et al. (2005) compared GH secretion and IGF-I/IGFBP3 (146732)
levels of the PTPN11 mutation-positive (mut+ group) versus the
mutation-negative individuals (mut- group). IGF-I and IGFBP3 levels were
significantly lower in the mut+ group. In contrast, GH levels showed a
tendency to be higher in the mut+ group during spontaneous secretion at
night and arginine stimulation. The mean change in height SDS after 1
year of rhGH therapy was +0.66 + 0.21 in the mut+ group (8 individuals),
but +1.26 + 0.36 in the mut- group (3 individuals; p = 0.007). The
authors concluded that PTPN11 mutations in Noonan syndrome cause mild GH
resistance by a post-receptor signaling defect, which seems to be
partially compensated for by elevated GH secretion.
MOLECULAR GENETICS
In more than 50% of patients with Noonan syndrome, Tartaglia et al.
(2001) identified mutations in the PTPN11 gene (see, e.g.,
176876.0001-176876.0003). All the PTPN11 missense mutations were
clustered in the interacting portions of the amino N-SH2 (Src homology
2) domain and the phosphotyrosine phosphatase (PTP) domains, which are
involved in switching the protein between its inactive and active
conformations. An energetics-based structural analysis of 2 N-SH2
mutants indicated that in these cases there may be a significant shift
of the equilibrium favoring the active conformation. The findings
suggested that gain-of-function changes resulting in excessive SHP2
activity underlie the pathogenesis of Noonan syndrome.
After germline mutations in PTPN11 (176876) were demonstrated in the
Noonan syndrome, Tartaglia et al. (2003) investigated defects in PTPN11
in myeloid disorders including cases of juvenile myelomonocytic leukemia
(JMML; 607785) in children with Noonan syndrome. Specific mutations in
PTPN11 associated with isolated JMML occurred as somatic changes and had
never been observed as germline defects, leading Tartaglia et al. (2003)
to speculate that these molecular defects are stronger and associated
with embryonic lethality. Conversely, most mutations in PTPN11
associated with Noonan syndrome, which were sufficient to perturb
developmental processes, were not fully leukemogenic, suggesting a
milder gain-of-function effect.
In 10 affected members from a large 4-generation Belgian family with
Noonan syndrome and some features suggestive of CFC syndrome, Schollen
et al. (2003) identified a missense mutation in the PTPN11 gene
(176876.0018). The mutation was not found in 7 unaffected relatives or 3
spouses.
Musante et al. (2003) screened the PTPN11 gene for mutations in 96
familial or sporadic Noonan syndrome patients and identified 15 missense
mutations in 32 patients (33%). No obvious clinical differences were
detected between subgroups of patients with mutations in different
PTPN11 domains. Analysis of the clinical features of their patients
revealed that several patients with facial abnormalities thought to be
pathognomonic for NS did not have a mutation in the PTPN11 gene. Widely
varying phenotypes among the 64 patients without PTPN11 mutations
indicated further genetic heterogeneity. Musante et al. (2003) also
screened 5 sporadic patients with CFC syndrome and found no mutations in
the PTPN11 gene.
Bertola et al. (2004) described a young woman with clinical features of
Noonan syndrome but with some characteristics of CFC as well, including
prominent ectodermal involvement (sparse and very coarse hair, and
sparse eyebrows and eyelashes), developmental delay, and mental
retardation. They identified a T411M mutation in the PTPN11 gene
(176876.0019); the same mutation was found in her mother and older
sister, not initially considered to be affected but who had subtle
clinical findings compatible with the diagnosis of Noonan syndrome. The
mother had 5 miscarriages, 2 of them twinning pregnancies. Bertola et
al. (2004) suggested that all first-degree relatives of patients with
confirmed Noonan syndrome, even those with no signs of the disorder, be
screened for PTPN11 mutations in order to provide accurate assessments
of recurrence risk.
Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical
assessment in 45 Japanese patients with Noonan syndrome. Sequence
analysis of the coding exons 1 through 15 of PTPN11 revealed a novel
3-bp deletion (176876.0024) and 10 recurrent missense mutations in 18
patients. The authors estimated that PTPN11 mutations account for
approximately 40% of Japanese Noonan syndrome patients.
Jongmans et al. (2005) performed mutation analysis of the PTPN11 gene in
170 Noonan syndrome patients and identified a mutation in 76 (45%) of
them. They described the distribution of these mutations, as well as
genotype-phenotype relationships. The usefulness of the Noonan syndrome
scoring system developed by van der Burgt et al. (1994) was
demonstrated; when physicians based their diagnosis on the scoring
system, the percentage of mutation-positive patients was higher.
Mutations in the KRAS gene (190070) can also cause Noonan syndrome (NS3;
609942). One patient with a T58I mutation (190070.0011) also had a
myeloproliferative disorder resembling juvenile myelomonocytic leukemia
(JMML) (Schubbert et al., 2006).
Tartaglia et al. (2006) proposed a model that splits NS- and
leukemia-associated PTPN11 mutations in the 2 major classes of
activating lesions with differential perturbing effects on development
and hematopoiesis. The results documented a strict correlation between
the identity of the lesion and disease, and demonstrated that
NS-causative mutations have less potency for promoting SHP2 gain of
function than do leukemia-associated ones.
Roberts et al. (2007) and Tartaglia et al. (2007) investigated sizable
groups of patients with Noonan syndrome but no mutation in PTPN11, which
accounts for approximately 50% of such cases. They found that many had
missense mutations in the SOS1 gene (182530) and that the SOS1-positive
case patients represented approximately 20% of cases of Noonan syndrome.
The phenotype of Noonan syndrome caused by SOS1 mutation, while within
the Noonan syndrome spectrum, appears to be distinctive (see NS4,
610733).
Kontaridis et al. (2006) examined the enzymatic properties of mutations
in PTPN11 causing LEOPARD syndrome and found that, in contrast to the
activating mutations that cause Noonan syndrome and neoplasia, LEOPARD
syndrome mutants are catalytically defective and act as
dominant-negative mutations that interfere with growth factor/ERK-MAPK
(see 176948)-mediated signaling. Kontaridis et al. (2006) concluded that
the pathogenesis of LEOPARD syndrome is distinct from that of Noonan
syndrome and suggested that these disorders should be distinguished by
mutation analysis rather than clinical presentation.
In a prospective multicenter study in 35 Noonan syndrome patients with
growth retardation, Limal et al. (2006) compared growth and hormonal
growth factors before and during recombinant human GH therapy in
patients with and without PTPN11 mutations. Sequencing of the PTPN11
coding sequence revealed 12 different heterozygous missense mutations in
20 of the 35 patients (57%). The results showed that among NS1 patients
with short stature, some neonates had birth length less than -2 SDS.
Growth of patients with mutations was reduced and responded less
efficiently to GH than that of patients without mutations. Limal et al.
(2006) concluded that the association of low IGF1 (147440) and
insulin-like growth factor-binding protein, acid-labile subunit (IGFALS;
601489) with normal IGFBP3 (146732) levels could explain growth
impairment of children with mutations and could suggest a GH resistance
by a late postreceptor signaling defect.
In a case of fetal demise at 12 weeks' gestation, Becker et al. (2007)
identified compound heterozygosity for the N308S (176876.0004) and Y63C
(176876.0008) mutations in the PTPN11 gene. The mother and father, who
exhibited facial features of Noonan syndrome and had both undergone
surgical correction of pulmonary valve stenosis, were heterozygous for
N308S and Y63C, respectively. A second pregnancy resulted in the birth
of a boy with Noonan syndrome carrying the paternal Y63C mutation.
Ferrero et al. (2008) identified PTPN11 mutations in 31.5% of 37
sporadic patients and 1 family with a clinical diagnosis of Noonan
syndrome. One of the remaining patients had a mutation in the SOS1 gene.
- Cooccurrence of NF1 and PTPN11 Mutations
Bertola et al. (2005) provided molecular evidence of the concurrence of
neurofibromatosis and Noonan syndrome in a patient with a de novo
missense mutation in the NF1 gene (613113.0043) and a mutation in the
PTPN11 gene (176876.0023) inherited from her father. The proposita was
noted to have cafe-au-lait spots at birth. Valvar and infundibular
pulmonary stenosis and aortic coarctation were diagnosed at 20 months of
age and surgically corrected at 3 years of age. As illustrated, the
patient had marked hypertelorism and proptosis as well as freckling and
cafe-au-lait spots. Lisch nodules were present. At the age of 8 years, a
pilocytic astrocytoma in the suprasellar region involving the optic
chiasm (first presenting symptomatically at 2 years of age), was
partially resected. The father, who was diagnosed with Noonan syndrome,
had downslanting palpebral fissures and prominent nasal labial folds. He
was of short stature (159 cm) and had pectus excavatum.
Electrocardiogram showed left-anterior hemiblock and complete right
bundle branch block.
Thiel et al. (2009) reported a patient with features of both
neurofibromatosis I and Noonan syndrome who was compound heterozygous
for mutations in both the NF1 (162200.0044) and PTPN11 (176876.0027)
genes. The PTPN11 mutation occurred de novo, and the NF1 mutation was
inherited from the patient's mother, who had mild features of
neurofibromatosis I, including the absence of optic gliomas. The proband
developed bilateral optic gliomas before age 2 years, suggesting an
additive effect of the 2 mutations on the Ras pathway. The proband also
had short stature, delayed development, sternal abnormalities, and
valvular pulmonary stenosis.
- Reviews
Tartaglia et al. (2010) provided a detailed review of the clinical and
molecular features of Noonan syndrome.
NOMENCLATURE
Dunlap et al. (1989) referred to Noonan syndrome with multiple giant
cells lesions as the Noonan syndrome-cherubism association. Cohen and
Gorlin (1991) recommended that it not be called Noonan syndrome,
pigmented villonodular synovitis, central giant cell granuloma, or
cherubism, because each of these is a specific diagnostic entity sui
generis and the use of such terms results in nosologic blinders that
tend to limit the workup of patients.
ANIMAL MODEL
In a mouse model of Noonan syndrome in which transgenic mice carried a
cardiomyocyte-specific gain-of-function Q79R mutation in the PTPN11 gene
(176876.0018), Nakamura et al. (2007) demonstrated that the
developmental effects of Q79R cardiac expression are stage-specific and
that ablation of subsequent ERK1/2 (see 176948) activation prevented the
development of cardiac abnormalities.
HISTORY
Cole (1980) pointed out that the blacksmith in the famous painting
'Among Those Left' by Ivan Le Lorraine Albright appears to have had
Noonan syndrome. The contour of the sternum, the low-set ears, and the
short stature are suggestive. Genetic confirmation was provided by
studies of a great-grandson with general features of the Noonan syndrome
and cardiac abnormalities consistent with that diagnosis (pulmonic
stenosis and regurgitation, abnormal architecture of the left
ventricular musculature). Opitz and Pallister (1979) reproduced the
first published illustration of the Noonan syndrome by Kobylinski
(1883), and Opitz (1985) republished the photograph of Rickey E., the
first patient with 'her' syndrome studied at the State University of
Iowa by Jacqueline A. Noonan.
*FIELD* SA
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Fisher et al. (1982); Golabi et al. (1985); Hall et al. (1982); Levy
et al. (1970); Linde et al. (1973); Miller and Motulsky (1978); Nora
et al. (1974); Pierini and Pierini (1979); Sharland et al. (1992);
Wiedemann (1991); Witt et al. (1985)
*FIELD* RF
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74. Musante, L.; Kehl, H. G.; Majewski, F.; Meinecke, P.; Schweiger,
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of mutations in PTPN11 and genotype-phenotype correlation in 96 patients
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75. Nakamura, T.; Colbert, M.; Krenz, M.; Molkentin, J. D.; Hahn,
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76. Neri, G.; Zollino, M.: More on the Noonan-CFC Controversy (Editorial) Am.
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78. Noonan, J. A.; Raaijmakers, R.; Hall, B. D.: Adult height in
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80. Nora, J. J.; Sinha, A. K.: Direct familial transmission of the
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82. Opitz, J. M.; Pallister, P. D.: Brief historical note: the concept
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84. Pierini, D. O.; Pierini, A. M.: Keratosis pilaris atrophicans
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85. Qazi, Q. H.; Arnon, R. G.; Paydar, M. H.; Mapa, H. C.: Familial
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86. Ranke, M. B.; Heidemann, P.; Knupfer, C.; Enders, H.; Schmaltz,
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2004.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature (postnatal onset);
[Other];
Failure to thrive in infancy;
Specific growth curves are available
HEAD AND NECK:
[Face];
Triangular face with age;
Micrognathia;
[Ears];
Low-set posteriorly rotated ears;
Nerve deafness;
[Eyes];
Ptosis;
Hypertelorism;
Downslanting palpebral fissures;
Epicanthal folds;
Myopia;
Blue-green irides;
[Mouth];
Deeply grooved philtrum;
High peaks of upper lip vermilion border;
High arched palate;
[Teeth];
Dental malocclusion;
[Neck];
Webbed neck;
Cystic hygroma;
Short neck
CARDIOVASCULAR:
[Heart];
Congenital heart defect;
Hypertrophic obstructive cardiomyopathy;
Atrial septal defects;
Ventricular septal defects;
Pulmonic stenosis;
[Vascular];
Patent ductus arteriosus;
Aortic coarctation
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Shield chest;
Pectus carinatum superiorly;
Pectus excavatum inferiorly
GENITOURINARY:
[Internal genitalia, male];
Occasional hypogonadism;
Cryptorchidism;
Male infertility in individuals with bilateral cryptorchidism
SKELETAL:
[Spine];
Vertebral abnormalities;
Kyphoscoliosis;
[Limbs];
Cubitus valgus;
Clinodactyly;
Brachydactyly;
Blunt fingertips;
Polyarticular villonodular synovitis (knees, ankles, wrists, elbows
- in some patients)
SKIN, NAILS, HAIR:
[Hair];
Woolly-like hair;
Low posterior hairline
MUSCLE, SOFT TISSUE:
Lymphedema
NEUROLOGIC:
[Central nervous system];
Articulation difficulties;
Mental retardation (25%)
HEMATOLOGY:
Amegakaryocytic thrombocytopenia;
Von Willebrand disease;
Bleeding tendency
NEOPLASIA:
Malignant schwannoma;
Multiple giant cell granulomas (bones, joints, soft tissues)
LABORATORY ABNORMALITIES:
Partial deficiency of factor XI(C);
Partial deficiency of factor XII(C);
Partial deficiency of factor XIII(C);
Thrombocytopenia
MISCELLANEOUS:
Genetic heterogeneity;
Allelic to LEOPARD syndrome (151100)
MOLECULAR BASIS:
Caused by mutation in the protein tyrosine phosphatase, nonreceptor-type,
11 gene (PTPN11, 176876.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 10/26/2010
Cassandra L. Kniffin - updated: 6/18/2009
Joanna S. Amberger - updated: 7/14/2006
Ada Hamosh - updated: 4/8/2002
Kelly A. Przylepa - revised: 12/7/1999
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 04/10/2012
joanna: 5/18/2011
ckniffin: 12/3/2010
ckniffin: 10/26/2010
joanna: 1/7/2010
ckniffin: 6/18/2009
joanna: 2/19/2009
terry: 2/12/2009
joanna: 7/14/2006
joanna: 10/10/2005
joanna: 3/14/2005
joanna: 3/30/2004
joanna: 4/4/2003
joanna: 2/27/2003
joanna: 4/8/2002
joanna: 1/13/2000
mgross: 12/7/1999
*FIELD* CN
Cassandra L. Kniffin - updated: 3/19/2012
Cassandra L. Kniffin - updated: 10/26/2010
Cassandra L. Kniffin - updated: 10/14/2010
Marla J. F. O'Neill - updated: 10/9/2009
Cassandra L. Kniffin - updated: 6/18/2009
Kelly A. Przylepa - updated: 2/2/2009
Marla J. F. O'Neill - updated: 4/24/2008
Marla J. F. O'Neill - updated: 2/1/2008
Marla J. F. O'Neill - updated: 12/21/2007
Marla J. F. O'Neill - updated: 10/24/2007
John A. Phillips, III - updated: 5/31/2007
John A. Phillips, III - updated: 4/18/2007
Marla J. F. O'Neill - updated: 3/9/2007
Victor A. McKusick - updated: 1/30/2007
John A. Phillips, III - updated: 11/17/2006
Victor A. McKusick - updated: 5/4/2006
Victor A. McKusick - updated: 2/24/2006
Victor A. McKusick - updated: 4/14/2005
Marla J. F. O'Neill - updated: 1/4/2005
Jane Kelly - updated: 11/9/2004
Marla J. F. O'Neill - updated: 5/12/2004
Marla J. F. O'Neill - updated: 4/2/2004
Natalie E. Krasikov - updated: 3/29/2004
Siobhan M. Dolan - updated: 2/19/2004
Victor A. McKusick - updated: 1/14/2004
Victor A. McKusick - updated: 5/15/2003
Victor A. McKusick - updated: 5/13/2003
Cassandra L. Kniffin - updated: 1/9/2003
Victor A. McKusick - updated: 11/27/2002
Victor A. McKusick - updated: 11/12/2001
Victor A. McKusick - updated: 8/6/2001
John A. Phillips, III - updated: 7/10/2001
Michael J. Wright - updated: 5/21/2001
Sonja A. Rasmussen - updated: 10/12/2000
Paul Brennan - updated: 4/10/2000
Victor A. McKusick - updated: 4/30/1998
Victor A. McKusick - updated: 12/19/1997
Iosif W. Lurie - updated: 1/8/1997
Iosif W. Lurie - updated: 9/12/1996
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 08/02/2013
ckniffin: 8/1/2013
carol: 6/20/2013
carol: 6/7/2013
carol: 7/27/2012
alopez: 3/30/2012
terry: 3/28/2012
ckniffin: 3/19/2012
carol: 12/8/2011
wwang: 6/2/2011
wwang: 2/7/2011
ckniffin: 1/21/2011
wwang: 1/10/2011
ckniffin: 12/23/2010
wwang: 11/12/2010
ckniffin: 11/8/2010
wwang: 11/5/2010
ckniffin: 10/26/2010
wwang: 10/19/2010
ckniffin: 10/14/2010
wwang: 10/6/2010
ckniffin: 9/28/2010
alopez: 1/28/2010
ckniffin: 1/19/2010
carol: 11/23/2009
wwang: 10/16/2009
terry: 10/9/2009
wwang: 7/21/2009
ckniffin: 6/18/2009
wwang: 6/3/2009
terry: 6/1/2009
terry: 4/29/2009
wwang: 3/10/2009
joanna: 2/9/2009
carol: 2/4/2009
terry: 2/2/2009
terry: 1/30/2009
carol: 5/22/2008
wwang: 4/24/2008
terry: 4/24/2008
wwang: 2/6/2008
terry: 2/1/2008
wwang: 1/8/2008
terry: 12/21/2007
wwang: 10/25/2007
terry: 10/24/2007
carol: 5/31/2007
carol: 5/30/2007
wwang: 4/19/2007
alopez: 4/18/2007
carol: 4/18/2007
wwang: 3/12/2007
terry: 3/9/2007
alopez: 2/19/2007
alopez: 1/31/2007
terry: 1/30/2007
carol: 11/27/2006
alopez: 11/17/2006
alopez: 5/4/2006
carol: 4/25/2006
alopez: 3/3/2006
terry: 2/24/2006
carol: 1/12/2006
terry: 12/21/2005
ckniffin: 6/30/2005
tkritzer: 4/27/2005
terry: 4/14/2005
carol: 1/5/2005
terry: 1/4/2005
tkritzer: 11/9/2004
tkritzer: 11/3/2004
carol: 5/13/2004
terry: 5/12/2004
tkritzer: 4/5/2004
terry: 4/2/2004
tkritzer: 3/30/2004
terry: 3/29/2004
tkritzer: 2/19/2004
terry: 2/19/2004
tkritzer: 1/15/2004
terry: 1/14/2004
terry: 11/19/2003
carol: 11/13/2003
terry: 7/31/2003
alopez: 6/3/2003
tkritzer: 5/19/2003
terry: 5/15/2003
alopez: 5/14/2003
terry: 5/13/2003
cwells: 1/14/2003
ckniffin: 1/9/2003
mgross: 12/10/2002
carol: 12/4/2002
tkritzer: 12/3/2002
terry: 11/27/2002
alopez: 1/7/2002
alopez: 11/27/2001
alopez: 11/21/2001
alopez: 11/13/2001
terry: 11/12/2001
carol: 8/6/2001
mcapotos: 7/26/2001
cwells: 7/19/2001
cwells: 7/10/2001
alopez: 5/21/2001
mcapotos: 10/13/2000
mcapotos: 10/12/2000
alopez: 4/10/2000
dholmes: 5/12/1998
carol: 5/2/1998
terry: 4/30/1998
dholmes: 12/31/1997
terry: 12/19/1997
jenny: 11/19/1997
alopez: 6/27/1997
terry: 3/6/1997
jenny: 3/4/1997
jenny: 1/21/1997
jenny: 1/8/1997
carol: 9/12/1996
terry: 8/19/1996
terry: 7/29/1996
carol: 6/25/1996
mark: 9/19/1995
carol: 1/31/1995
terry: 12/22/1994
mimadm: 12/2/1994
jason: 7/27/1994
davew: 7/14/1994
*RECORD*
*FIELD* NO
163950
*FIELD* TI
#163950 NOONAN SYNDROME 1; NS1
;;NOONAN SYNDROME;;
MALE TURNER SYNDROME;;
FEMALE PSEUDO-TURNER SYNDROME;;
read moreTURNER PHENOTYPE WITH NORMAL KARYOTYPE
PTERYGIUM COLLI SYNDROME, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because Noonan syndrome-1
(NS1) is caused by heterozygous mutation in the PTPN11 gene (176876) on
chromosome 12q24.1.
DESCRIPTION
Noonan syndrome (NS) is an autosomal dominant disorder characterized by
short stature, facial dysmorphism, and a wide spectrum of congenital
heart defects. The distinctive facial features consist of a broad
forehead, hypertelorism, downslanting palpebral fissures, a high-arched
palate, and low-set, posteriorly rotated ears. Cardiac involvement is
present in up to 90% of patients. Pulmonic stenosis and hypertrophic
cardiomyopathy are the most common forms of cardiac disease, but a
variety of other lesions are also observed. Additional relatively
frequent features include multiple skeletal defects (chest and spine
deformities), webbed neck, mental retardation, cryptorchidism, and
bleeding diathesis (summary by Tartaglia et al., 2002).
- Genetic Heterogeneity of Noonan Syndrome
See also NS3 (609942), caused by mutation in the KRAS gene (190070); NS4
(610733), caused by mutation in the SOS1 gene (182530); NS5 (611553),
caused by mutation in the RAF1 gene (164760); NS6 (613224), caused by
mutation in the NRAS gene (164790); NS7 (613706), caused by mutation in
the BRAF gene (164757); and NS8 (615355), caused by mutation in the RIT1
gene (609591).
See also NS2 (605275) for a possible autosomal recessive form of NS;
Noonan syndrome-like disorder with loose anagen hair (NSLH; 607721),
caused by mutation in the SHOC2 gene (602775); and Noonan syndrome-like
disorder with or without juvenile myelomonocytic leukemia (NSLL;
613563), caused by mutation in the CBL gene (165360).
Mutations in the neurofibromin gene (NF1; 613113), which is the site of
mutations causing classic neurofibromatosis type I (NF1; 162200), have
been found in neurofibromatosis-Noonan syndrome (NFNS; 601321).
CLINICAL FEATURES
The disorder now known as Noonan syndrome bears similarities to the
disorder described by Turner (1938) and shown by Ford et al. (1959) to
have its basis in a 45,X chromosomal aberration called Turner syndrome,
Ullrich-Turner syndrome (Wiedemann and Glatzl, 1991), or monosomy X.
Migeon and Whitehouse (1967) described 2 families, each with 2 sibs with
somatic features of the Turner phenotype. In 1 family, 2 brothers had
webbing of the neck, coarctation of the aorta, and cryptorchidism. In
the second, a brother and sister were affected.
Diekmann et al. (1967) described 2 brothers and a sister, with normal
and unrelated parents, who had somatic characteristics of the Turner
syndrome, particularly pterygium colli and deformed sternum, and had
myocardiopathy leading to death at ages 12 and 10 years in 2 of them.
Noonan (1968) reported 19 patients of whom 17 had pulmonary stenosis and
2 had patent ductus arteriosus (see 607411). Twelve were males and 7
were females. Deformity of the sternum with precocious closure of
sutures was a frequent feature.
Among 95 male patients with pulmonary stenosis, Celermajer et al. (1968)
found the Turner phenotype in 8. In 5 of these, karyotyping was
performed. In 4 the chromosomes were normal; in 1, an extra acrocentric
chromosome was present.
Kaplan et al. (1968) described 2 brothers with Noonan syndrome and
elevated alkaline phosphatase levels, one of whom also had malignant
schwannoma of the forearm.
Nora and Sinha (1968) observed mother-to-offspring transmission in 3
families; in 1 family, transmission was through 3 generations.
Baird and De Jong (1972) described 7 cases in 3 generations. One
affected woman had 5 affected children (out of 6) with 2 different
husbands. Seizures and anomalous upper lateral incisors may have been
coincidental.
Simpson et al. (1969) reported experiences suggesting that rubella
embryopathy may result in the Turner phenotype, thereby accounting for
either the male Turner syndrome or the female pseudo-Turner syndrome. A
particularly convincing pedigree for autosomal dominant inheritance was
reported by Bolton et al. (1974), who found the condition in a man and 4
sons (in a sibship of 10). Four of the 5 affected persons had pulmonic
stenosis. Father-to-son transmission was reported by Qazi et al. (1974).
Koretzky et al. (1969) described an unusual type of pulmonary valvular
dysplasia which showed a familial tendency with either affected parent
and offspring or affected sibs. Although some relatives had pulmonary
valvular stenosis of the standard dome-shaped variety, the valvular
dysplasia in others was characterized by the presence of three distinct
cusps and no commissural fusion. The obstructive mechanism was related
to markedly thickened, immobile cusps, with disorganized myxomatous
tissue. Other features were retarded growth, abnormal facies (triangular
face, hypertelorism, low-set ears and ptosis of the eyelids), absence of
ejection click, and unusually marked right axis deviation by
electrocardiogram. It now seems clear that the patients of Koretzky et
al. (1969) had Noonan syndrome.
Mendez and Opitz (1985) stated that the Watson syndrome (193520) and the
LEOPARD syndrome (151100) 'are essentially indistinguishable from the
Noonan syndrome.' Witt et al. (1987) reviewed the occurrence of
lymphedema in Noonan syndrome. When it does occur, it opens the
possibility of prenatal diagnosis by imaging methods or by AFP level.
Noonan syndrome was one of the causes found for posterior cervical
hygroma in a series of previable fetuses studied by Kalousek and Seller
(1987). The authors found, furthermore, that 45,X Turner syndrome lethal
in the fetal period showed a constant association of 3 defects,
posterior cervical cystic hygroma, generalized subcutaneous edema, and
preductal aortic coarctation.
Evans et al. (1991) found a large cutaneous lymphangioma of the right
cheek and amegakaryocytic thrombocytopenia in a male infant with Noonan
syndrome.
Donnenfeld et al. (1991) presented a case of Noonan syndrome in which
posterior nuchal cystic hygroma was diagnosed at 13 to 14 weeks of
gestation by ultrasonography. The hygroma had regressed by the time of
birth leaving nuchal skin fold redundancy and pterygium colli.
On the basis of studies of genital tract function in 11 adult males with
Noonan syndrome, Elsawi et al. (1994) concluded that bilateral
testicular maldescent was a main factor in contributing to impairment of
fertility. Four of the 11 men had fathered children.
Lee et al. (1992) reviewed the ophthalmologic and orthoptic findings in
58 patients with Noonan syndrome. External features were hypertelorism
(74%), downward sloping palpebral apertures (38%), epicanthal folds
(39%), and ptosis (48%). Orthoptic examination revealed strabismus in
48%, refractive errors in 61%, amblyopia in 33%, and nystagmus in 9% of
cases. Anterior segment changes, found in 63% of patients, included
prominent corneal nerves (46%), anterior stromal dystrophy (4%),
cataracts (8%), and panuveitis (2%). Fundal changes occurred in 20% of
patients and included optic nerve head drusen, optic disc hypoplasia,
colobomas, and myelinated nerve fiber layer. Lee et al. (1992)
recommended early ophthalmic examination of children with Noonan
syndrome.
Allanson et al. (1985) studied the changes in facial appearance with
age. They pointed out that the manifestations may be subtle in adults.
Ranke et al. (1988) analyzed the clinical features of 144 patients from
2 West German centers. The size at birth was normal in both sexes. In
both males and females, the mean height followed along the 3rd
percentile until puberty, but decreased transiently due to an
approximately 2-year delay in onset of puberty. Final height approaches
the lower limits of normal at the end of the second decade of life. The
mean adult height was 162.5 cm in males and 152.7 cm in females,
respectively. Allanson (1987) provided a useful review. The fetal
primidone syndrome, occurring in the offspring of mothers taking this
anticonvulsant, closely simulates the Noonan syndrome.
Baraitser and Patton (1986) reported 4 unrelated children (2 boys, 2
girls) with a Noonan-like syndrome associated with sparse hair as a
conspicuous feature. See 115150.
Leichtman (1996) reported a family suggesting that cardiofaciocutaneous
syndrome (CFC; 115150) is a variable expression of Noonan syndrome. He
described a 4-year-old girl who had all of the manifestations of CFC
syndrome (characteristic facial and cardiac anomalies, developmental
delay, hypotrichosis, eczematic eruption with resistance to treatment),
whose mother had typical characteristics of Noonan syndrome. Lorenzetti
and Fryns (1996) reported a 13-year-old boy with Noonan syndrome and
retinitis pigmentosa. Because similar eye defects are found in CFC
syndrome, the authors suggested that CFC and Noonan syndromes might be
variable manifestations of the same entity. However, Neri and Zollino
(1996) noted distinctions between the patient reported by Lorenzetti and
Fryns (1996) and CFC syndrome, and stated that similarity of eye defects
is not enough to conclude that CFC and Noonan syndromes are the same
condition.
Early feeding difficulties are common in Noonan syndrome but often go
unrecognized. Shah et al. (1999) studied a consecutive series of
children with Noonan syndrome whose diagnosis had been confirmed by a
clinical geneticist. Sixteen had poor feeding (poor suck or refusal to
take solids or liquids) and symptoms of gastrointestinal dysfunction
(vomiting, constipation, abdominal pain, and bloating). All 16 had
required nasogastric tube feeding. Seven of the 25 had foregut
dysmotility and gastroesophageal reflux. In 4 of these,
electrogastrography and antroduodenal manometry demonstrated immature
gastric motility reminiscent of that of a preterm infant of 32 to 35
weeks' gestation. Other children had less severe forms of gastric
dysmotility. The authors highlighted the importance of recognizing this
common, treatable feature of Noonan syndrome.
Lemire (2002) described a father, son, and daughter with an apparently
autosomal dominant disorder characterized by craniofacial anomalies,
coarctation of the aorta, hypertrophic cardiomyopathy, and other
structural heart defects with normal psychomotor development. Some
clinical features such as webbed neck, low-set ears, low posterior
hairline, and widely spaced nipples suggested Noonan syndrome.
Alternatively, a previously unrecognized disorder was considered. The
paternal age at the father's birth was 50 years. The father presented at
age 13 years when postductal coarctation of the aorta was discovered
during routine physical examination. Preoperative evaluation showed
hypertrophied interventricular septum with pulmonic stenosis and
bicuspid aortic valve in addition to the aortic coarctation. At age 22
years, echocardiogram showed marked systolic thickening of
interventricular septum and posterior wall of the left ventricle and
concentric left ventricular hypertrophy. He later developed atrial
flutter and congestive heart failure. His son was recognized at birth to
have 2 small ventricular septal defects, mildly hypoplastic aortic arch,
and coarctation of the aorta. The coarctation was repaired at age 14
days and bilateral inguinal hernias at age 5 weeks. At age 9 months, he
was found to have congestive heart failure due to a restrictive
cardiomyopathy. At age 10 months, studies confirmed the presence of
spongy myocardium with much impaired diastolic function. He died of
early acute graft failure at age 14 months after heart transplantation.
Autopsy showed restrictive cardiomyopathy with generalized myocardium
hypertrophy. The daughter was found at birth to have a small ventricular
septal defect, small patent ductus arteriosus, aneurysm of the atrial
septum, and coarctation of the aorta. Cardiomyopathy was suspected on
the basis of excessive thickening of the lower two-thirds of the
interventricular septum and of the free wall of the right ventricle.
Coarctation of the aorta was repaired surgically at age 19 days. At age
10.5 months, she was noted to have plagiocephaly, facial asymmetry with
left side smaller than the right, webbed neck, asymmetric chest with
widely spaced nipples, and edema of the dorsum of the feet. At age 2
years, bicuspid aortic valve and diffuse concentric hypertrophy of the
left ventricle were noted.
Juvenile myelomonocytic leukemia (JMML; 607785) has been observed in
some cases of Noonan syndrome (Bader-Meunier et al., 1997; Fukuda et
al., 1997; Choong et al., 1999).
Holder-Espinasse and Winter (2003) described a 6-year-old girl with
clinical features of Noonan syndrome, short stature, and headache who
was noted to have Arnold-Chiari malformation (207950) on MRI. They cited
3 previous reports of Noonan syndrome and Chiari malformation and/or
syringomelia (Ball and Peiris, 1982; Gabrielli et al., 1990; Colli et
al., 2001). Holder-Espinasse and Winter (2003) concluded that Chiari
malformation should be considered part of the Noonan syndrome spectrum
and that brain and cervical spine MRI should be required in patients
with Noonan syndrome, particularly if headaches or neurologic symptoms
are present.
For a comprehensive review of Turner syndrome, including clinical
management, see Ranke and Saenger (2001).
Kondoh et al. (2003) described a transient leukemoid reaction and an
apparently spontaneously regressing neuroblastoma in a 3-month-old
Japanese patient with Noonan syndrome and a de novo missense mutation in
the PTPN11 gene (176876.0007).
Noonan et al. (2003) reported their findings in 73 adults over 21 years
of age with Noonan syndrome. In 30%, adult height was in the normal
range between the 10th and 90th percentiles. More than half of the
females and nearly 40% of males had an adult height below the third
percentile. The presence or severity of heart disease was not a factor,
and none of the adults with normal height had been treated with growth
hormone. Serial measurements of height over many years through childhood
to adulthood were available in only a few patients, but their pattern of
growth suggested that catch up may occur in late adolescence. The
possible benefit of growth hormone therapy could not be evaluated.
Croonen et al. (2008) evaluated ECG findings and cardiographic
abnormalities in 84 patients with Noonan syndrome, 54 (67%) of whom were
positive for a mutation in the PTPN11 gene. As reported previously,
pulmonary stenosis was the most common cardiac abnormality, followed by
atrial septal defect and hypertrophic cardiomyopathy. ECG showed at
least 1 characteristic finding in 50% of cases, including left axis
deviation in 38 (45%), small R waves in the left precordial leads in 20
(24%), and an abnormal Q wave in 5 (6%) Noonan patients; however, these
ECG findings were not associated with a PTPN11 mutation or with a
specific cardiac anomaly.
Among 40 Italian patients with Noonan syndrome, Ferrero et al. (2008)
found short stature in 92%, congenital heart defect in 82.5%, isolated
pulmonic stenosis in 60.6%, and hypertrophic obstructive cardiomyopathy
in 12.2%. Prenatal anomalies were observed in 25% of cases, with
polyhydramnios being the most common. PTPN11 mutations were detected in
11 sporadic patients and 1 family, totaling 12 (31.5%) of 38 cases. One
patient without a detectable mutation had a Chiari I malformation with
seizures. Another of the remaining patients had a mutation in the SOS1
gene.
OTHER FEATURES
- Giant Cell Lesions
Some patients with Noonan syndrome develop multiple giant cell lesions
of the jaw or other bony or soft tissues, which are classified as
pigmented villonodular synovitis (PVNS) when occurring in the jaw or
joints. Early reports described this as a separate disorder (Leszczynski
et al., 1975; Lindenbaum and Hunt, 1977; Wagner et al., 1981); however,
it is now considered part of the phenotypic spectrum of Noonan syndrome
(Tartaglia et al., 2010).
Cohen et al. (1974) described a patient with short stature, ocular
hypertelorism, prominent posteriorly angulated ears, short webbed neck,
cubitus valgus, pulmonic stenosis, multiple lentigines, and giant cell
lesions of both bone and soft tissue. Cohen (1982) presented a
photographic montage of the patient. Cohen and Gorlin (1991) reviewed
further known cases to a total of 14. Chuong et al. (1986) studied
central giant cell lesions of the jaw in 17 patients and noted that 2 of
these occurred in patients with Noonan syndrome.
Ucar et al. (1998) described a patient with Noonan syndrome and PVNS. As
indicated by the photographs provided, the patient showed facies and
sternal configuration typical of Noonan syndrome. Cubitus valgus,
pulmonary valve stenosis, and patent foramen ovale, as well as
cryptorchidism, were also present. A central giant cell granuloma was
found originating from the lateral wall of the right maxillary sinus and
caused the presenting complaint of proptosis of the right eye. (Giant
cell granulomas in the head and neck region are called central when they
occur in bone and peripheral when they occur in gingiva or alveolar
mucosa.) In this family the patient's father also had the phenotype of
Noonan syndrome, suggesting autosomal dominant inheritance.
Bertola et al. (2001) described a family with typical clinical findings
of Noonan syndrome associated with giant cell lesions in maxilla and
mandible. The authors raised the possibility that Noonan syndrome and
Noonan syndrome-like disorder with multiple giant cell lesions might be
allelic disorders. This was indeed demonstrated to be the case by
Tartaglia et al. (2002), who found a mutation in the PTPN11 gene
(176876.0004), which is the site of mutation in about half of unrelated
individuals with sporadic or familial Noonan syndrome.
- Hematologic Abnormalities
Thrombocytopenia occurs in some cases of the Noonan syndrome (Goldstein,
1979). Partial deficiency of factor XI was described by Kitchens and
Alexander (1983). Out of 9 patients with Noonan syndrome, de Haan et al.
(1988) found 4 with partial deficiency of factor XI (30-65% of normal).
They reviewed the other reports of bleeding tendency associated with
thrombocytopenia or with abnormal platelet function.
Witt et al. (1988) described bleeding diathesis in 19 patients with
Noonan syndrome. Several different defects were identified in the
coagulation and platelet systems, occurring singly or in combination;
for example, 2 patients had factor XI deficiency, 3 had presumptive von
Willebrand disease, and 1 had thrombocytopenia. In 5 of the patients an
unusually pungent odor of urine and sweat was noted by parents. One of
these patients was reported by Humbert et al. (1970) as a case of
trimethylaminuria (136131) and another patient was suspected of having
this condition. Sharland et al. (1990) also described a variety of
coagulation factor deficiencies. The most common abnormality was a
partial factor XI deficiency in the heterozygote range, found in 21 of
31 patients. Of 72 patients studied (37 male, 35 female, mean age 11.4
years) by Sharland et al. (1992), 47 (65%) had a history of abnormal
bruising or bleeding. In 29 patients (40%), prolonged activated partial
thromboplastin time was found. In 36 patients (50%) specific
abnormalities were found in the intrinsic pathway of coagulation, i.e.,
partial deficiency of factor XI:C, XII:C, and VIII:C. Multiple
abnormalities among these 36 patients included combined deficiencies of
factors XI and XII (4 patients), of factors XI and VIII (4 patients),
and of factors VIII, XI, and XII (1 patient). In 5 families, similar
coagulation-factor deficiencies were present in first-degree relatives.
Sharland et al. (1992) suggested that because of the involvement of
several factors, either singly or in combination, there are likely to be
regulatory factors that control the intrinsic (contact activation)
system; that these factors are under chromosomal genetic control; and
that abnormalities of this regulation occur in Noonan syndrome.
Derbent et al. (2011) examined the hematologic profile of 30 patients
with Noonan syndrome, of whom 11 (36.7%) had proven PTPN11 mutations.
There were no statistically significant differences between the
mutation-positive and mutation-negative groups with respect to any of
the hematology results or the presence of moderate mental retardation,
pulmonic stenosis, chest deformity, genitourinary anomalies, or
sensorineural hearing loss. However, short stature and mild mental
retardation were more common in PTPN11 carriers. Only 1 of the patients
had a history of easy bruising; however, his hematologic and coagulation
tests were normal. None of the other patients had clinical coagulation
problems. Noonan syndrome patients had significantly lower values for
platelet count, activity of factors XI, XII, and protein C (612283)
compared to controls. Patient values for PT, aPTT, INR, and bleeding
time were also statistically different from the corresponding control
findings, but the absence of clinical problems rendered the tests
diagnostically inconclusive. Two patients had low protein C activity
(about 50% of normal), but neither had a thrombotic event or any
complication during about 3 years of follow-up. Derbent et al. (2011)
concluded that patients with Noonan syndrome should have a thorough
coagulation evaluation, but complications related to coagulation are
unlikely and extensive testing is unnecessary.
INHERITANCE
Noonan syndrome is inherited in an autosomal dominant pattern (Tartaglia
et al., 2010).
Wendt et al. (1986) reported a man with polyarticular pigmented
villonodular synovitis who had an affected son and daughter. Dunlap et
al. (1989) made reference to the fact that the father of one of his
cases was affected with Noonan syndrome and PVNS.
Elalaoui et al. (2010) reported 2 sibs, born of unrelated Moroccan
parents, with Noonan syndrome resulting from the same heterozygous
mutation in the PTPN11 gene (176876.0003). Both had characteristic
features of Noonan syndrome, including pulmonic stenosis and facial
anomalies, but neither parent showed any signs of the disorder.
Molecular analysis did not detect the mutation in multiple tissues of
either parent, excluding somatic mosaicism. Both affected children
inherited the same haplotypes from their mother and father, whereas
their unaffected brother inherited distinct haplotypes. This suggested
that a common somatic germ cell event in 1 of the parents was
responsible for the mutation, likely the father as he was 45 years of
age, but the parental origin could not be definitively determined.
Elalaoui et al. (2010) suggested an empirical recurrence rate of less
than 1% in this family.
POPULATION GENETICS
Noonan syndrome has an estimated incidence of 1 in 1,000 to 2,500 live
births (Tartaglia et al., 2001).
MAPPING
By means of a genomewide linkage analysis in a large Dutch kindred with
autosomal dominant Noonan syndrome, Jamieson et al. (1994) localized the
gene to chromosome 12; maximum lod = 4.04 at theta = 0.0. Linkage
analysis using chromosome 12 markers in 20 smaller, 2-generation
families gave a maximum lod of 2.89 at theta = 0.07, but haplotype
analysis showed nonlinkage in 1 family. These data suggested that a gene
for Noonan syndrome is located in the 12q22-qter region between markers
D12S84 and D12S366. Clinical studies in this kindred were reported by
van der Burgt et al. (1994).
Brady et al. (1997) further analyzed the 3-generation Dutch family
studied by Jamieson et al. (1994) using newly isolated CA-repeat markers
derived from the interval between D12S84 and D12S366. In this way they
were able to reduce the localization to an interval bounded by markers
D12S105 and NOS1 (163731), which has been mapped to 12q24.2-q24.31.
Legius et al. (1998) performed linkage analysis in a 4-generation
Belgian family with Noonan syndrome in some individuals and CFC syndrome
in others. Clinical and linkage data in this family indicated that the 2
syndromes result from variable expression of the same genetic defect.
They found a maximum lod score of 4.43 at zero recombination for marker
D12S84 in 12q24. A crossover in this pedigree narrowed the candidate
gene region to a 5-cM interval between D12S84 and D12S1341. A remarkable
feature of the family studied by Legius et al. (1998) was the presence
of 3 dizygotic twins in the offspring of 2 affected females. A dizygotic
twin pair was observed in the offspring of an affected female in the
family in which linkage was studied by Jamieson et al. (1994). It is
possible that an increased frequency of dizygotic twinning is associated
with NS1/CFC linked to 12q24. The fragile X syndrome (300624) is another
mendelian disorder with a possibly increased frequency of dizygotic
twinning (Partington et al., 1996; Schwartz et al., 1994).
- Exclusion Studies
Using a number of probes at the neurofibromatosis type I locus in the
study of 11 families with Noonan syndrome in 2 or 3 generations,
Sharland et al. (1992) excluded proximal 17q as the location of the
gene. Studying six 2-generation families with classic Noonan syndrome,
Flintoff et al. (1993) could find no evidence of linkage of this
disorder to NF1 on 17q or to NF2 (101000) on 22q.
In a study of candidate genes, Ion et al. (2000) excluded the genes EPS8
(600206) and DCN (125255) from the critical region by FISH analysis.
They also excluded the MYL2 (160781) and RPL6 (603703) genes by mutation
analysis.
CYTOGENETICS
Robin et al. (1995) described 6 patients with Noonan syndrome who
underwent molecular evaluation for submicroscopic deletion of chromosome
22q11. None of these patients presented with conotruncal heart defects.
Evidence for 22q11 hemizygosity was demonstrated in only 1 patient. This
patient had Noonan-like manifestations without clinical manifestations
of DiGeorge (188400) or velocardiofacial (192430) syndromes. Digilio et
al. (1996) studied 4 patients with Noonan syndrome and tetralogy of
Fallot. Chromosome analysis was normal in all 4 patients. DNA analysis
showed no hemizygosity for the 22q11 region in any of the patients.
- Duplication of Chromosome 12q24.13
Shchelochkov et al. (2008) described a 3-year-old girl with clinical
features consistent with Noonan syndrome. She presented with
postnatal-onset failure to thrive, microcephaly, velopalatal
incompetence, pectus excavatum, aortic coarctation, and atrial and
ventricular septal defects. Facial features included ptosis,
hypertelorism, epicanthal folds, cupped simple ears, and wide mouth with
downturned corners. Speech and fine and gross motor development were at
the level of a 12- to 18-month-old child, atypical for a child with
Noonan syndrome. Array CGH showed an interstitial 10-Mb duplication,
12q24.11-q24.23, that includes the genes PTPN11 (176876), TBX5 (601620),
and TBX3 (601621). This was confirmed by FISH analysis and chromosome
analysis. Sequencing of PTPN11, KRAS (190070), SOS1 (182530), and the
coding region of RAF1 (164760) did not reveal any pathogenic mutations.
Shchelochkov et al. (2008) proposed that duplications of the region
containing PTPN11 may result in a Noonan syndrome phenotype and may
account for the basis of Noonan syndrome in some of the 15 to 30% of
patients for whom no mutations can be detected by sequencing of
components of the RAS/MAPK signaling pathway.
Graham et al. (2009) reported another patient with Noonan syndrome
caused by an 8.98-Mb duplication on chromosome 12q24.13 encompassing the
PTPN11 gene, which was confirmed by FISH analysis. However, duplications
were not observed in a screening of more than 250 Noonan syndrome cases
without mutations in known disease-causing genes. Changes affecting the
3-prime untranslated region of the PTPN11 transcript were also not found
in 36 patients without disease-causing mutations. In contrast to
Shchelochkov et al. (2008), Graham et al. (2009) concluded that
duplication of PTPN11 represents an uncommon cause of Noonan syndrome.
However, the rare observation of NS in individuals with duplications
involving the PTPN11 locus suggested that increased dosage of this gene
may have dysregulating effects on intracellular signaling.
DIAGNOSIS
Butler et al. (2000) used metacarpophalangeal pattern profile (MCPP)
analysis to evaluate 15 individuals with Noonan syndrome. Discriminant
analysis resulted in the correct classification of 93% of Noonan
syndrome patients based on 2 MCPP variables (metacarpal 1 and middle
phalanx 3). The authors suggested that MCPP analysis may be useful as a
diagnostic tool in screening subjects for Noonan syndrome.
CLINICAL MANAGEMENT
MacFarlane et al. (2001) reported growth data from the first 3 years of
a multicenter study examining the efficacy and safety of recombinant
human GH in 23 children with Noonan syndrome. Sixteen male and 7 female
patients (aged 9.3 +/- 2.6 years at onset of GH therapy, mean +/- SD;
range 4.8-13.7) were each assessed at 1, 2, and 3 years after starting
treatment. Comparisons were made with a group of 8 subjects (6 males and
2 females, aged 9.0 +/- 4.1 years; range 4.1-14.8) with Noonan syndrome
and not treated with recombinant GH, and measured over the same period.
All treated subjects underwent annual cardiac assessment. Height SD
score increased from -2.7 +/- 0.4 at the start of GH therapy to -1.9 +/-
0.9 three years later. This corresponded to an increase in height from
116.1 +/- 13.2 to 137.3 +/- 14.0 cm. Height velocity increased from 4.4
+/- 1.7 cm/year in the year before treatment to 8.4 +/- 1.7, 6.2 +/-
1.7, and 5.8 +/- 1.8 during the first, second, and third years of GH
treatment, respectively. Height acceleration was not significant during
the second or third years when pubertal subjects were excluded. The
authors concluded that the increase in growth rate in Noonan syndrome
resulting from 1 year of GH therapy seems to be maintained during the
second year, although height velocity shows a less significant increase
over pretherapy values. Possible abnormal anabolic effects of
recombinant GH on myocardial thickness were not confirmed, and no
treated patient developed features of hypertrophic cardiomyopathy.
Kirk et al. (2001) presented data on 66 Noonan syndrome patients (54
males) treated with growth hormone. Treatment improved height velocity
in the short term, but longer-term therapy resulted in a waning of
effect. The study indicated that final height is not substantially
improved in most patients.
From a study of 14 children with Noonan syndrome who were treated with
human growth hormone, half of whom had a missense mutation in the PTPN11
gene, Ferreira et al. (2005) found that those with a PTPN11 mutation had
a lower increase in IGF-I (147440) levels during treatment and a
significantly lower gain in height SD score after 3 years of treatment
compared with those without mutations.
Binder et al. (2005) compared GH secretion and IGF-I/IGFBP3 (146732)
levels of the PTPN11 mutation-positive (mut+ group) versus the
mutation-negative individuals (mut- group). IGF-I and IGFBP3 levels were
significantly lower in the mut+ group. In contrast, GH levels showed a
tendency to be higher in the mut+ group during spontaneous secretion at
night and arginine stimulation. The mean change in height SDS after 1
year of rhGH therapy was +0.66 + 0.21 in the mut+ group (8 individuals),
but +1.26 + 0.36 in the mut- group (3 individuals; p = 0.007). The
authors concluded that PTPN11 mutations in Noonan syndrome cause mild GH
resistance by a post-receptor signaling defect, which seems to be
partially compensated for by elevated GH secretion.
MOLECULAR GENETICS
In more than 50% of patients with Noonan syndrome, Tartaglia et al.
(2001) identified mutations in the PTPN11 gene (see, e.g.,
176876.0001-176876.0003). All the PTPN11 missense mutations were
clustered in the interacting portions of the amino N-SH2 (Src homology
2) domain and the phosphotyrosine phosphatase (PTP) domains, which are
involved in switching the protein between its inactive and active
conformations. An energetics-based structural analysis of 2 N-SH2
mutants indicated that in these cases there may be a significant shift
of the equilibrium favoring the active conformation. The findings
suggested that gain-of-function changes resulting in excessive SHP2
activity underlie the pathogenesis of Noonan syndrome.
After germline mutations in PTPN11 (176876) were demonstrated in the
Noonan syndrome, Tartaglia et al. (2003) investigated defects in PTPN11
in myeloid disorders including cases of juvenile myelomonocytic leukemia
(JMML; 607785) in children with Noonan syndrome. Specific mutations in
PTPN11 associated with isolated JMML occurred as somatic changes and had
never been observed as germline defects, leading Tartaglia et al. (2003)
to speculate that these molecular defects are stronger and associated
with embryonic lethality. Conversely, most mutations in PTPN11
associated with Noonan syndrome, which were sufficient to perturb
developmental processes, were not fully leukemogenic, suggesting a
milder gain-of-function effect.
In 10 affected members from a large 4-generation Belgian family with
Noonan syndrome and some features suggestive of CFC syndrome, Schollen
et al. (2003) identified a missense mutation in the PTPN11 gene
(176876.0018). The mutation was not found in 7 unaffected relatives or 3
spouses.
Musante et al. (2003) screened the PTPN11 gene for mutations in 96
familial or sporadic Noonan syndrome patients and identified 15 missense
mutations in 32 patients (33%). No obvious clinical differences were
detected between subgroups of patients with mutations in different
PTPN11 domains. Analysis of the clinical features of their patients
revealed that several patients with facial abnormalities thought to be
pathognomonic for NS did not have a mutation in the PTPN11 gene. Widely
varying phenotypes among the 64 patients without PTPN11 mutations
indicated further genetic heterogeneity. Musante et al. (2003) also
screened 5 sporadic patients with CFC syndrome and found no mutations in
the PTPN11 gene.
Bertola et al. (2004) described a young woman with clinical features of
Noonan syndrome but with some characteristics of CFC as well, including
prominent ectodermal involvement (sparse and very coarse hair, and
sparse eyebrows and eyelashes), developmental delay, and mental
retardation. They identified a T411M mutation in the PTPN11 gene
(176876.0019); the same mutation was found in her mother and older
sister, not initially considered to be affected but who had subtle
clinical findings compatible with the diagnosis of Noonan syndrome. The
mother had 5 miscarriages, 2 of them twinning pregnancies. Bertola et
al. (2004) suggested that all first-degree relatives of patients with
confirmed Noonan syndrome, even those with no signs of the disorder, be
screened for PTPN11 mutations in order to provide accurate assessments
of recurrence risk.
Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical
assessment in 45 Japanese patients with Noonan syndrome. Sequence
analysis of the coding exons 1 through 15 of PTPN11 revealed a novel
3-bp deletion (176876.0024) and 10 recurrent missense mutations in 18
patients. The authors estimated that PTPN11 mutations account for
approximately 40% of Japanese Noonan syndrome patients.
Jongmans et al. (2005) performed mutation analysis of the PTPN11 gene in
170 Noonan syndrome patients and identified a mutation in 76 (45%) of
them. They described the distribution of these mutations, as well as
genotype-phenotype relationships. The usefulness of the Noonan syndrome
scoring system developed by van der Burgt et al. (1994) was
demonstrated; when physicians based their diagnosis on the scoring
system, the percentage of mutation-positive patients was higher.
Mutations in the KRAS gene (190070) can also cause Noonan syndrome (NS3;
609942). One patient with a T58I mutation (190070.0011) also had a
myeloproliferative disorder resembling juvenile myelomonocytic leukemia
(JMML) (Schubbert et al., 2006).
Tartaglia et al. (2006) proposed a model that splits NS- and
leukemia-associated PTPN11 mutations in the 2 major classes of
activating lesions with differential perturbing effects on development
and hematopoiesis. The results documented a strict correlation between
the identity of the lesion and disease, and demonstrated that
NS-causative mutations have less potency for promoting SHP2 gain of
function than do leukemia-associated ones.
Roberts et al. (2007) and Tartaglia et al. (2007) investigated sizable
groups of patients with Noonan syndrome but no mutation in PTPN11, which
accounts for approximately 50% of such cases. They found that many had
missense mutations in the SOS1 gene (182530) and that the SOS1-positive
case patients represented approximately 20% of cases of Noonan syndrome.
The phenotype of Noonan syndrome caused by SOS1 mutation, while within
the Noonan syndrome spectrum, appears to be distinctive (see NS4,
610733).
Kontaridis et al. (2006) examined the enzymatic properties of mutations
in PTPN11 causing LEOPARD syndrome and found that, in contrast to the
activating mutations that cause Noonan syndrome and neoplasia, LEOPARD
syndrome mutants are catalytically defective and act as
dominant-negative mutations that interfere with growth factor/ERK-MAPK
(see 176948)-mediated signaling. Kontaridis et al. (2006) concluded that
the pathogenesis of LEOPARD syndrome is distinct from that of Noonan
syndrome and suggested that these disorders should be distinguished by
mutation analysis rather than clinical presentation.
In a prospective multicenter study in 35 Noonan syndrome patients with
growth retardation, Limal et al. (2006) compared growth and hormonal
growth factors before and during recombinant human GH therapy in
patients with and without PTPN11 mutations. Sequencing of the PTPN11
coding sequence revealed 12 different heterozygous missense mutations in
20 of the 35 patients (57%). The results showed that among NS1 patients
with short stature, some neonates had birth length less than -2 SDS.
Growth of patients with mutations was reduced and responded less
efficiently to GH than that of patients without mutations. Limal et al.
(2006) concluded that the association of low IGF1 (147440) and
insulin-like growth factor-binding protein, acid-labile subunit (IGFALS;
601489) with normal IGFBP3 (146732) levels could explain growth
impairment of children with mutations and could suggest a GH resistance
by a late postreceptor signaling defect.
In a case of fetal demise at 12 weeks' gestation, Becker et al. (2007)
identified compound heterozygosity for the N308S (176876.0004) and Y63C
(176876.0008) mutations in the PTPN11 gene. The mother and father, who
exhibited facial features of Noonan syndrome and had both undergone
surgical correction of pulmonary valve stenosis, were heterozygous for
N308S and Y63C, respectively. A second pregnancy resulted in the birth
of a boy with Noonan syndrome carrying the paternal Y63C mutation.
Ferrero et al. (2008) identified PTPN11 mutations in 31.5% of 37
sporadic patients and 1 family with a clinical diagnosis of Noonan
syndrome. One of the remaining patients had a mutation in the SOS1 gene.
- Cooccurrence of NF1 and PTPN11 Mutations
Bertola et al. (2005) provided molecular evidence of the concurrence of
neurofibromatosis and Noonan syndrome in a patient with a de novo
missense mutation in the NF1 gene (613113.0043) and a mutation in the
PTPN11 gene (176876.0023) inherited from her father. The proposita was
noted to have cafe-au-lait spots at birth. Valvar and infundibular
pulmonary stenosis and aortic coarctation were diagnosed at 20 months of
age and surgically corrected at 3 years of age. As illustrated, the
patient had marked hypertelorism and proptosis as well as freckling and
cafe-au-lait spots. Lisch nodules were present. At the age of 8 years, a
pilocytic astrocytoma in the suprasellar region involving the optic
chiasm (first presenting symptomatically at 2 years of age), was
partially resected. The father, who was diagnosed with Noonan syndrome,
had downslanting palpebral fissures and prominent nasal labial folds. He
was of short stature (159 cm) and had pectus excavatum.
Electrocardiogram showed left-anterior hemiblock and complete right
bundle branch block.
Thiel et al. (2009) reported a patient with features of both
neurofibromatosis I and Noonan syndrome who was compound heterozygous
for mutations in both the NF1 (162200.0044) and PTPN11 (176876.0027)
genes. The PTPN11 mutation occurred de novo, and the NF1 mutation was
inherited from the patient's mother, who had mild features of
neurofibromatosis I, including the absence of optic gliomas. The proband
developed bilateral optic gliomas before age 2 years, suggesting an
additive effect of the 2 mutations on the Ras pathway. The proband also
had short stature, delayed development, sternal abnormalities, and
valvular pulmonary stenosis.
- Reviews
Tartaglia et al. (2010) provided a detailed review of the clinical and
molecular features of Noonan syndrome.
NOMENCLATURE
Dunlap et al. (1989) referred to Noonan syndrome with multiple giant
cells lesions as the Noonan syndrome-cherubism association. Cohen and
Gorlin (1991) recommended that it not be called Noonan syndrome,
pigmented villonodular synovitis, central giant cell granuloma, or
cherubism, because each of these is a specific diagnostic entity sui
generis and the use of such terms results in nosologic blinders that
tend to limit the workup of patients.
ANIMAL MODEL
In a mouse model of Noonan syndrome in which transgenic mice carried a
cardiomyocyte-specific gain-of-function Q79R mutation in the PTPN11 gene
(176876.0018), Nakamura et al. (2007) demonstrated that the
developmental effects of Q79R cardiac expression are stage-specific and
that ablation of subsequent ERK1/2 (see 176948) activation prevented the
development of cardiac abnormalities.
HISTORY
Cole (1980) pointed out that the blacksmith in the famous painting
'Among Those Left' by Ivan Le Lorraine Albright appears to have had
Noonan syndrome. The contour of the sternum, the low-set ears, and the
short stature are suggestive. Genetic confirmation was provided by
studies of a great-grandson with general features of the Noonan syndrome
and cardiac abnormalities consistent with that diagnosis (pulmonic
stenosis and regurgitation, abnormal architecture of the left
ventricular musculature). Opitz and Pallister (1979) reproduced the
first published illustration of the Noonan syndrome by Kobylinski
(1883), and Opitz (1985) republished the photograph of Rickey E., the
first patient with 'her' syndrome studied at the State University of
Iowa by Jacqueline A. Noonan.
*FIELD* SA
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Fisher et al. (1982); Golabi et al. (1985); Hall et al. (1982); Levy
et al. (1970); Linde et al. (1973); Miller and Motulsky (1978); Nora
et al. (1974); Pierini and Pierini (1979); Sharland et al. (1992);
Wiedemann (1991); Witt et al. (1985)
*FIELD* RF
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88. Roberts, A. E.; Araki, T.; Swanson, K. D.; Montgomery, K. T.;
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89. Robin, N. H.; Sellinger, B.; McDonald-McGinn, D.; Zackai, E. H.;
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90. Schollen, E.; Matthijs, G.; Gewillig, M.; Fryns, J.-P.; Legius,
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cause Noonan syndrome. Nature Genet. 38: 331-336, 2006. Note: Erratum:
Nature Genet. 38: 598 only, 2006.
92. Schwartz, C. E.; Dean, J.; Howard-Peebles, P. N.; Bugge, M.; Mikkelson,
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93. Shah, N.; Rodriguez, M.; St. Louis, D.; Lindley, K.; Milla, P.
J.: Feeding difficulties and foregut dysmotility in Noonan's syndrome. Arch.
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95. Sharland, M.; Patton, M. A.; Talbot, S.; Chitolie, A.; Bevan,
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96. Sharland, M.; Taylor, R.; Patton, M. A.; Jeffery, S.: Absence
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97. Shchelochkov, O. A.; Patel, A.; Weissenberger, G. M.; Chinault,
A. C.; Wiszniewska, J.; Fernandes, P. H.; Eng, C.; Kukolich, M. K.;
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in apparent Noonan syndrome. Am. J. Med. Genet. 146A: 1042-1048,
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98. Simpson, J. W.; Nora, J. J.; Singer, D. B.; McNamara, D. G.:
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99. Tartaglia, M.; Kalidas, K.; Shaw, A.; Song, X.; Musat, D. L.;
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1555-1563, 2002.
100. Tartaglia, M.; Martinelli, S.; Stella, L.; Bocchinfuso, G.; Flex,
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T. C.; Sorcini, M.; Schoch, C.; Foa, R.; Emanuel, P. D.; Gelb, B.
D.: Diversity and functional consequences of germline and somatic
PTPN11 mutations in human disease. Am. J. Hum. Genet. 78: 279-290,
2006.
101. Tartaglia, M.; Mehler, E. L.; Goldberg, R.; Zampino, G.; Brunner,
H. G.; Kremer, H.; van der Burgt, I.; Crosby, A. H.; Ion, A.; Jeffery,
S.; Kalidas, K.; Patton, M. A.; Kucherlapati, R. S.; Gelb, B. D.:
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2,
cause Noonan syndrome. Nature Genet. 29: 465-468, 2001. Note: Erratum:
Nature Genet. 29: 491 only, 2001; Nature Genet. 30: 123 only, 2002.
102. Tartaglia, M.; Niemeyer, C. M.; Fragale, A.; Song, X.; Buechner,
J.; Jung, A.; Hahlen, K.; Hasle, H.; Licht, J. D.; Gelb, B. D.: Somatic
mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic
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103. Tartaglia, M.; Pennacchio, L. A.; Zhao, C.; Yadav, K. K.; Fodale,
V.; Sarkozy, A.; Pandit, B.; Oishi, K.; Martinelli, S.; Schackwitz,
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aspects and molecular pathogenesis. Molec. Syndromol. 1: 2-26, 2010.
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108. van der Burgt, I.; Berends, E.; Lommen, E.; van Beersum, S.;
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1994.
109. Wagner, M. L.; Spjut, H. J.; Dutton, R. V.; Glassman, A. L.;
Askew, J. B.: Polyarticular pigmented villonodular synovitis. Am.
J. Roentgen. 136: 821-823, 1981.
110. Wendt, R. G.; Wolfe, F.; McQueen, D.; Murphy, P.; Solomon, H.;
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111. Wiedemann, H.-R.: Otto Ullrich and his syndromes. Am. J. Med.
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patient with 'Ullrich-Turner' syndrome. Am. J. Med. Genet. 41: 134-136,
1991.
113. Witt, D.; Allanson, J.; Wadsworth, L.; Hall, J. G.: Bleeding
disorders in 7 cases of Noonan syndrome; further evidence of heterogeneity.
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115. Witt, D. R.; McGillivray, B. C.; Allanson, J. E.; Hughes, H.
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305-317, 1988.
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nonreceptor type 11 mutation analysis and clinical assessment in 45
patients with Noonan syndrome. J. Clin. Endocr. Metab. 89: 3359-3364,
2004.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Short stature (postnatal onset);
[Other];
Failure to thrive in infancy;
Specific growth curves are available
HEAD AND NECK:
[Face];
Triangular face with age;
Micrognathia;
[Ears];
Low-set posteriorly rotated ears;
Nerve deafness;
[Eyes];
Ptosis;
Hypertelorism;
Downslanting palpebral fissures;
Epicanthal folds;
Myopia;
Blue-green irides;
[Mouth];
Deeply grooved philtrum;
High peaks of upper lip vermilion border;
High arched palate;
[Teeth];
Dental malocclusion;
[Neck];
Webbed neck;
Cystic hygroma;
Short neck
CARDIOVASCULAR:
[Heart];
Congenital heart defect;
Hypertrophic obstructive cardiomyopathy;
Atrial septal defects;
Ventricular septal defects;
Pulmonic stenosis;
[Vascular];
Patent ductus arteriosus;
Aortic coarctation
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Shield chest;
Pectus carinatum superiorly;
Pectus excavatum inferiorly
GENITOURINARY:
[Internal genitalia, male];
Occasional hypogonadism;
Cryptorchidism;
Male infertility in individuals with bilateral cryptorchidism
SKELETAL:
[Spine];
Vertebral abnormalities;
Kyphoscoliosis;
[Limbs];
Cubitus valgus;
Clinodactyly;
Brachydactyly;
Blunt fingertips;
Polyarticular villonodular synovitis (knees, ankles, wrists, elbows
- in some patients)
SKIN, NAILS, HAIR:
[Hair];
Woolly-like hair;
Low posterior hairline
MUSCLE, SOFT TISSUE:
Lymphedema
NEUROLOGIC:
[Central nervous system];
Articulation difficulties;
Mental retardation (25%)
HEMATOLOGY:
Amegakaryocytic thrombocytopenia;
Von Willebrand disease;
Bleeding tendency
NEOPLASIA:
Malignant schwannoma;
Multiple giant cell granulomas (bones, joints, soft tissues)
LABORATORY ABNORMALITIES:
Partial deficiency of factor XI(C);
Partial deficiency of factor XII(C);
Partial deficiency of factor XIII(C);
Thrombocytopenia
MISCELLANEOUS:
Genetic heterogeneity;
Allelic to LEOPARD syndrome (151100)
MOLECULAR BASIS:
Caused by mutation in the protein tyrosine phosphatase, nonreceptor-type,
11 gene (PTPN11, 176876.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 10/26/2010
Cassandra L. Kniffin - updated: 6/18/2009
Joanna S. Amberger - updated: 7/14/2006
Ada Hamosh - updated: 4/8/2002
Kelly A. Przylepa - revised: 12/7/1999
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 04/10/2012
joanna: 5/18/2011
ckniffin: 12/3/2010
ckniffin: 10/26/2010
joanna: 1/7/2010
ckniffin: 6/18/2009
joanna: 2/19/2009
terry: 2/12/2009
joanna: 7/14/2006
joanna: 10/10/2005
joanna: 3/14/2005
joanna: 3/30/2004
joanna: 4/4/2003
joanna: 2/27/2003
joanna: 4/8/2002
joanna: 1/13/2000
mgross: 12/7/1999
*FIELD* CN
Cassandra L. Kniffin - updated: 3/19/2012
Cassandra L. Kniffin - updated: 10/26/2010
Cassandra L. Kniffin - updated: 10/14/2010
Marla J. F. O'Neill - updated: 10/9/2009
Cassandra L. Kniffin - updated: 6/18/2009
Kelly A. Przylepa - updated: 2/2/2009
Marla J. F. O'Neill - updated: 4/24/2008
Marla J. F. O'Neill - updated: 2/1/2008
Marla J. F. O'Neill - updated: 12/21/2007
Marla J. F. O'Neill - updated: 10/24/2007
John A. Phillips, III - updated: 5/31/2007
John A. Phillips, III - updated: 4/18/2007
Marla J. F. O'Neill - updated: 3/9/2007
Victor A. McKusick - updated: 1/30/2007
John A. Phillips, III - updated: 11/17/2006
Victor A. McKusick - updated: 5/4/2006
Victor A. McKusick - updated: 2/24/2006
Victor A. McKusick - updated: 4/14/2005
Marla J. F. O'Neill - updated: 1/4/2005
Jane Kelly - updated: 11/9/2004
Marla J. F. O'Neill - updated: 5/12/2004
Marla J. F. O'Neill - updated: 4/2/2004
Natalie E. Krasikov - updated: 3/29/2004
Siobhan M. Dolan - updated: 2/19/2004
Victor A. McKusick - updated: 1/14/2004
Victor A. McKusick - updated: 5/15/2003
Victor A. McKusick - updated: 5/13/2003
Cassandra L. Kniffin - updated: 1/9/2003
Victor A. McKusick - updated: 11/27/2002
Victor A. McKusick - updated: 11/12/2001
Victor A. McKusick - updated: 8/6/2001
John A. Phillips, III - updated: 7/10/2001
Michael J. Wright - updated: 5/21/2001
Sonja A. Rasmussen - updated: 10/12/2000
Paul Brennan - updated: 4/10/2000
Victor A. McKusick - updated: 4/30/1998
Victor A. McKusick - updated: 12/19/1997
Iosif W. Lurie - updated: 1/8/1997
Iosif W. Lurie - updated: 9/12/1996
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 08/02/2013
ckniffin: 8/1/2013
carol: 6/20/2013
carol: 6/7/2013
carol: 7/27/2012
alopez: 3/30/2012
terry: 3/28/2012
ckniffin: 3/19/2012
carol: 12/8/2011
wwang: 6/2/2011
wwang: 2/7/2011
ckniffin: 1/21/2011
wwang: 1/10/2011
ckniffin: 12/23/2010
wwang: 11/12/2010
ckniffin: 11/8/2010
wwang: 11/5/2010
ckniffin: 10/26/2010
wwang: 10/19/2010
ckniffin: 10/14/2010
wwang: 10/6/2010
ckniffin: 9/28/2010
alopez: 1/28/2010
ckniffin: 1/19/2010
carol: 11/23/2009
wwang: 10/16/2009
terry: 10/9/2009
wwang: 7/21/2009
ckniffin: 6/18/2009
wwang: 6/3/2009
terry: 6/1/2009
terry: 4/29/2009
wwang: 3/10/2009
joanna: 2/9/2009
carol: 2/4/2009
terry: 2/2/2009
terry: 1/30/2009
carol: 5/22/2008
wwang: 4/24/2008
terry: 4/24/2008
wwang: 2/6/2008
terry: 2/1/2008
wwang: 1/8/2008
terry: 12/21/2007
wwang: 10/25/2007
terry: 10/24/2007
carol: 5/31/2007
carol: 5/30/2007
wwang: 4/19/2007
alopez: 4/18/2007
carol: 4/18/2007
wwang: 3/12/2007
terry: 3/9/2007
alopez: 2/19/2007
alopez: 1/31/2007
terry: 1/30/2007
carol: 11/27/2006
alopez: 11/17/2006
alopez: 5/4/2006
carol: 4/25/2006
alopez: 3/3/2006
terry: 2/24/2006
carol: 1/12/2006
terry: 12/21/2005
ckniffin: 6/30/2005
tkritzer: 4/27/2005
terry: 4/14/2005
carol: 1/5/2005
terry: 1/4/2005
tkritzer: 11/9/2004
tkritzer: 11/3/2004
carol: 5/13/2004
terry: 5/12/2004
tkritzer: 4/5/2004
terry: 4/2/2004
tkritzer: 3/30/2004
terry: 3/29/2004
tkritzer: 2/19/2004
terry: 2/19/2004
tkritzer: 1/15/2004
terry: 1/14/2004
terry: 11/19/2003
carol: 11/13/2003
terry: 7/31/2003
alopez: 6/3/2003
tkritzer: 5/19/2003
terry: 5/15/2003
alopez: 5/14/2003
terry: 5/13/2003
cwells: 1/14/2003
ckniffin: 1/9/2003
mgross: 12/10/2002
carol: 12/4/2002
tkritzer: 12/3/2002
terry: 11/27/2002
alopez: 1/7/2002
alopez: 11/27/2001
alopez: 11/21/2001
alopez: 11/13/2001
terry: 11/12/2001
carol: 8/6/2001
mcapotos: 7/26/2001
cwells: 7/19/2001
cwells: 7/10/2001
alopez: 5/21/2001
mcapotos: 10/13/2000
mcapotos: 10/12/2000
alopez: 4/10/2000
dholmes: 5/12/1998
carol: 5/2/1998
terry: 4/30/1998
dholmes: 12/31/1997
terry: 12/19/1997
jenny: 11/19/1997
alopez: 6/27/1997
terry: 3/6/1997
jenny: 3/4/1997
jenny: 1/21/1997
jenny: 1/8/1997
carol: 9/12/1996
terry: 8/19/1996
terry: 7/29/1996
carol: 6/25/1996
mark: 9/19/1995
carol: 1/31/1995
terry: 12/22/1994
mimadm: 12/2/1994
jason: 7/27/1994
davew: 7/14/1994
MIM
176876
*RECORD*
*FIELD* NO
176876
*FIELD* TI
*176876 PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11
;;PROTEIN-TYROSINE PHOSPHATASE 2C; PTP2C;;
read moreTYROSINE PHOSPHATASE SHP2; SHP2
*FIELD* TX
DESCRIPTION
The protein-tyrosine phosphatases are a highly pleomorphic set of
molecules that have a role in regulating the responses of eukaryotic
cells to extracellular signals (Dechert et al., 1995). They achieve this
by regulating the phosphotyrosine content of specific intracellular
proteins. The PTPases have been grouped by virtue of the characteristic
catalytic domain sequence similarities that define this family. Dechert
et al. (1995) noted that the noncatalytic domain shows a striking degree
of sequence heterogeneity. In general, however, mammalian PTPases can be
subdivided into 1 of 2 broad categories: (1) transmembrane receptor
PTPases that contain linked cytoplasmic catalytic domains, and (2)
intracellular PTPases. Included within the latter category are 2 closely
related mammalian intracellular PTPases whose sequences encode 2 tandem
SRC homology 2 (SH2) domains that are located at the amino-terminal side
of a single PTPase catalytic domain. SH2 domains enable the binding of
these SH2 domain-containing PTPases to specific phosphotyrosine residues
within protein sequences. The first mammalian SH2 domain-containing
PTPase identified was PTP1C (PTPN6; 176883). The second mammalian SH2
domain-containing PTPase identified is encoded by the PTPN11 gene.
CLONING
Ahmad et al. (1993) isolated a cDNA encoding a nontransmembrane
protein-tyrosine phosphatase (PTP; EC 3.1.3.48), termed PTP2C, from a
human umbilical cord cDNA library. The open reading frame consists of
1,779 nucleotides potentially encoding a protein of 593 amino acids with
a predicted molecular mass of 68 kD. The identity between the 2 SH2
domains of PTP2C (PTPN11) and PTP1C (PTPN6) is 50 to 60%, higher than
the identity between the 2 SH2 domains within the same molecule. Unlike
PTP1C, which is restricted to hematopoietic and epithelial cells, PTP2C
is widely expressed in human tissues and is particularly abundant in
heart, brain, and skeletal muscle. Ahmad et al. (1993) also identified a
variant of PTP2C, termed PTP2Ci by them, which had an in-frame insertion
of 12 basepairs within the catalytic domain.
MAPPING
By fluorescence in situ hybridization, Isobe et al. (1994) mapped the
PTP2C gene to 12q24.1. It is noteworthy that the PTP1C gene maps to the
short arm of chromosome 12, whereas PTP2C maps to the long arm. Dechert
et al. (1995) used a 2.1-kb SH-PTP2 cDNA clone (Bastien et al., 1993) to
localize the PTPN11 gene to 12q24.1-q24.3 by isotopic in situ
hybridization. The presence of cross-hybridizing sequences located on a
number of other chromosomes suggested that latent genes or pseudogenes
are present in the human genome.
BIOCHEMICAL FEATURES
- Crystal Structure
Hof et al. (1998) described the crystal structure of amino acid residues
1 to 527 of the PTPN11 protein at 2.0-angstrom resolution. The crystal
structure showed how its catalytic activity is regulated by its two SH2
domains. In the absence of a tyrosine-phosphorylated binding partner,
the N-terminal SH2 domain binds the phosphatase domain and directly
blocks its active site. This interaction alters the structure of the
N-SH2 domain, disrupting its phosphopeptide-binding cleft. Conversely,
interaction of the N-SH2 domain with phosphopeptide disrupts its
phosphatase recognition surface. Thus, the N-SH2 domain is a
conformational switch; it either binds and inhibits the phosphatase, or
it binds phosphoproteins and activates the enzyme. The C-terminal SH2
domain contributes binding energy and specificity, but does not have a
direct role in activation.
GENE FUNCTION
Zhao and Zhao (1998) presented evidence indicating that MPZL1 (604376)
and PTPNS1 (602461) are substrates for PTPN11.
Helicobacter pylori CagA protein is injected from the attached H. pylori
into host cells in the stomach and undergoes tyrosine phosphorylation.
Higashi et al. (2002) demonstrated that wildtype but not
phosphorylation-resistant CagA induces a growth factor-like response in
gastric epithelial cells by forming a physical complex with SHP2 in a
phosphorylation-dependent manner and stimulating the phosphatase
activity. Disruption of the CagA-SHP2 complex abolishes the
CagA-dependent cellular response. Conversely, the CagA effect on cells
was reproduced by constitutively active SHP2. Thus, Higashi et al.
(2002) concluded that upon translocation, CagA perturbs cellular
functions by deregulating SHP2.
Kwon et al. (2005) showed that activation of T-cell antigen receptor
(see 186880) in human Jurkat T cells and in mouse T-cell blasts induced
transient inactivation of SHP2 by the oxidation of the SHP2 active site
cysteine. SHP2 was recruited to the LAT (602354)-GADS (GRAP2;
604518)-SLP76 (LCP2; 601603) complex and regulated the phosphorylation
of VAV1 (164875) and ADAP (FYB; 602731). The association of ADAP with
the SLP76 complex was regulated by SHP2 in a redox-dependent manner.
Kwon et al. (2005) concluded that TCR-mediated ROS generation leads to
SHP2 oxidation, which promotes T-cell adhesion through effects on
SLP76-dependent signaling.
Kikkawa et al. (2010) identified a putative microRNA-489 (MIR489;
614523) target site in the 3-prime UTR of PTPN11, which encodes a
protein tyrosine phosphatase that can activate RAS (HRAS; 190020)-MAP
kinase (see 176948) signaling in response to growth factors and
cytokines. Overexpression of MIR489 in a human squamous cell carcinoma
cell line reduced PTPN11 mRNA and protein expression and inhibited
expression of a reporter gene containing a partial PTPN11 3-prime UTR.
PTPN11 mRNA expression was significantly higher in hypopharyngeal
squamous cell carcinomas compared with adjacent normal tissue from 16
patients. In contrast, MIR489 was downregulated in hypopharyngeal
squamous cell carcinomas.
MOLECULAR GENETICS
- Noonan Syndrome
In more than 50% of patients with Noonan syndrome (163950), Tartaglia et
al. (2001) identified mutations in the PTPN11 gene (see, e.g.,
176876.0001-176876.0003). All the PTPN11 missense mutations were
clustered in the interacting portions of the amino N-SH2 domain and the
phosphotyrosine phosphatase (PTP) domains, which are involved in
switching the protein between its inactive and active conformations. An
energetics-based structural analysis of 2 N-SH2 mutants indicated that
in these cases there may be a significant shift of the equilibrium
favoring the active conformation. The findings suggested that
gain-of-function changes resulting in excessive SHP-2 activity underlie
the pathogenesis of Noonan syndrome.
Tartaglia et al. (2002) identified a PTPN11 mutation (176876.0004) in a
family inheriting Noonan syndrome with multiple giant cell lesions in
bone.
Using direct DNA sequencing, Maheshwari et al. (2002) surveyed 16
subjects with the clinical diagnosis of Noonan syndrome from 12 families
and their relevant family members for mutations in the PTPN11/SHP2 gene,
and found 3 different mutations among 5 families. Two unrelated subjects
shared a de novo ser502-to-thr (S502T; 176876.0007) substitution in exon
13; 2 additional unrelated families had a tyr63-to-cys (Y63C;
176876.0008) mutation in exon 3; and 1 subject had a tyr62-to-asp (Y62D;
176876.0009) substitution, also in exon 3. In the mature protein model,
the exon 3 mutants and the exon 13 mutant amino acids cluster at the
interface between the N-terminal SH2 domain and the phosphatase
catalytic domain. Six of 8 subjects with mutations had pulmonary valve
stenosis, while no mutations were identified in 4 subjects with
hypertrophic cardiomyopathy. An additional 4 subjects with possible
Noonan syndrome were evaluated, but no mutations in PTPN11 were
identified. These results confirmed that mutations in PTPN11 underlie a
common form of Noonan syndrome, and that the disease exhibits both
allelic and locus heterogeneity. The observation of recurrent mutations
supports the hypothesis that a special class of gain-of-function
mutations in SHP2 gives rise to Noonan syndrome.
Kosaki et al. (2002) analyzed the PTPN11 gene in 21 Japanese patients
with Noonan syndrome. Mutation analysis of the 15 coding exons and their
flanking introns by denaturing HPLC and direct sequencing revealed 6
different heterozygous missense mutations in 7 cases. The mutations
clustered either in the N-Src homology 2 domain or in the
protein-tyrosine phosphatase domain. The clinical features of the
mutation-positive and mutation-negative patients were comparable.
Musante et al. (2003) screened the PTPN11 gene for mutations in 96
familial or sporadic Noonan syndrome patients. They identified 15
mutations, all of which were missense mutations; 11 of them were located
in exon 3, which encodes the N-SH2 domain. No obvious clinical
differences were detected between subgroups of patients with mutations
in different PTPN11 domains. Analysis of the clinical features of the
patients revealed that several patients with facial abnormalities
thought to be pathognomonic for NS did not have a mutation in the PTPN11
gene. Widely varying phenotypes among the group of 64 patients without
PTPN11 mutations suggested further genetic heterogeneity.
Tartaglia et al. (2004) investigated the parental origin of de novo
PTPN11 lesions and explored the effect of paternal age in Noonan
syndrome. By analyzing intronic positions that flank the exonic PTPN11
lesions in 49 sporadic Noonan syndrome cases, they traced the parental
origin of mutations in 14 families. All mutations were inherited from
the father, despite the fact that no substitution affected a CpG
dinucleotide. They also found advanced paternal age among cohorts of
sporadic Noonan syndrome cases with and without PTPN11 mutations and
that a significant sex-ratio bias favoring transmission to males was
present in subjects with sporadic Noonan syndrome caused by PTPN11
mutations, as well as in families inheriting the disorder. They favored
sex-specific developmental effects as the explanation for the sex-ratio
distortion in PTPN11-associated Noonan syndrome, because fetal lethality
has been documented in this disorder.
Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical
assessment in 45 Japanese patients with Noonan syndrome. Sequence
analysis of the coding exons 1 through 15 of PTPN11 revealed a novel
3-bp deletion (176876.0024) and 10 recurrent missense mutations in 18
patients.
Becker et al. (2007) reported what they stated was the first known case
of compound heterozygosity for NS-causing mutations in the PTPN11 gene
(see 176876.0004 and 176876.0008), resulting in early fetal death.
Shchelochkov et al. (2008) and Graham et al. (2009) reported 2 unrelated
patients with a Noonan syndrome phenotype associated with respective
10-Mb and 8.98-Mb duplications on chromosome 12q24.13, encompassing the
PTPN11 gene. Graham et al. (2009) did not identify additional
duplications in a screening of more than 250 Noonan syndrome cases
without mutations in known disease-causing genes. Graham et al. (2009)
concluded that duplication of PTPN11 represents an uncommon cause of
Noonan syndrome. However, the rare observation of NS in individuals with
duplications involving the PTPN11 locus suggested that increased dosage
of this gene may have dysregulating effects on intracellular signaling.
- LEOPARD Syndrome
LEOPARD syndrome (151100) is an autosomal dominant disorder
characterized by lentigines and cafe-au-lait spots, facial anomalies,
and cardiac defects, sharing several clinical features with Noonan
syndrome. Digilio et al. (2002) screened 9 patients with LEOPARD
syndrome (including a mother-daughter pair), and 2 children with Noonan
syndrome who had multiple cafe-au-lait spots, for mutations in the
PTPN11 gene. They found, in 10 of the 11 patients, 1 of 2 novel missense
mutations, in exon 7 (176876.0005) or exon 12 (176876.0006). Both
mutations affected the PTPN11 phosphotyrosine phosphatase domain, which
is involved in less than 30% of the Noonan syndrome PTPN11 mutations.
This study demonstrated that LEOPARD syndrome and Noonan syndrome are
allelic disorders. The detected mutations suggested that distinct
molecular and pathogenetic mechanisms cause the peculiar cutaneous
manifestations of the LEOPARD syndrome subtype of Noonan syndrome.
In 4 of 6 Japanese patients with LEOPARD syndrome, Yoshida et al. (2004)
identified 1 of 3 heterozygous missense mutations: tyr279 to cys
(Y279C), ala461 to thr (A461T; 176876.0020), or gly464 to ala (G464A;
176876.0021).
Kontaridis et al. (2006) examined the enzymatic properties of mutations
in PTPN11 causing LEOPARD syndrome and found that, in contrast to the
activating mutations that cause Noonan syndrome and neoplasia, LEOPARD
syndrome mutants are catalytically defective and act as
dominant-negative mutations that interfere with growth factor/ERK-MAPK
(see 176948)-mediated signaling. Molecular modeling and biochemical
studies suggested that LEOPARD syndrome mutations control the SHP2
catalytic domain and result in open, inactive forms of SHP2. Kontaridis
et al. (2006) concluded that the pathogenesis of LEOPARD syndrome is
distinct from that of Noonan syndrome and suggested that these disorders
should be distinguished by mutation analysis rather than clinical
presentation.
- Cardiofaciocutaneous Syndrome
Patients affected with cardiofaciocutaneous syndrome (CFC; 115150)
present with symptoms that some considered to represent a more severe
expression of Noonan syndrome, namely, congenital heart defects,
cutaneous abnormalities, Noonan-like facial features, and severe
psychomotor developmental delay. Because mutations in PTPN11 are
responsible for Noonan syndrome, Ion et al. (2002) investigated the
possibility that this gene may be involved in CFC syndrome. A cohort of
28 CFC subjects rigorously assessed as having CFC 'based on OMIM
diagnostic criteria' was examined for mutations in the PTPN11 coding
sequence by means of denaturing high-performance liquid chromatography
(DHPLC). No abnormalities in the coding region of the gene were found in
any patient, nor any evidence of major deletions within the gene.
Musante et al. (2003) screened for mutations in the PTPN11 gene in 5
sporadic patients with CFC syndrome and found none.
In 10 affected members from a large 4-generation Belgian family with
Noonan syndrome and some features suggestive of CFC syndrome, Schollen
et al. (2003) identified a missense mutation in the PTPN11 gene
(176876.0018). The mutation was not found in 7 unaffected relatives or 3
spouses. The authors noted that in D. melanogaster and C. elegans, the
Ptpn11 gene has been implicated in oogenesis. In this family, there were
3 sets of dizygotic twins among the offspring of 2 affected females,
suggesting that PTPN11 might also be involved in oogenesis and twinning
in humans.
Bertola et al. (2004) described a young woman with clinical features of
Noonan syndrome but with some characteristics of CFC as well, including
prominent ectodermal involvement, developmental delay, and mental
retardation. They identified a T411M mutation in the PTPN11 gene
(176876.0019); the same mutation was found in her mother and older
sister, not initially considered to be affected but who had subtle
clinical findings compatible with the diagnosis of Noonan syndrome. The
mother had 5 miscarriages, 2 of them twinning pregnancies.
- Juvenile Myelomonocytic Leukemia
Juvenile myelomonocytic leukemia (JMML; 607785), a disorder with
excessive proliferation of myelomonocytic cells, constitutes
approximately 30% of childhood cases of myelodysplastic syndrome (MDS)
and 2% of leukemia. JMML is observed occasionally in patients with
Noonan syndrome, leading Tartaglia et al. (2003) to consider whether
defects in PTPN11 are present in myeloid disorders. In 5 unrelated
children with Noonan syndrome and JMML, they found heterozygosity with
respect to a mutation in exon 3 of PTPN11. Four of the children shared
the same mutation (218C-T; 176876.0011). In 2 unrelated individuals with
growth retardation, pulmonic stenosis, and JMML, they found missense
defects in PTPN11: the 218C-T transition, and a defect in exon 13
affecting the protein tyrosine phosphatase domain. Analysis of germline
and parental DNAs for these 6 cases indicated that the mutations were de
novo germline events.
Tartaglia et al. (2003) also identified somatic missense mutations in
PTPN11 in 21 of 62 individuals with JMML but without Noonan syndrome,
with 9 different molecular defects in exon 3 and 1 in exon 13.
Nonhematologic DNAs were available for 9 individuals with a mutation in
PTPN11 in their leukemic cells, and none harbored the defect.
Tartaglia et al. (2003) identified no mutation in PTPN11 among 8
individuals with JMML and neurofibromatosis type I (162200). Molecular
screening for mutations in exons 1 and 2 of NRAS (164790) and KRAS2
(190070) identified defects in 5 and 7 individuals with isolated cases
of JMML, respectively, none of whom harbored a mutation in PTPN11. This
indicated that defects in RAS, neurofibromin, and SHP2, all involved in
regulation of the MAPK cascade, are mutually exclusive in JMML.
Comparison of phenotypes and karyotypes did not identify differences
between individuals with JMML who did or did not have mutations in
PTPN11.
- Other Malignancies
Tartaglia et al. (2003) investigated the prevalence of somatic mutations
in PTPN11 among 50 children with myelodysplastic syndrome. They
identified no mutation among 23 children with refractory anemia, but
observed missense mutations in exon 3 in 5 of 27 children with an excess
of blasts. Three of these mutations were also associated with JMML in
other patients. Among 24 children with de novo AML (601626), they
identified a novel trinucleotide substitution in an infant with acute
monoblastic leukemia.
Bentires-Alj et al. (2004) demonstrated that mutations in PTPN11 occur
at low frequency in several human cancers, especially neuroblastoma
(256700) and AML.
- Metachondromatosis
Using whole-genome sequencing in 1 affected individual from a
5-generation family with metachondromatosis (METCDS; 156250), Sobreira
et al. (2010) identified a heterozygous 11-bp deletion in the PTPN11
gene (176876.0025) that segregated with the disease. Sequencing of
PTPN11 in another family with metachondromatosis revealed a heterozygous
nonsense mutation (176876.0026) in affected individuals. Neither
mutation was detected in 469 controls.
Bowen et al. (2011) used a targeted array to capture exons and promoter
sequences from an 8.6-Mb linked interval in 16 participants from 11
metachondromatosis families, and sequenced the captured DNA using
high-throughput parallel sequencing technologies. By this method, they
identified heterozygous putative loss-of-function mutations in the
PTPN11 gene in 4 of the 11 families (176876.0028-176876.0031). Sanger
sequence analysis of PTPN11 coding regions in the 7 remaining families
and in 6 additional metachondromatosis families identified novel
heterozygous mutations in 4 families (176876.0032-176876.0035). Copy
number analysis of sequencing reads from a second targeted capture that
included the entire PTPN11 gene identified an METCDS patient with a
15-kb deletion spanning exon 7 of PTPN11 (176876.0036). In total, of 17
METCDS families, Bowen et al. (2011) identified mutations in 11 (5
frameshift, 2 nonsense, 3 splice site, and 1 large deletion). Each
family had a different mutation, and the mutations were scattered across
the gene. Microdissected METCDS lesions from 2 patients with PTPN11
mutations demonstrated loss of heterozygosity for the wildtype allele.
Bowen et al. (2011) suggested that metachondromatosis may be genetically
heterogeneous because 1 familial and 5 sporadically occurring cases
lacked obvious disease-causing PTPN11 mutations.
GENOTYPE/PHENOTYPE CORRELATIONS
Tartaglia et al. (2002) reported the spectrum and distribution of PTPN11
mutations in a large, well-characterized cohort with NS. They found
mutations in 54 of 119 (45%) unrelated individuals with sporadic or
familial NS. There was a significantly higher prevalence of mutations
among familial cases than among sporadic ones. All defects were missense
and several were recurrent. Pulmonic stenosis was more prevalent among
the group of subjects with NS who had PTPN11 mutations than it was in
the group without them: 70.6% vs 46.2% (P less than 0.01); hypertrophic
cardiomyopathy was less prevalent among those with PTPN11 mutations:
5.9% vs 26.2%; (P less than 0.005). The prevalence of other congenital
heart malformations, short stature, pectus deformity, cryptorchidism,
and developmental delay did not differ between the 2 groups. A PTPN11
mutation was identified in a family inheriting Noonan syndrome with
multiple giant cell lesions in bone, extending the phenotypic range of
disease associated with this gene (see 176876.0004).
Sarkozy et al. (2003) analyzed the PTPN11 gene in 71 Italian patients
with Noonan syndrome and 13 with multiple lentigines/LEOPARD syndrome
(ML/LS) and identified 14 different missense mutations in 34 patients,
23 with Noonan syndrome and 11 with ML/LS. The distribution of
congenital heart defects was markedly different between the 2 groups.
Pulmonary valve stenosis, the most common congenital heart defect in
Noonan syndrome, was related to an exon 8 mutation hotspot at residue
asn308 (see, e.g., 176876.0003 and 176876.0004), whereas hypertrophic
cardiomyopathy, predominant in patients with ML/LS, was associated with
mutations in exon 7 (see, e.g., Y279C; 176876.0005) and exon 12 (see,
e.g., T468M; 176876.0006). Atrial septal defects were related to exon 3
mutations (see, e.g., Y62D; 176876.0009), whereas atrioventricular canal
defects and mitral valve anomalies were found in association with
different exon mutations.
Niihori et al. (2005) identified PTPN11 mutations in 16 of 41 patients
with Noonan syndrome and 3 of 29 patients with childhood leukemia.
Immune complex tyrosine phosphatase assays showed that all the mutations
resulted in increased phosphatase activity compared to wildtype. Several
mutations in the N-SH2 domain, including T73I (176876.0011), showed a 6-
to 12-fold increase in activity. Other N-SH2 mutations (Y63C;
176876.0008 and Q79R; 176876.0018) and PTP-domain mutations (N308D;
176876.0003 and S502T; 176876.0007) showed a 2- to 4-fold increase in
activity. These results and a review of previously reported cases
indicated that high phosphatase activity observed in mutations at codons
61, 71, 72, and 76 was significantly associated with leukemogenesis. Two
mutations associated with Noonan syndrome failed to promote the RAS/MAPK
downstream signaling pathway.
Tartaglia et al. (2006) proposed a model that splits Noonan syndrome-
and leukemia-associated PTPN11 mutations in the 2 major classes of
activating lesions with differential perturbing effects on development
and hematopoiesis. To test this model, they investigated further the
diversity of germline and somatic PTPN11 mutations, delineated the
association of those mutations with disease, characterized biochemically
a panel of mutant SHP2 proteins recurring in Noonan syndrome, LEOPARD
syndrome, and leukemia, and performed molecular dynamics simulations to
determine the structural effects of selected mutations. The results
documented a strict correlation between the identity of the lesion and
disease, and demonstrated that Noonan syndrome-causative mutations have
less potency for promoting SHP2 gain of function than do
leukemia-associated ones. Furthermore, they showed that the recurrent
LEOPARD syndrome-causing Y279C (176876.0005) and T468M (176876.0006)
amino acid substitutions engender loss of SHP2 catalytic activity,
identifying a previously unrecognized behavior of this class of missense
PTPN11 mutations. By molecular modeling and biochemical studies,
Kontaridis et al. (2006) showed that LEOPARD syndrome mutations control
the SHP2 catalytic domain and result in open, inactive forms of SHP2.
They concluded that pathogenesis of LEOPARD syndrome is distinct from
that of Noonan syndrome and suggested that these disorders should be
distinguished by mutation analysis rather than clinical presentation.
Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical
assessment in 45 Japanese patients with Noonan syndrome. They identified
11 mutations in 18 patients. Clinical assessment showed that the growth
pattern was similar in mutation-positive and mutation-negative patients.
Pulmonary valve stenosis was more frequent in mutation-positive patients
than in mutation-negative patients, as was atrial septal defect, whereas
hypertrophic cardiomyopathy was present in 5 mutation-negative patients
only. Hematologic abnormalities such as bleeding diathesis and juvenile
myelomonocytic leukemia were exclusively present in mutation-positive
patients.
Limongelli et al. (2008) studied 24 LEOPARD syndrome patients, 16 with
mutations in the PTPN11 gene, 2 with mutations in the RAF1 gene
(164760), and 6 in whom no mutation had been found. Patients without
PTPN11 mutations showed a significantly higher frequency of family
history of sudden death, increased left atrial dimensions, and cardiac
arrhythmias, and seemed to be at higher risk for adverse cardiac events.
Three patients with mutations in exon 13 of the PTPN11 gene had a severe
form of biventricular obstructive LVH with early onset of heart failure
symptoms, consistent with previous observations.
ANIMAL MODEL
Atrioventricular and semilunar valve abnormalities are common birth
defects. During studies of genetic interaction between Egr2 and Ptpn11,
encoding the protein-tyrosine phosphatase Shp2, Chen et al. (2000) found
that Egfr (131550) is required for semilunar, but not atrioventricular,
valve development. Although unnoticed in earlier studies, mice
homozygous for the hypomorphic Egfr allele 'waved-2' exhibited semilunar
valve enlargement resulting from overabundant mesenchymal cells. Egfr
-/- mice (on CD1 background) had similar defects. The penetrance and
severity of the defects in the homozygous 'waved-2' mice were enhanced
by heterozygosity for targeted mutation of exon 2 of Ptpn11. Compound
mutant mice also showed premature lethality. Electrocardiography,
echocardiography, and hemodynamic analyses showed that affected mice
developed aortic stenosis and regurgitation. The results identified Egfr
and Shp2 as components of a growth-factor signaling pathway required
specifically for semilunar valvulogenesis, supported the hypothesis that
Shp2 is required for Egfr signaling in vivo, and provided an animal
model for aortic valve disease.
Shp2 can potentiate signaling for the MAP kinase pathway (see 602425)
and is required during early mouse development for gastrulation.
Chimeric analysis can identify, by study of phenotypically normal
embryos, tissues that tolerate mutant cells, and therefore do not
require the mutated gene, or lack mutant cells and presumably require
the mutated gene during the developmental history. Saxton et al. (2000)
therefore generated chimeric mouse embryos to explore the cellular
requirements for Shp2. This analysis revealed an obligatory role for
Shp2 during outgrowth of the limb. Shp2 is specifically required in
mesenchyme cells of the progress zone, directly beneath the distal
ectoderm of the limb bud. Comparison of Ptpn11 mutant and Fgfr1 (136350)
mutant chimeric limbs indicated that in both cases mutant cells failed
to contribute to the progress zone of phenotypically normal chimeras,
leading to the hypothesis that a signal transduction pathway, initiated
by Fgfr1 and acting through Shp2, is essential within progress zone
cells. Rather than integrating proliferative signals, Shp2 probably
exerts its effects on limb development by influencing cell shape,
movement, or adhesion. Furthermore, the branchial arches, which also use
Fgfs during bud outgrowth, similarly require Shp2. Thus, Shp2 regulates
phosphotyrosine-signaling events during the complex
ectodermal-mesenchymal interactions that regulate mammalian budding
morphogenesis.
Saxton et al. (1997) generated mice deficient in Shp2 by targeted
disruption. Homozygous Shp2 -/- mice die at midgestation with multiple
defects in mesodermal patterning, while heterozygous mutants appear
normal. Qu et al. (1998) aggregated homozygous mutant embryonic stem
(ES) cells and wildtype embryos to create Shp2 -/- wildtype chimeric
animals. They reported an essential role of Shp2 in the control of blood
cell development. Despite the widespread contribution of mutant cells to
various tissues, no Shp2 -/- progenitors for erythroid or myeloid cells
were detected in the fetal liver or bone marrow of chimeric animals by
using the in vitro colony forming unit (CFU) assay. Furthermore,
hematopoiesis was defective in Shp2 -/- yolk sacs. In addition, the Shp2
mutant caused multiple developmental defects in chimeric mice,
characterized by short hind legs, aberrant limb features, split lumbar
vertebrae, abnormal rib patterning, and pathologic changes in the lungs,
intestines, and skin. Qu et al. (1998) concluded that Shp2 is involved
in the differentiation of multiple tissue-specific cells and in body
organization. They suggested that the requirement for Shp2 appears to be
more stringent in hematopoiesis than in other systems.
Zhang et al. (2004) selectively deleted Shp2 in postmitotic forebrain
neurons of mice and observed the development of early-onset obesity with
increased serum levels of leptin (164160), insulin (176730), glucose,
and triglycerides, although the mutant mice were not hyperphagic. In
wildtype mice, the authors found that Shp2 downregulation of Jak2
(147796)/Stat3 (102582) activation by leptin in the hypothalamus was
offset by a dominant Shp2 promotion of the leptin-stimulated Erk (see
601795) pathway; thus, Shp2 deletion in the brain results in induction
rather than suppression of leptin resistance. Zhang et al. (2004)
suggested that a primary function of SHP2 in the postmitotic forebrain
is to control energy balance and metabolism, and that SHP2 is a critical
signaling component of the leptin receptor (601007) in the hypothalamus.
Using a constitutively active mouse Shp2 mutant, He et al. (2012) found
that Shp2 integrated leptin and estrogen signaling in transgenic female
mice. Transgenic females, but not males, were resistant to high-fat
diet-induced obesity and liver steatosis via enhanced leptin and insulin
sensitivity and downstream ERK activation. SHP2 and estrogen
receptor-alpha (ESR1; 133430) interacted directly in MCF-7 cells and
female mouse tissues, and the interaction was enhanced by estrogen
stimulation. Ovariectomy of transgenic mice reversed their resistance to
high-fat diet-induced obesity.
Nakamura et al. (2007) generated Q79R (176876.0018) transgenic mice in
which the mutated protein was expressed in cardiomyocytes either during
gestation or following birth. Q79R Shp2 embryonic hearts showed altered
cardiomyocyte cell cycling, ventricular noncompaction, and ventricular
septal defects, whereas in the postnatal cardiomyocyte, Q79R Shp2
expression was benign. Fetal expression of Q79R led to the specific
activation of the ERK1/2 pathway (see 176948), and breeding Q79R
transgenics into Erk1/2-null backgrounds confirmed that the pathway was
necessary and sufficient for mediating the effects of mutant Shp2.
Nakamura et al. (2007) concluded that there are developmental
stage-specific effects of Q79R cardiac expression in Noonan syndrome,
and that ablation of subsequent ERK1/2 activation prevents the
development of cardiac abnormalities.
In cultured mouse embryonic cortical precursor cells, Gauthier et al.
(2007) found that Shp2 enhanced neurogenesis and inhibited
cytokine-mediated astrocytosis. Inhibition of Shp2 resulted in decreased
neurogenesis, aberrant migration of neurons, and premature gliogenesis.
Expression of a Noonan syndrome-associated Shp2 mutant with enhanced
activity promoted neurogenesis and inhibited astrogenesis in vitro and
in vivo. Further studies showed that Shp2 promotes neurogenesis via
activation of the MEK-ERK pathway, and inhibits gliogenesis by
suppressing the gp130 (IL6ST; 600694)-JAK-STAT pathway. Gauthier et al.
(2007) suggesting that the cognitive impairment observed in some
patients with Noonan syndrome may result from aberrant neuron cell-fate
and a perturbation in the relative ratios of these brain cell types
during development.
To study the developmental effects of the Y279C and T468M mutations in
the PTPN11 gene, Oishi et al. (2009) generated the equivalent mutations
in the orthologous Drosophila corkscrew (csw) gene. Ubiquitous
expression of the mutant csw alleles resulted in ectopic wing veins and,
for the Y279C allele, rough eyes with increased R7 photoreceptor
numbers. These were gain-of-function phenotypes mediated by increased
RAS/MAPK signaling and requiring the residual phosphatase activity of
the mutant Y279C and T468M alleles.
Princen et al. (2009) created mice with deletion of Shp2 directed to
striated muscle. Homozygous mutant mice were born at the expected
frequency, but developed severe dilated cardiomyopathy, resulting in
heart failure and death within 2 weeks of birth. Development of
cardiomyopathy was associated with insulin resistance, glucose
intolerance, and impaired insulin-stimulated glucose uptake in striated
muscle. No significant abnormalities were observed in other tissues and
organs, including skeletal muscle.
Xu et al. (2010) found that mice with a germline heterozygous D61G
mutation (176876.0010) developed a JMML-like myeloproliferative disorder
with excessive myeloid expansion in the bone marrow and spleen.
Homozygous mutant mice were embryonic lethal due to cardiac
developmental defects. Heterozygous mutant mice had higher levels of
short- and long-term hematopoietic stem cells in the bone marrow and
spleen compared to wildtype mice. Stem cells from heterozygous mutant
mice showed enhanced entry of quiescent stem cells (G0 phase) into the
cell cycle, as well as decreased apoptosis, and showed a greater
long-term repopulating ability in transplanted mice compared to wildtype
cells. Primary and secondary recipient mice transplanted with
D61G-mutant bone marrow cells or purified lineage-negative Sca1+/Kit+
(LSK) cells developed a myeloproliferative disorder, suggesting that the
pathogenic effects of the Ptpn11 mutation are cell autonomous and occur
at the level of the hematopoietic stem cell. D61G-mutant cells also
showed an enhanced response to stimulation with IL3 (147740). Studies
with heterozygous D61G/Gab2 (606203)-null mice and cells showed
attenuation of the increased number of stem cells, indicating that Gab2
is an important mediator of the myeloproliferative disorder induced by
the D61G mutation. Gab2 is a prominent PTPN11-interacting protein with a
role in cell signaling.
To investigate the pathogenesis of metachondromatosis (156250), Yang et
al. (2013) used a conditional knockout (floxed) Ptpn11 allele
(Ptpn11(fl)) and Cre recombinase transgenic mice to delete Ptpn11
specifically in monocytes, macrophages, and osteoclasts (lysozyme
(153450) M-Cre; LysMCre) or in cathepsin K (Ctsk; 601105)-expressing
cells, theretofore thought to be osteoclasts. The LysMCre;Ptpn11(fl/fl)
mice had mild osteopetrosis. However, CtskCre;Ptpn11(fl/fl) mice
developed features very similar to metachondromatosis. Lineage tracing
revealed a novel population of CtskCre-expressing cells in the
perichondrial groove of Ranvier that display markers and functional
properties consistent with mesenchymal progenitors (Ctsk+ chondroid
progenitors, or CCPs). Chondroid neoplasms arise from these cells and
show decreased extracellular signal-regulated kinase (ERK) pathway
activation, increased Indian hedgehog (Ihh; 600726) and parathyroid
hormone-related protein (Pthrp; 168470) expression and excessive
proliferation. Shp2-deficient chondroprogenitors had decreased
fibroblast growth factor (FGF)-evoked ERK activation and enhanced Ihh
and Pthrp expression, whereas fibroblast growth factor receptor (FGFR;
see 136350) or mitogen-activated protein kinase kinase (MEK; see 176872)
inhibitor treatment of chondroid cells increased Ihh and Pthrp
expression. Importantly, smoothened (601500) inhibitor treatment
ameliorated metachondromatosis features in the CtskCre;Ptpn11(fl/fl)
mice. Yang et al. (2013) concluded that thus, in contrast to its
prooncogenic role in hematopoietic and epithelial cells, Ptpn11 is a
tumor suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent
pathway in a novel progenitor cell population to prevent excessive Ihh
production.
*FIELD* AV
.0001
NOONAN SYNDROME 1
PTPN11, ALA72SER
In a family with Noonan syndrome (163950), Tartaglia et al. (2001) found
that affected members had a G-to-T transversion at position 214 in exon
3 of the PTPN11 gene, predicting an ala72-to-ser (A72S) substitution in
the N-SH2 domain. This mutation was also identified by Kosaki et al.
(2002).
.0002
NOONAN SYNDROME 1
PTPN11, ALA72GLY
In a family with Noonan syndrome (163950), Tartaglia et al. (2001) found
that affected members had a C-to-G transversion at nucleotide 215 in
exon 3 of the PTPN11 gene, predicting an ala72-to-gly (A72G) amino acid
substitution.
.0003
NOONAN SYNDROME 1
PTPN11, ASN308ASP
In affected members of 3 families and in a sporadic case of Noonan
syndrome (163950), Tartaglia et al. (2001) found a 922A-G transition in
exon 8 of the PTPN11 gene, predicting an asn308-to-asp (N308D) amino
acid change. This missense mutation affected the phosphotyrosine
phosphatase (PTP) domain.
In a comprehensive study of Tartaglia et al. (2002), about one-third of
the patients who had mutations in the PTPN11 gene had this mutation,
which was by far the most common. This was the mutation present in the
large 3-generation family that was used originally to establish linkage
to the locus on 12q. That codon 308 is a hotspot for Noonan syndrome was
further indicated by the finding of an asn308-to-ser (176876.0004)
missense mutation in 2 families (Tartaglia et al., 2002). In the cohort
of Noonan syndrome patients studied by Tartaglia et al. (2002) noted
that in their cohort, no patient carrying the N308D mutation was
enrolled in special education.
Kosaki et al. (2002) found this mutation in a Japanese patient.
In 13 (23%) of 56 patients with Noonan syndrome, Jongmans et al. (2005)
identified the N308D mutation, confirming the reputation of nucleotide
922 as a mutation hotspot. Among these 13 patients only 3 attended
special school. Except for this suspected correlation with normal
education, the phenotype observed in patients with the mutation at
nucleotide 922 did not differ from the phenotype in patients with other
mutations.
Yoon et al. (2013) calculated that the de novo mutation frequency of the
922A-G (N308D) mutation exceeds the genome average A-G mutation
frequency by more than 2,400-fold. Yoon et al. (2013) examined the
spacial distribution of the mutation in testes of 15 unaffected men and
found that the mutations were not uniformly distributed across each
testis as would be the expected for a mutation hot spot but were highly
clustered and showed an age-dependent germline mosaicism. Computational
modeling that used different stem cell division schemes confirmed that
the data were inconsistent with hypermutation, but consistent with
germline selection: mutated spermatogonial stem cells gained an
advantage that allowed them to increase in frequency. SHP-2, the protein
encoded by PTPN11, interacts with the transcriptional activator STAT3
(102582). Given STAT3's function in mouse spermatogonial stem cells,
Yoon et al. (2013) suggested that this interaction might explain the
mutant's selective advantage by means of repression of stem cell
differentiation signals. Repression of STAT3 activity by cyclin D1
(168461) might also play a role in providing a germline-selective
advantage to spermatogonia for the recurrent mutations in the receptor
tyrosine kinases that cause Apert syndrome (101200) and MEN2B (162300).
.0004
NOONAN SYNDROME 1
PTPN11, ASN308SER
Whereas the very frequent N308D missense mutation (176876.0003) is
caused by a change of nucleotide 922, 2 families with Noonan syndrome
(163950) studied by Tartaglia et al. (2002) showed an asn308-to-ser
(N308S) missense mutation due to an A-to-G transition at the adjacent
nucleotide 923. Thus, codon 308 is a hotspot for Noonan syndrome. One of
the 2 families in which the N308S mutation was observed had typical
features of Noonan syndrome associated with multiple giant cell lesions
in bone.
In a case of fetal demise at 12 weeks' gestation, Becker et al. (2007)
identified compound heterozygosity for the N308S and Y63C (176876.0008)
mutations in the PTPN11 gene. The mother and father, who exhibited
facial features of Noonan syndrome and had both undergone surgical
correction of pulmonary valve stenosis, were heterozygous for N308S and
Y63C, respectively. A second pregnancy resulted in the birth of a boy
with Noonan syndrome carrying the paternal Y63C mutation.
.0005
LEOPARD SYNDROME
PTPN11, TYR279CYS
In 3 patients with LEOPARD syndrome (151100), Digilio et al. (2002)
found an A-to-G transition at nucleotide 836 in exon 7 of the PTPN11
gene resulting in a tyr279-to-cys (Y279C) mutation.
Yoshida et al. (2004) identified heterozygosity for the Y279C mutation
in 2 Japanese patients with LEOPARD syndrome.
Edouard et al. (2010) found that the Y279C mutation caused elevated EGF
(131530)-induced PI3 kinase (see 601232)/AKT (164730) phosphorylation
and activation in LEOPARD syndrome patient fibroblasts and transfected
HEK293 cells compared with normal controls. This upregulation was due to
impaired dephosphorylation of GAB1 (604439), which resulted in enhanced
binding between GAB1 and the PI3 kinase regulatory subunit p85 (see
PIK3R1; 171833). PI3 kinase hyperactivation in Y279C mutant cells also
enhanced myocardin (MYOCD; 606127)/SRF (600589) activity.
.0006
LEOPARD SYNDROME
PTPN11, THR468MET
In 5 unrelated patients and in a mother-daughter pair with LEOPARD
syndrome (151100), Digilio et al. (2002) found a thr468-to-met (T468M)
mutation resulting from a C-to-T transition at nucleotide 1403 in exon
12 of the PTPN11 gene.
Carvajal-Vergara et al. (2010) generated induced pluripotent stem cells
(iPSCs) derived from 2 unrelated LEOPARD patients who were heterozygous
for the T468M mutation in the PTPN11 gene. The iPSCs were extensively
characterized and produced multiple differentiated cell lineages. A
major disease phenotype in patients with LEOPARD syndrome is
hypertrophic cardiomyopathy. Carvajal-Vergara et al. (2010) showed that
in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger,
have a higher degree of sarcomeric organization, and have preferential
localization of NFATC4 (602699) in the nucleus when compared with
cardiomyocytes derived from human embryonic stem cells or wildtype iPSCs
derived from a healthy brother of one of the LEOPARD syndrome patients.
These features correlated with a potential hypertrophic state.
Carvajal-Vergara et al. (2010) also provided molecular insights into
signaling pathways that may promote the disease phenotype.
Carvajal-Vergara et al. (2010) showed that basic fibroblast growth
factor treatment increased the phosphorylation of ERK1/2 levels over
time in several cell lines but did not have a similar effect in the
LEOPARD syndrome iPSCs despite higher basal phosphorylated ERK levels in
the LEOPARD syndrome iPSCs compared with the other cell lines.
Edouard et al. (2010) found that the T468M mutation caused elevated EGF
(131530)-induced PI3 kinase (see 601232)/AKT (164730) phosphorylation
and activation in LEOPARD syndrome patient fibroblasts and transfected
HEK293 cells compared with normal controls. This upregulation was due to
impaired dephosphorylation of GAB1 (604439), which resulted in enhanced
binding between GAB1 and the PI3 kinase regulatory subunit p85 (see
PIK3R1; 171833). PI3 kinase hyperactivation in T468M mutant cells also
enhanced myocardin (MYOCD; 606127)/SRF (600589) activity and promoted
hypertrophic growth in cultured chicken embryo myocardial cushions and
primary human cardiomyocytes.
.0007
NOONAN SYNDROME 1
PTPN11, SER502THR
Maheshwari et al. (2002) found a de novo ser502-to-thr (S502T)
substitution in exon 13 in 2 unrelated subjects with Noonan syndrome
(163950).
Kondoh et al.(2003) described a transient leukemoid reaction and an
apparently spontaneously regressing neuroblastoma in a Japanese infant
with Noonan syndrome and the S502T mutation.
.0008
NOONAN SYNDROME 1
PTPN11, TYR63CYS
In 2 unrelated families, Maheshwari et al. (2002) found that probands
with Noonan syndrome (163950) had a tyr63-to-cys (Y63C) mutation in exon
3. This same mutation was identified by Tartaglia et al. (2001). This
mutation was also identified by Kosaki et al. (2002) in 2 patients.
See 176876.0004 and Becker et al. (2007).
.0009
NOONAN SYNDROME 1
PTPN11, TYR62ASP
In a subject with Noonan syndrome (163950), Maheshwari et al. (2002)
found a tyr62-to-asp (Y62D) substitution in exon 3 of the PTPN11 gene.
This same mutation was identified by Tartaglia et al. (2002).
.0010
NOONAN SYNDROME 1
PTPN11, ASP61GLY
In a Japanese patient with sporadic Noonan syndrome (163950), Kosaki et
al. (2002) found an A-to-G transition at nucleotide 182 in exon 3 of the
PTPN11 gene, which resulted in an asp61-to-gly (D61G) amino acid
substitution.
.0011
NOONAN SYNDROME 1
PTPN11, THR73ILE
In a Japanese patient with sporadic Noonan syndrome (163950), Kosaki et
al. (2002) identified a 218C-T transition in exon 3 of the PTPN11 gene,
resulting in a thr73-to-ile (T73I) substitution.
In 4 children with Noonan syndrome who developed juvenile myelomonocytic
leukemia, Tartaglia et al. (2003) observed a heterozygous germline T73I
mutation, which alters the N-terminal Src homology 2 (SH2) domain. The
T73I mutation was also identified in an individual with growth
retardation, pulmonic stenosis, and JMML. Analysis of germline and
parental DNAs indicated that the mutations were de novo germline events.
Jongmans et al. (2005) described a patient with Noonan syndrome and mild
JMML who carried the T73I mutation.
.0012
NOONAN SYNDROME 1
PTPN11, PHE285SER
In a Japanese patient with sporadic Noonan syndrome (163950), Kosaki et
al. (2002) found a T-to-C transition at nucleotide 854 in exon 8 of the
PTPN11 gene, resulting in a phe285-to-ser (F285S) amino acid
substitution.
.0013
MOVED TO 176876.0011
.0014
LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC
PTPN11, GLU76LYS
Tartaglia et al. (2003) identified somatic missense mutations in PTPN11
in 21 of 62 individuals with JMML (607785) but without Noonan syndrome.
A 226G-A transition predicting a glu76-to-lys (E76K) substitution within
the N-SH2 domain accounted for 25% of the total number of mutations.
Codon 76 was a mutation hotspot for JMML, with 4 different amino acid
substitutions predicted among 8 individuals: in addition to E76K, which
was present in 5 cases, E76V (176876.0015), E76G (176876.0016), and E76A
(176876.0017) were each present in 1 case.
.0015
LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC
PTPN11, GLU76VAL
See 176876.0014 and Tartaglia et al. (2003).
.0016
LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC
PTPN11, GLU76GLY
See 176876.0014 and Tartaglia et al. (2003).
.0017
LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC
PTPN11, GLU76ALA
See 176876.0014 and Tartaglia et al. (2003).
.0018
NOONAN SYNDROME
PTPN11, GLN79ARG
In 10 affected members from a large 4-generation Belgian family with
Noonan syndrome (163950) and some features suggestive of
cardiofaciocutaneous syndrome (115150), Schollen et al. (2003)
identified a 236A-G transition in exon 3 of the PTPN11 gene, resulting
in a gln79-to-arg (Q79R) mutation. The mutation was not found in 7
unaffected relatives or 3 spouses.
.0019
NOONAN SYNDROME
PTPN11, THR411MET
In a 24-year-old female with clinical features of Noonan syndrome
(163950) but with some characteristics of cardiofaciocutaneous syndrome
(CFC; 115150) as well, including prominent ectodermal involvement
(sparse and very coarse hair, and sparse eyebrows and eyelashes),
developmental delay, and mental retardation, Bertola et al. (2004)
identified a T-to-C transition in exon 11 of the PTPN11 gene, resulting
in a thr411-to-met (T411M) substitution. Molecular dynamic studies
indicated that this mutation favors a more active protein conformation.
The mutation was also found in the patient's mother and older sister,
who had subtle clinical findings compatible with the diagnosis of Noonan
syndrome. The mother had 5 miscarriages, 2 of them twinning pregnancies.
.0020
LEOPARD SYNDROME
PTPN11, ALA461THR
In a Japanese patient with LEOPARD syndrome (151100), Yoshida et al.
(2004) identified heterozygosity for a 1381G-A transition in exon 12 of
the PTPN11 gene, resulting in an ala461-to-thr (A461T) substitution.
.0021
LEOPARD SYNDROME
PTPN11, GLY464ALA
In a Japanese patient with LEOPARD syndrome (151100), Yoshida et al.
(2004) identified heterozygosity for a 1391G-C transition in exon 12 of
the PTPN11 gene, resulting in a gly464-to-ala (G464A) substitution.
.0022
LEOPARD SYNDROME
PTPN11, GLN510PRO
In the proband of a family with 3 individuals with LEOPARD syndrome
(151100), Kalidas et al. (2005) found a 1529A-C transversion in exon 13
of the PTPN11 gene resulting in a gln510-to-pro (Q510P) substitution.
Edouard et al. (2010) found that PTPN11 with the Q510P mutation elevated
EGF (131530)-induced PI3 kinase (see 601232)/AKT (164730)
phosphorylation and activation in transfected HEK293 cells compared with
wildtype PTPN11. This upregulation was due to impaired dephosphorylation
of GAB1 (604439), which enhanced binding between GAB1 and the PI3 kinase
regulatory subunit p85 (PIK3R1; 171833).
.0023
NOONAN SYNDROME
PTPN11, GLN510ARG
Bertola et al. (2005) described a girl with both neurofibromatosis I
(162200) and Noonan syndrome (163590) who had a de novo mutation in the
NF1 gene (613113.0043) and a mutation in the PTPN11 gene inherited from
her father who was mildly affected with Noonan syndrome. The PTPN11
mutation was a 1909A-G transition, resulting in a gln510-to-arg
substitution.
.0024
NOONAN SYNDROME
PTPN11, 3-BP DEL, 181GTG
In a Japanese patient with Noonan syndrome (163950), Yoshida et al.
(2004) identified a 3-bp deletion in exon 3 of the PTPN11 gene,
181delGTG, that resulted in deletion of the gly60 codon in the N-SH2
domain of the protein. Because gly60 is directly involved in the
N-SH2/PTP interaction, loss of this residue was predicted to disrupt
N-SH2/PTP binding, activating the phosphatase function. Yoshida et al.
(2004) stated that 181delGTG was the sole deletion mutation identified
in the PTPN11 gene to that time.
.0025
METACHONDROMATOSIS
PTPN11, 11-BP DEL, NT514
In affected members of a 5-generation family segregating autosomal
dominant metachondromatosis (METCDS; 156250), Sobreira et al. (2010)
identified heterozygosity for an 11-bp deletion (514del11) in exon 4 of
the PTPN11 gene, predicted to cause a frameshift leading to a new
sequence of 12 codons followed by a premature stop codon. Two apparently
unaffected individuals who carried the deletion were found upon
examination to have manifestations of the disease. The mutation was not
found in 469 controls, 60% of whom were ethnically matched.
.0026
METACHONDROMATOSIS
PTPN11, ARG138TER
In affected members of a 3-generation family segregating autosomal
dominant metachondromatosis (156250), Sobreira et al. (2010) identified
heterozygosity for a C-to-T transition in exon 4 of the PTPN11 gene,
resulting in an arg138-to-ter (R138X) substitution. A brother and
sister, both parents of affected children, were unaffected carriers of
the mutation, indicating incomplete penetrance. The mutation was not
found in 469 controls, 60% of whom were ethnically matched.
.0027
NOONAN SYNDROME
PTPN11, THR2ILE
In a girl with both Noonan syndrome (163950) and neurofibromatosis I
(162200), Thiel et al. (2009) found compound heterozygosity for 2
mutations: a de novo 5C-T transition in the PTPN11 gene, resulting in a
thr2-to-ile (T2I) substitution, and a splice site mutation in the NF1
gene (613113.0044). The PTPN11 mutation was predicted to destabilize the
inactive form of PTPN11, resulting in increased basal activity and a
gain of function. The proband had hypertelorism, low-set ears, short
stature, delayed development, sternal abnormalities, and valvular
pulmonary stenosis. The NF1 mutation was inherited from her mother who
had mild features of neurofibromatosis I. The proband's brother, who
carried the heterozygous NF1 mutation, also had mild features of
neurofibromatosis I. Neither the mother nor the brother had optic
gliomas. However, the girl developed bilateral optic gliomas before age
2 years, suggesting an additive effect of the 2 mutations on the Ras
pathway. Compound heterozygosity for mutations in NF1 and PTPN11 were
also reported by Bertola et al. (2005) in a patient with a combination
of neurofibromatosis I and Noonan syndrome.
.0028
METACHONDROMATOSIS
PTPN11, 5-BP DEL, NT409
In 2 affected members of a family (family A) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous 5-bp deletion in exon 4 of the PTPN11 gene (409_413del5)
resulting in a frameshift (Val137ArgfsX17). The mutation was not found
in an unaffected family member.
.0029
METACHONDROMATOSIS
PTPN11, 11-BP DEL/24-BP INS, NT458
In 2 affected members of a family (family B) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous complex deletion/insertion mutation in exon 4 of the PTPN11
gene (458_468del11ins24), resulting in a frameshift (Thr153LysfsX8). The
mutation was not found in an unaffected family member.
.0030
METACHONDROMATOSIS
PTPN11, 2-BP DEL, NT353
In affected members of a family (family C) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous 2-bp deletion in exon 4 of the PTPN11 gene (353_354del2),
resulting in a frameshift (Ser118TrpfsX10).
.0031
METACHONDROMATOSIS
PTPN11, GLN506TER
In affected members of a family (family E) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous 1516C-T transition in exon 13 of the PTPN11 gene, resulting
in a gln506-to-ter (Q506X) nonsense mutation.
.0032
METACHONDROMATOSIS
PTPN11, 1-BP DEL, NT1315
In affected members of a family (family D) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous 1-bp deletion in exon 11 of the PTPN11 gene (1315del1),
resulting in a frameshift (Leu439TrpfsX33).
.0033
METACHONDROMATOSIS
PTPN11, IVS5AS, A-C, -2
In 2 affected sibs in a family (family F) segregating metachondromatosis
(156250), Bowen et al. (2011) identified a heterozygous acceptor splice
site mutation in intron 5 of the PTPN11 gene (643-2A-C). The mutation
was not found in either parent, including the affected mother. Bowen et
al. (2011) suggested that the mother was mosaic for a PTPN11 mutation.
.0034
METACHONDROMATOSIS
PTPN11, LYS99TER
In affected members of a family (family I) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous 295A-T transversion in exon 3 of the PTPN11 gene, resulting
in a lys99-to-ter (K99X) nonsense mutation.
.0035
METACHONDROMATOSIS
PTPN11, IVS9AS, G-T, -1
In an affected member of a family (family G) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous acceptor splice site mutation in intron 9 of the PTPN11
gene (1093-1G-T).
.0036
METACHONDROMATOSIS
PTPN11, 15-KB DEL
Using copy number analysis of sequencing reads from a second targeted
capture that included the entire PTPN11 gene, Bowen et al. (2011)
identified heterozygosity for a 15-kb deletion spanning exon 7 of the
PTPN11 gene (Thr253LeufsX54) in a patient (patient S) with
metachondromatosis (156250).
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33. Princen, F.; Bard, E.; Sheikh, F.; Zhang, S. S.; Wang, J.; Zago,
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Y.; Reed, J. C.; Tong, G. G.; Mercola, M.; Chen, J.; Feng, G.-S.:
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insulin resistance, and premature death. Molec. Cell. Biol. 29:
378-388, 2009.
34. Qu, C.-K.; Yu, W.-M.; Azzarelli, B.; Cooper, S.; Broxmeyer, H.
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35. Sarkozy, A.; Conti, E.; Seripa, D.; Digilio, M. C.; Grifone, N.;
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704-708, 2003.
36. Saxton, T. M.; Ciruna, B. G.; Holmyard, D.; Kulkarni, S.; Harpal,
K.; Rossant, J.; Pawson, T.: The SH2 tyrosine phosphatase Shp2 is
required for mammalian limb development. Nature Genet. 24: 420-423,
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37. Saxton, T. M.; Henkemeyer, M.; Gasca, S.; Shen, R.; Rossi, D.
J.; Shalaby, F.; Feng, G.-S.; Pawson, T.: Abnormal mesoderm patterning
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38. Schollen, E.; Matthijs, G.; Gewillig, M.; Fryns, J.-P.; Legius,
E.: PTPN11 mutation in a large family with Noonan syndrome and dizygous
twinning. Europ. J. Hum. Genet. 11: 85-88, 2003.
39. Shchelochkov, O. A.; Patel, A.; Weissenberger, G. M.; Chinault,
A. C.; Wiszniewska, J.; Fernandes, P. H.; Eng, C.; Kukolich, M. K.;
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in apparent Noonan syndrome. Am. J. Med. Genet. 146A: 1042-1048,
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40. Sobreira, N. L. M.; Cirulli, E. T.; Avramopoulos, D.; Wohler,
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D.; Hoover-Fong, J. E.; Goldstein, D. B.: Whole-genome sequencing
of a single proband together with linkage analysis identifies a mendelian
disease gene. PLoS Genet. 6: e1000991, 2010. Note: Electronic Article.
41. Tartaglia, M.; Cordeddu, V.; Chang, H.; Shaw, A.; Kalidas, K.;
Crosby, A.; Patton, M. A.; Sorcini, M.; van der Burgt, I.; Jeffery,
S.; Gelb, B. D.: Paternal germline origin and sex-ratio distortion
in transmission of PTPN11 mutations in Noonan syndrome. Am. J. Hum.
Genet. 75: 492-497, 2004.
42. Tartaglia, M.; Kalidas, K.; Shaw, A.; Song, X.; Musat, D. L.;
van der Burgt, I.; Brunner, H. G.; Bertola, D. R.; Crosby, A.; Ion,
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PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype
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1555-1563, 2002.
43. Tartaglia, M.; Martinelli, S.; Stella, L.; Bocchinfuso, G.; Flex,
E.; Cordeddu, V.; Zampino, G.; van der Burgt, I.; Palleschi, A.; Petrucci,
T. C.; Sorcini, M.; Schoch, C.; Foa, R.; Emanuel, P. D.; Gelb, B.
D.: Diversity and functional consequences of germline and somatic
PTPN11 mutations in human disease. Am. J. Hum. Genet. 78: 279-290,
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44. Tartaglia, M.; Mehler, E. L.; Goldberg, R.; Zampino, G.; Brunner,
H. G.; Kremer, H.; van der Burgt, I.; Crosby, A. H.; Ion, A.; Jeffery,
S.; Kalidas, K.; Patton, M. A.; Kucherlapati, R. S.; Gelb, B. D.:
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2,
cause Noonan syndrome. Nature Genet. 29: 465-468, 2001. Note: Erratum:
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45. Tartaglia, M.; Niemeyer, C. M.; Fragale, A.; Song, X.; Buechner,
J.; Jung, A.; Hahlen, K.; Hasle, H.; Licht, J. D.; Gelb, B. D.: Somatic
mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic
syndromes and acute myeloid leukemia. Nature Genet. 34: 148-150,
2003.
46. Thiel, C.; Wilken, M.; Zenker, M.; Sticht, H.; Fahsold, R.; Gusek-Schneider,
G.-C.; Rauch, A.: Independent NF1 and PTPN11 mutations in a family
with neurofibromatosis-Noonan syndrome. Am. J. Med. Genet. 149A:
1263-1267, 2009.
47. Xu, D.; Wang, S.; Yu, W.-M.; Chan, G.; Araki, T.; Bunting, K.
D.; Neel, B. G.; Qu, C.-K.: A germline gain-of-function mutation
in Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by
aberrant activation of hematopoietic stem cells. Blood 116: 3611-3621,
2010.
48. Yang, W.; Wang, J.; Moore, D. C.; Liang, H.; Dooner, M.; Wu, Q.;
Terek, R.; Chen, Q.; Ehrlich, M. G.; Quesenberry, P. J.; Neel, B.
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by inducing hedgehog signalling. Nature 499: 491-495, 2013.
49. Yoon, S.-R.; Choi, S.-K.; Eboreime, J.; Gelb, B. D.; Calabrese,
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Noonan syndrome mutation shows the signature of germline selection. Am.
J. Hum. Genet. 92: 917-926, 2013.
50. Yoshida, R.; Hasegawa, T.; Hasegawa, Y.; Nagai, T.; Kinoshita,
E.; Tanaka, Y.; Kanegane, H.; Ohyama, K.; Onishi, T.; Hanew, K.; Okuyama,
T.; Horikawa, R.; Tanaka, T.; Ogata, T.: Protein-tyrosine phosphatase,
nonreceptor type 11 mutation analysis and clinical assessment in 45
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2004.
51. Yoshida, R.; Nagai, T.; Hasegawa, T.; Kinoshita, E.; Tanaka, T.;
Ogata, T.: Two novel and one recurrent PTPN11 mutations in LEOPARD
syndrome. (Letter) Am. J. Med. Genet. 130A: 432-434, 2004.
52. Zhang, E. E.; Chapeau, E.; Hagihara, K.; Feng, G.-S.: Neuronal
Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc.
Nat. Acad. Sci. 101: 16064-16069, 2004.
53. Zhao, Z. J.; Zhao, R.: Purification and cloning of PZR, a binding
protein and putative physiological substrate of tyrosine phosphatase
SHP-2. J. Biol. Chem. 273: 29367-29372, 1998.
*FIELD* CN
Ada Hamosh - updated: 10/1/2013
Ada Hamosh - updated: 8/26/2013
Patricia A. Hartz - updated: 4/19/2013
Nara Sobreira - updated: 5/15/2012
Patricia A. Hartz - updated: 4/10/2012
Patricia A. Hartz - updated: 3/8/2012
Patricia A. Hartz - updated: 2/13/2012
Cassandra L. Kniffin - updated: 8/1/2011
Cassandra L. Kniffin - updated: 11/8/2010
Ada Hamosh - updated: 8/20/2010
Marla J. F. O'Neill - updated: 6/28/2010
Cassandra L. Kniffin - updated: 12/29/2009
George E. Tiller - updated: 10/23/2009
Marla J. F. O'Neill - updated: 7/10/2009
Marla J. F. O'Neill - updated: 4/9/2008
Marla J. F. O'Neill - updated: 2/1/2008
Marla J. F. O'Neill - updated: 12/21/2007
Marla J. F. O'Neill - updated: 3/9/2007
John A. Phillips, III - updated: 11/17/2006
Patricia A. Hartz - updated: 10/19/2006
Victor A. McKusick - updated: 5/4/2006
Victor A. McKusick - updated: 9/21/2005
Cassandra L. Kniffin - updated: 6/30/2005
Victor A. McKusick - updated: 4/14/2005
Victor A. McKusick - updated: 3/15/2005
Victor A. McKusick - updated: 3/7/2005
Marla J. F. O'Neill - updated: 1/4/2005
Victor A. McKusick - updated: 9/8/2004
Marla J. F. O'Neill - updated: 5/12/2004
Marla J. F. O'Neill - updated: 4/2/2004
Natalie E. Krasikov - updated: 3/29/2004
Victor A. McKusick - updated: 5/13/2003
John A. Phillips, III - updated: 1/21/2003
Victor A. McKusick - updated: 11/13/2002
Victor A. McKusick - updated: 11/1/2002
Victor A. McKusick - updated: 8/16/2002
Victor A. McKusick - updated: 6/12/2002
Ada Hamosh - updated: 1/29/2002
Ada Hamosh - updated: 7/20/2000
Ada Hamosh - updated: 3/30/2000
Victor A. McKusick - updated: 3/1/2000
Paul J. Converse - updated: 12/28/1999
Stylianos E. Antonarakis - updated: 4/25/1998
*FIELD* CD
Victor A. McKusick: 4/28/1993
*FIELD* ED
mgross: 10/04/2013
alopez: 10/1/2013
alopez: 8/26/2013
mgross: 4/19/2013
carol: 7/27/2012
carol: 5/25/2012
mgross: 5/15/2012
terry: 5/15/2012
carol: 5/15/2012
terry: 4/10/2012
mgross: 3/8/2012
mgross: 2/17/2012
terry: 2/13/2012
wwang: 8/11/2011
ckniffin: 8/1/2011
wwang: 5/18/2011
ckniffin: 5/3/2011
wwang: 11/12/2010
ckniffin: 11/8/2010
wwang: 11/5/2010
ckniffin: 10/26/2010
wwang: 10/19/2010
ckniffin: 10/14/2010
wwang: 10/6/2010
alopez: 8/30/2010
terry: 8/20/2010
carol: 6/28/2010
terry: 6/28/2010
wwang: 1/14/2010
ckniffin: 12/29/2009
carol: 11/23/2009
wwang: 11/2/2009
terry: 10/23/2009
wwang: 7/22/2009
terry: 7/10/2009
wwang: 4/9/2008
wwang: 2/6/2008
terry: 2/1/2008
wwang: 1/8/2008
terry: 12/21/2007
wwang: 4/19/2007
wwang: 3/12/2007
terry: 3/9/2007
alopez: 11/17/2006
carol: 10/25/2006
terry: 10/19/2006
alopez: 5/4/2006
carol: 4/25/2006
terry: 9/21/2005
terry: 8/3/2005
wwang: 7/7/2005
wwang: 7/5/2005
ckniffin: 6/30/2005
wwang: 4/27/2005
tkritzer: 4/27/2005
terry: 4/14/2005
wwang: 3/18/2005
terry: 3/15/2005
wwang: 3/9/2005
terry: 3/7/2005
carol: 1/5/2005
terry: 1/4/2005
tkritzer: 11/3/2004
alopez: 9/8/2004
terry: 9/8/2004
carol: 5/13/2004
terry: 5/12/2004
tkritzer: 4/5/2004
terry: 4/2/2004
tkritzer: 3/30/2004
terry: 3/29/2004
alopez: 6/3/2003
alopez: 5/14/2003
terry: 5/13/2003
terry: 2/24/2003
alopez: 1/21/2003
tkritzer: 11/22/2002
tkritzer: 11/18/2002
terry: 11/13/2002
tkritzer: 11/7/2002
tkritzer: 11/4/2002
terry: 11/1/2002
tkritzer: 8/23/2002
tkritzer: 8/21/2002
terry: 8/16/2002
alopez: 6/14/2002
terry: 6/12/2002
alopez: 1/30/2002
terry: 1/29/2002
alopez: 1/7/2002
alopez: 11/27/2001
alopez: 11/21/2001
alopez: 11/13/2001
terry: 11/12/2001
terry: 11/8/2000
mcapotos: 8/1/2000
mcapotos: 7/28/2000
terry: 7/20/2000
alopez: 3/31/2000
terry: 3/30/2000
alopez: 3/1/2000
terry: 3/1/2000
carol: 12/28/1999
alopez: 6/9/1999
psherman: 12/21/1998
terry: 11/13/1998
dkim: 7/23/1998
carol: 6/22/1998
terry: 6/3/1998
carol: 4/25/1998
terry: 3/26/1996
mark: 1/29/1996
jason: 7/26/1994
carol: 6/23/1993
carol: 4/28/1993
*RECORD*
*FIELD* NO
176876
*FIELD* TI
*176876 PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11
;;PROTEIN-TYROSINE PHOSPHATASE 2C; PTP2C;;
read moreTYROSINE PHOSPHATASE SHP2; SHP2
*FIELD* TX
DESCRIPTION
The protein-tyrosine phosphatases are a highly pleomorphic set of
molecules that have a role in regulating the responses of eukaryotic
cells to extracellular signals (Dechert et al., 1995). They achieve this
by regulating the phosphotyrosine content of specific intracellular
proteins. The PTPases have been grouped by virtue of the characteristic
catalytic domain sequence similarities that define this family. Dechert
et al. (1995) noted that the noncatalytic domain shows a striking degree
of sequence heterogeneity. In general, however, mammalian PTPases can be
subdivided into 1 of 2 broad categories: (1) transmembrane receptor
PTPases that contain linked cytoplasmic catalytic domains, and (2)
intracellular PTPases. Included within the latter category are 2 closely
related mammalian intracellular PTPases whose sequences encode 2 tandem
SRC homology 2 (SH2) domains that are located at the amino-terminal side
of a single PTPase catalytic domain. SH2 domains enable the binding of
these SH2 domain-containing PTPases to specific phosphotyrosine residues
within protein sequences. The first mammalian SH2 domain-containing
PTPase identified was PTP1C (PTPN6; 176883). The second mammalian SH2
domain-containing PTPase identified is encoded by the PTPN11 gene.
CLONING
Ahmad et al. (1993) isolated a cDNA encoding a nontransmembrane
protein-tyrosine phosphatase (PTP; EC 3.1.3.48), termed PTP2C, from a
human umbilical cord cDNA library. The open reading frame consists of
1,779 nucleotides potentially encoding a protein of 593 amino acids with
a predicted molecular mass of 68 kD. The identity between the 2 SH2
domains of PTP2C (PTPN11) and PTP1C (PTPN6) is 50 to 60%, higher than
the identity between the 2 SH2 domains within the same molecule. Unlike
PTP1C, which is restricted to hematopoietic and epithelial cells, PTP2C
is widely expressed in human tissues and is particularly abundant in
heart, brain, and skeletal muscle. Ahmad et al. (1993) also identified a
variant of PTP2C, termed PTP2Ci by them, which had an in-frame insertion
of 12 basepairs within the catalytic domain.
MAPPING
By fluorescence in situ hybridization, Isobe et al. (1994) mapped the
PTP2C gene to 12q24.1. It is noteworthy that the PTP1C gene maps to the
short arm of chromosome 12, whereas PTP2C maps to the long arm. Dechert
et al. (1995) used a 2.1-kb SH-PTP2 cDNA clone (Bastien et al., 1993) to
localize the PTPN11 gene to 12q24.1-q24.3 by isotopic in situ
hybridization. The presence of cross-hybridizing sequences located on a
number of other chromosomes suggested that latent genes or pseudogenes
are present in the human genome.
BIOCHEMICAL FEATURES
- Crystal Structure
Hof et al. (1998) described the crystal structure of amino acid residues
1 to 527 of the PTPN11 protein at 2.0-angstrom resolution. The crystal
structure showed how its catalytic activity is regulated by its two SH2
domains. In the absence of a tyrosine-phosphorylated binding partner,
the N-terminal SH2 domain binds the phosphatase domain and directly
blocks its active site. This interaction alters the structure of the
N-SH2 domain, disrupting its phosphopeptide-binding cleft. Conversely,
interaction of the N-SH2 domain with phosphopeptide disrupts its
phosphatase recognition surface. Thus, the N-SH2 domain is a
conformational switch; it either binds and inhibits the phosphatase, or
it binds phosphoproteins and activates the enzyme. The C-terminal SH2
domain contributes binding energy and specificity, but does not have a
direct role in activation.
GENE FUNCTION
Zhao and Zhao (1998) presented evidence indicating that MPZL1 (604376)
and PTPNS1 (602461) are substrates for PTPN11.
Helicobacter pylori CagA protein is injected from the attached H. pylori
into host cells in the stomach and undergoes tyrosine phosphorylation.
Higashi et al. (2002) demonstrated that wildtype but not
phosphorylation-resistant CagA induces a growth factor-like response in
gastric epithelial cells by forming a physical complex with SHP2 in a
phosphorylation-dependent manner and stimulating the phosphatase
activity. Disruption of the CagA-SHP2 complex abolishes the
CagA-dependent cellular response. Conversely, the CagA effect on cells
was reproduced by constitutively active SHP2. Thus, Higashi et al.
(2002) concluded that upon translocation, CagA perturbs cellular
functions by deregulating SHP2.
Kwon et al. (2005) showed that activation of T-cell antigen receptor
(see 186880) in human Jurkat T cells and in mouse T-cell blasts induced
transient inactivation of SHP2 by the oxidation of the SHP2 active site
cysteine. SHP2 was recruited to the LAT (602354)-GADS (GRAP2;
604518)-SLP76 (LCP2; 601603) complex and regulated the phosphorylation
of VAV1 (164875) and ADAP (FYB; 602731). The association of ADAP with
the SLP76 complex was regulated by SHP2 in a redox-dependent manner.
Kwon et al. (2005) concluded that TCR-mediated ROS generation leads to
SHP2 oxidation, which promotes T-cell adhesion through effects on
SLP76-dependent signaling.
Kikkawa et al. (2010) identified a putative microRNA-489 (MIR489;
614523) target site in the 3-prime UTR of PTPN11, which encodes a
protein tyrosine phosphatase that can activate RAS (HRAS; 190020)-MAP
kinase (see 176948) signaling in response to growth factors and
cytokines. Overexpression of MIR489 in a human squamous cell carcinoma
cell line reduced PTPN11 mRNA and protein expression and inhibited
expression of a reporter gene containing a partial PTPN11 3-prime UTR.
PTPN11 mRNA expression was significantly higher in hypopharyngeal
squamous cell carcinomas compared with adjacent normal tissue from 16
patients. In contrast, MIR489 was downregulated in hypopharyngeal
squamous cell carcinomas.
MOLECULAR GENETICS
- Noonan Syndrome
In more than 50% of patients with Noonan syndrome (163950), Tartaglia et
al. (2001) identified mutations in the PTPN11 gene (see, e.g.,
176876.0001-176876.0003). All the PTPN11 missense mutations were
clustered in the interacting portions of the amino N-SH2 domain and the
phosphotyrosine phosphatase (PTP) domains, which are involved in
switching the protein between its inactive and active conformations. An
energetics-based structural analysis of 2 N-SH2 mutants indicated that
in these cases there may be a significant shift of the equilibrium
favoring the active conformation. The findings suggested that
gain-of-function changes resulting in excessive SHP-2 activity underlie
the pathogenesis of Noonan syndrome.
Tartaglia et al. (2002) identified a PTPN11 mutation (176876.0004) in a
family inheriting Noonan syndrome with multiple giant cell lesions in
bone.
Using direct DNA sequencing, Maheshwari et al. (2002) surveyed 16
subjects with the clinical diagnosis of Noonan syndrome from 12 families
and their relevant family members for mutations in the PTPN11/SHP2 gene,
and found 3 different mutations among 5 families. Two unrelated subjects
shared a de novo ser502-to-thr (S502T; 176876.0007) substitution in exon
13; 2 additional unrelated families had a tyr63-to-cys (Y63C;
176876.0008) mutation in exon 3; and 1 subject had a tyr62-to-asp (Y62D;
176876.0009) substitution, also in exon 3. In the mature protein model,
the exon 3 mutants and the exon 13 mutant amino acids cluster at the
interface between the N-terminal SH2 domain and the phosphatase
catalytic domain. Six of 8 subjects with mutations had pulmonary valve
stenosis, while no mutations were identified in 4 subjects with
hypertrophic cardiomyopathy. An additional 4 subjects with possible
Noonan syndrome were evaluated, but no mutations in PTPN11 were
identified. These results confirmed that mutations in PTPN11 underlie a
common form of Noonan syndrome, and that the disease exhibits both
allelic and locus heterogeneity. The observation of recurrent mutations
supports the hypothesis that a special class of gain-of-function
mutations in SHP2 gives rise to Noonan syndrome.
Kosaki et al. (2002) analyzed the PTPN11 gene in 21 Japanese patients
with Noonan syndrome. Mutation analysis of the 15 coding exons and their
flanking introns by denaturing HPLC and direct sequencing revealed 6
different heterozygous missense mutations in 7 cases. The mutations
clustered either in the N-Src homology 2 domain or in the
protein-tyrosine phosphatase domain. The clinical features of the
mutation-positive and mutation-negative patients were comparable.
Musante et al. (2003) screened the PTPN11 gene for mutations in 96
familial or sporadic Noonan syndrome patients. They identified 15
mutations, all of which were missense mutations; 11 of them were located
in exon 3, which encodes the N-SH2 domain. No obvious clinical
differences were detected between subgroups of patients with mutations
in different PTPN11 domains. Analysis of the clinical features of the
patients revealed that several patients with facial abnormalities
thought to be pathognomonic for NS did not have a mutation in the PTPN11
gene. Widely varying phenotypes among the group of 64 patients without
PTPN11 mutations suggested further genetic heterogeneity.
Tartaglia et al. (2004) investigated the parental origin of de novo
PTPN11 lesions and explored the effect of paternal age in Noonan
syndrome. By analyzing intronic positions that flank the exonic PTPN11
lesions in 49 sporadic Noonan syndrome cases, they traced the parental
origin of mutations in 14 families. All mutations were inherited from
the father, despite the fact that no substitution affected a CpG
dinucleotide. They also found advanced paternal age among cohorts of
sporadic Noonan syndrome cases with and without PTPN11 mutations and
that a significant sex-ratio bias favoring transmission to males was
present in subjects with sporadic Noonan syndrome caused by PTPN11
mutations, as well as in families inheriting the disorder. They favored
sex-specific developmental effects as the explanation for the sex-ratio
distortion in PTPN11-associated Noonan syndrome, because fetal lethality
has been documented in this disorder.
Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical
assessment in 45 Japanese patients with Noonan syndrome. Sequence
analysis of the coding exons 1 through 15 of PTPN11 revealed a novel
3-bp deletion (176876.0024) and 10 recurrent missense mutations in 18
patients.
Becker et al. (2007) reported what they stated was the first known case
of compound heterozygosity for NS-causing mutations in the PTPN11 gene
(see 176876.0004 and 176876.0008), resulting in early fetal death.
Shchelochkov et al. (2008) and Graham et al. (2009) reported 2 unrelated
patients with a Noonan syndrome phenotype associated with respective
10-Mb and 8.98-Mb duplications on chromosome 12q24.13, encompassing the
PTPN11 gene. Graham et al. (2009) did not identify additional
duplications in a screening of more than 250 Noonan syndrome cases
without mutations in known disease-causing genes. Graham et al. (2009)
concluded that duplication of PTPN11 represents an uncommon cause of
Noonan syndrome. However, the rare observation of NS in individuals with
duplications involving the PTPN11 locus suggested that increased dosage
of this gene may have dysregulating effects on intracellular signaling.
- LEOPARD Syndrome
LEOPARD syndrome (151100) is an autosomal dominant disorder
characterized by lentigines and cafe-au-lait spots, facial anomalies,
and cardiac defects, sharing several clinical features with Noonan
syndrome. Digilio et al. (2002) screened 9 patients with LEOPARD
syndrome (including a mother-daughter pair), and 2 children with Noonan
syndrome who had multiple cafe-au-lait spots, for mutations in the
PTPN11 gene. They found, in 10 of the 11 patients, 1 of 2 novel missense
mutations, in exon 7 (176876.0005) or exon 12 (176876.0006). Both
mutations affected the PTPN11 phosphotyrosine phosphatase domain, which
is involved in less than 30% of the Noonan syndrome PTPN11 mutations.
This study demonstrated that LEOPARD syndrome and Noonan syndrome are
allelic disorders. The detected mutations suggested that distinct
molecular and pathogenetic mechanisms cause the peculiar cutaneous
manifestations of the LEOPARD syndrome subtype of Noonan syndrome.
In 4 of 6 Japanese patients with LEOPARD syndrome, Yoshida et al. (2004)
identified 1 of 3 heterozygous missense mutations: tyr279 to cys
(Y279C), ala461 to thr (A461T; 176876.0020), or gly464 to ala (G464A;
176876.0021).
Kontaridis et al. (2006) examined the enzymatic properties of mutations
in PTPN11 causing LEOPARD syndrome and found that, in contrast to the
activating mutations that cause Noonan syndrome and neoplasia, LEOPARD
syndrome mutants are catalytically defective and act as
dominant-negative mutations that interfere with growth factor/ERK-MAPK
(see 176948)-mediated signaling. Molecular modeling and biochemical
studies suggested that LEOPARD syndrome mutations control the SHP2
catalytic domain and result in open, inactive forms of SHP2. Kontaridis
et al. (2006) concluded that the pathogenesis of LEOPARD syndrome is
distinct from that of Noonan syndrome and suggested that these disorders
should be distinguished by mutation analysis rather than clinical
presentation.
- Cardiofaciocutaneous Syndrome
Patients affected with cardiofaciocutaneous syndrome (CFC; 115150)
present with symptoms that some considered to represent a more severe
expression of Noonan syndrome, namely, congenital heart defects,
cutaneous abnormalities, Noonan-like facial features, and severe
psychomotor developmental delay. Because mutations in PTPN11 are
responsible for Noonan syndrome, Ion et al. (2002) investigated the
possibility that this gene may be involved in CFC syndrome. A cohort of
28 CFC subjects rigorously assessed as having CFC 'based on OMIM
diagnostic criteria' was examined for mutations in the PTPN11 coding
sequence by means of denaturing high-performance liquid chromatography
(DHPLC). No abnormalities in the coding region of the gene were found in
any patient, nor any evidence of major deletions within the gene.
Musante et al. (2003) screened for mutations in the PTPN11 gene in 5
sporadic patients with CFC syndrome and found none.
In 10 affected members from a large 4-generation Belgian family with
Noonan syndrome and some features suggestive of CFC syndrome, Schollen
et al. (2003) identified a missense mutation in the PTPN11 gene
(176876.0018). The mutation was not found in 7 unaffected relatives or 3
spouses. The authors noted that in D. melanogaster and C. elegans, the
Ptpn11 gene has been implicated in oogenesis. In this family, there were
3 sets of dizygotic twins among the offspring of 2 affected females,
suggesting that PTPN11 might also be involved in oogenesis and twinning
in humans.
Bertola et al. (2004) described a young woman with clinical features of
Noonan syndrome but with some characteristics of CFC as well, including
prominent ectodermal involvement, developmental delay, and mental
retardation. They identified a T411M mutation in the PTPN11 gene
(176876.0019); the same mutation was found in her mother and older
sister, not initially considered to be affected but who had subtle
clinical findings compatible with the diagnosis of Noonan syndrome. The
mother had 5 miscarriages, 2 of them twinning pregnancies.
- Juvenile Myelomonocytic Leukemia
Juvenile myelomonocytic leukemia (JMML; 607785), a disorder with
excessive proliferation of myelomonocytic cells, constitutes
approximately 30% of childhood cases of myelodysplastic syndrome (MDS)
and 2% of leukemia. JMML is observed occasionally in patients with
Noonan syndrome, leading Tartaglia et al. (2003) to consider whether
defects in PTPN11 are present in myeloid disorders. In 5 unrelated
children with Noonan syndrome and JMML, they found heterozygosity with
respect to a mutation in exon 3 of PTPN11. Four of the children shared
the same mutation (218C-T; 176876.0011). In 2 unrelated individuals with
growth retardation, pulmonic stenosis, and JMML, they found missense
defects in PTPN11: the 218C-T transition, and a defect in exon 13
affecting the protein tyrosine phosphatase domain. Analysis of germline
and parental DNAs for these 6 cases indicated that the mutations were de
novo germline events.
Tartaglia et al. (2003) also identified somatic missense mutations in
PTPN11 in 21 of 62 individuals with JMML but without Noonan syndrome,
with 9 different molecular defects in exon 3 and 1 in exon 13.
Nonhematologic DNAs were available for 9 individuals with a mutation in
PTPN11 in their leukemic cells, and none harbored the defect.
Tartaglia et al. (2003) identified no mutation in PTPN11 among 8
individuals with JMML and neurofibromatosis type I (162200). Molecular
screening for mutations in exons 1 and 2 of NRAS (164790) and KRAS2
(190070) identified defects in 5 and 7 individuals with isolated cases
of JMML, respectively, none of whom harbored a mutation in PTPN11. This
indicated that defects in RAS, neurofibromin, and SHP2, all involved in
regulation of the MAPK cascade, are mutually exclusive in JMML.
Comparison of phenotypes and karyotypes did not identify differences
between individuals with JMML who did or did not have mutations in
PTPN11.
- Other Malignancies
Tartaglia et al. (2003) investigated the prevalence of somatic mutations
in PTPN11 among 50 children with myelodysplastic syndrome. They
identified no mutation among 23 children with refractory anemia, but
observed missense mutations in exon 3 in 5 of 27 children with an excess
of blasts. Three of these mutations were also associated with JMML in
other patients. Among 24 children with de novo AML (601626), they
identified a novel trinucleotide substitution in an infant with acute
monoblastic leukemia.
Bentires-Alj et al. (2004) demonstrated that mutations in PTPN11 occur
at low frequency in several human cancers, especially neuroblastoma
(256700) and AML.
- Metachondromatosis
Using whole-genome sequencing in 1 affected individual from a
5-generation family with metachondromatosis (METCDS; 156250), Sobreira
et al. (2010) identified a heterozygous 11-bp deletion in the PTPN11
gene (176876.0025) that segregated with the disease. Sequencing of
PTPN11 in another family with metachondromatosis revealed a heterozygous
nonsense mutation (176876.0026) in affected individuals. Neither
mutation was detected in 469 controls.
Bowen et al. (2011) used a targeted array to capture exons and promoter
sequences from an 8.6-Mb linked interval in 16 participants from 11
metachondromatosis families, and sequenced the captured DNA using
high-throughput parallel sequencing technologies. By this method, they
identified heterozygous putative loss-of-function mutations in the
PTPN11 gene in 4 of the 11 families (176876.0028-176876.0031). Sanger
sequence analysis of PTPN11 coding regions in the 7 remaining families
and in 6 additional metachondromatosis families identified novel
heterozygous mutations in 4 families (176876.0032-176876.0035). Copy
number analysis of sequencing reads from a second targeted capture that
included the entire PTPN11 gene identified an METCDS patient with a
15-kb deletion spanning exon 7 of PTPN11 (176876.0036). In total, of 17
METCDS families, Bowen et al. (2011) identified mutations in 11 (5
frameshift, 2 nonsense, 3 splice site, and 1 large deletion). Each
family had a different mutation, and the mutations were scattered across
the gene. Microdissected METCDS lesions from 2 patients with PTPN11
mutations demonstrated loss of heterozygosity for the wildtype allele.
Bowen et al. (2011) suggested that metachondromatosis may be genetically
heterogeneous because 1 familial and 5 sporadically occurring cases
lacked obvious disease-causing PTPN11 mutations.
GENOTYPE/PHENOTYPE CORRELATIONS
Tartaglia et al. (2002) reported the spectrum and distribution of PTPN11
mutations in a large, well-characterized cohort with NS. They found
mutations in 54 of 119 (45%) unrelated individuals with sporadic or
familial NS. There was a significantly higher prevalence of mutations
among familial cases than among sporadic ones. All defects were missense
and several were recurrent. Pulmonic stenosis was more prevalent among
the group of subjects with NS who had PTPN11 mutations than it was in
the group without them: 70.6% vs 46.2% (P less than 0.01); hypertrophic
cardiomyopathy was less prevalent among those with PTPN11 mutations:
5.9% vs 26.2%; (P less than 0.005). The prevalence of other congenital
heart malformations, short stature, pectus deformity, cryptorchidism,
and developmental delay did not differ between the 2 groups. A PTPN11
mutation was identified in a family inheriting Noonan syndrome with
multiple giant cell lesions in bone, extending the phenotypic range of
disease associated with this gene (see 176876.0004).
Sarkozy et al. (2003) analyzed the PTPN11 gene in 71 Italian patients
with Noonan syndrome and 13 with multiple lentigines/LEOPARD syndrome
(ML/LS) and identified 14 different missense mutations in 34 patients,
23 with Noonan syndrome and 11 with ML/LS. The distribution of
congenital heart defects was markedly different between the 2 groups.
Pulmonary valve stenosis, the most common congenital heart defect in
Noonan syndrome, was related to an exon 8 mutation hotspot at residue
asn308 (see, e.g., 176876.0003 and 176876.0004), whereas hypertrophic
cardiomyopathy, predominant in patients with ML/LS, was associated with
mutations in exon 7 (see, e.g., Y279C; 176876.0005) and exon 12 (see,
e.g., T468M; 176876.0006). Atrial septal defects were related to exon 3
mutations (see, e.g., Y62D; 176876.0009), whereas atrioventricular canal
defects and mitral valve anomalies were found in association with
different exon mutations.
Niihori et al. (2005) identified PTPN11 mutations in 16 of 41 patients
with Noonan syndrome and 3 of 29 patients with childhood leukemia.
Immune complex tyrosine phosphatase assays showed that all the mutations
resulted in increased phosphatase activity compared to wildtype. Several
mutations in the N-SH2 domain, including T73I (176876.0011), showed a 6-
to 12-fold increase in activity. Other N-SH2 mutations (Y63C;
176876.0008 and Q79R; 176876.0018) and PTP-domain mutations (N308D;
176876.0003 and S502T; 176876.0007) showed a 2- to 4-fold increase in
activity. These results and a review of previously reported cases
indicated that high phosphatase activity observed in mutations at codons
61, 71, 72, and 76 was significantly associated with leukemogenesis. Two
mutations associated with Noonan syndrome failed to promote the RAS/MAPK
downstream signaling pathway.
Tartaglia et al. (2006) proposed a model that splits Noonan syndrome-
and leukemia-associated PTPN11 mutations in the 2 major classes of
activating lesions with differential perturbing effects on development
and hematopoiesis. To test this model, they investigated further the
diversity of germline and somatic PTPN11 mutations, delineated the
association of those mutations with disease, characterized biochemically
a panel of mutant SHP2 proteins recurring in Noonan syndrome, LEOPARD
syndrome, and leukemia, and performed molecular dynamics simulations to
determine the structural effects of selected mutations. The results
documented a strict correlation between the identity of the lesion and
disease, and demonstrated that Noonan syndrome-causative mutations have
less potency for promoting SHP2 gain of function than do
leukemia-associated ones. Furthermore, they showed that the recurrent
LEOPARD syndrome-causing Y279C (176876.0005) and T468M (176876.0006)
amino acid substitutions engender loss of SHP2 catalytic activity,
identifying a previously unrecognized behavior of this class of missense
PTPN11 mutations. By molecular modeling and biochemical studies,
Kontaridis et al. (2006) showed that LEOPARD syndrome mutations control
the SHP2 catalytic domain and result in open, inactive forms of SHP2.
They concluded that pathogenesis of LEOPARD syndrome is distinct from
that of Noonan syndrome and suggested that these disorders should be
distinguished by mutation analysis rather than clinical presentation.
Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical
assessment in 45 Japanese patients with Noonan syndrome. They identified
11 mutations in 18 patients. Clinical assessment showed that the growth
pattern was similar in mutation-positive and mutation-negative patients.
Pulmonary valve stenosis was more frequent in mutation-positive patients
than in mutation-negative patients, as was atrial septal defect, whereas
hypertrophic cardiomyopathy was present in 5 mutation-negative patients
only. Hematologic abnormalities such as bleeding diathesis and juvenile
myelomonocytic leukemia were exclusively present in mutation-positive
patients.
Limongelli et al. (2008) studied 24 LEOPARD syndrome patients, 16 with
mutations in the PTPN11 gene, 2 with mutations in the RAF1 gene
(164760), and 6 in whom no mutation had been found. Patients without
PTPN11 mutations showed a significantly higher frequency of family
history of sudden death, increased left atrial dimensions, and cardiac
arrhythmias, and seemed to be at higher risk for adverse cardiac events.
Three patients with mutations in exon 13 of the PTPN11 gene had a severe
form of biventricular obstructive LVH with early onset of heart failure
symptoms, consistent with previous observations.
ANIMAL MODEL
Atrioventricular and semilunar valve abnormalities are common birth
defects. During studies of genetic interaction between Egr2 and Ptpn11,
encoding the protein-tyrosine phosphatase Shp2, Chen et al. (2000) found
that Egfr (131550) is required for semilunar, but not atrioventricular,
valve development. Although unnoticed in earlier studies, mice
homozygous for the hypomorphic Egfr allele 'waved-2' exhibited semilunar
valve enlargement resulting from overabundant mesenchymal cells. Egfr
-/- mice (on CD1 background) had similar defects. The penetrance and
severity of the defects in the homozygous 'waved-2' mice were enhanced
by heterozygosity for targeted mutation of exon 2 of Ptpn11. Compound
mutant mice also showed premature lethality. Electrocardiography,
echocardiography, and hemodynamic analyses showed that affected mice
developed aortic stenosis and regurgitation. The results identified Egfr
and Shp2 as components of a growth-factor signaling pathway required
specifically for semilunar valvulogenesis, supported the hypothesis that
Shp2 is required for Egfr signaling in vivo, and provided an animal
model for aortic valve disease.
Shp2 can potentiate signaling for the MAP kinase pathway (see 602425)
and is required during early mouse development for gastrulation.
Chimeric analysis can identify, by study of phenotypically normal
embryos, tissues that tolerate mutant cells, and therefore do not
require the mutated gene, or lack mutant cells and presumably require
the mutated gene during the developmental history. Saxton et al. (2000)
therefore generated chimeric mouse embryos to explore the cellular
requirements for Shp2. This analysis revealed an obligatory role for
Shp2 during outgrowth of the limb. Shp2 is specifically required in
mesenchyme cells of the progress zone, directly beneath the distal
ectoderm of the limb bud. Comparison of Ptpn11 mutant and Fgfr1 (136350)
mutant chimeric limbs indicated that in both cases mutant cells failed
to contribute to the progress zone of phenotypically normal chimeras,
leading to the hypothesis that a signal transduction pathway, initiated
by Fgfr1 and acting through Shp2, is essential within progress zone
cells. Rather than integrating proliferative signals, Shp2 probably
exerts its effects on limb development by influencing cell shape,
movement, or adhesion. Furthermore, the branchial arches, which also use
Fgfs during bud outgrowth, similarly require Shp2. Thus, Shp2 regulates
phosphotyrosine-signaling events during the complex
ectodermal-mesenchymal interactions that regulate mammalian budding
morphogenesis.
Saxton et al. (1997) generated mice deficient in Shp2 by targeted
disruption. Homozygous Shp2 -/- mice die at midgestation with multiple
defects in mesodermal patterning, while heterozygous mutants appear
normal. Qu et al. (1998) aggregated homozygous mutant embryonic stem
(ES) cells and wildtype embryos to create Shp2 -/- wildtype chimeric
animals. They reported an essential role of Shp2 in the control of blood
cell development. Despite the widespread contribution of mutant cells to
various tissues, no Shp2 -/- progenitors for erythroid or myeloid cells
were detected in the fetal liver or bone marrow of chimeric animals by
using the in vitro colony forming unit (CFU) assay. Furthermore,
hematopoiesis was defective in Shp2 -/- yolk sacs. In addition, the Shp2
mutant caused multiple developmental defects in chimeric mice,
characterized by short hind legs, aberrant limb features, split lumbar
vertebrae, abnormal rib patterning, and pathologic changes in the lungs,
intestines, and skin. Qu et al. (1998) concluded that Shp2 is involved
in the differentiation of multiple tissue-specific cells and in body
organization. They suggested that the requirement for Shp2 appears to be
more stringent in hematopoiesis than in other systems.
Zhang et al. (2004) selectively deleted Shp2 in postmitotic forebrain
neurons of mice and observed the development of early-onset obesity with
increased serum levels of leptin (164160), insulin (176730), glucose,
and triglycerides, although the mutant mice were not hyperphagic. In
wildtype mice, the authors found that Shp2 downregulation of Jak2
(147796)/Stat3 (102582) activation by leptin in the hypothalamus was
offset by a dominant Shp2 promotion of the leptin-stimulated Erk (see
601795) pathway; thus, Shp2 deletion in the brain results in induction
rather than suppression of leptin resistance. Zhang et al. (2004)
suggested that a primary function of SHP2 in the postmitotic forebrain
is to control energy balance and metabolism, and that SHP2 is a critical
signaling component of the leptin receptor (601007) in the hypothalamus.
Using a constitutively active mouse Shp2 mutant, He et al. (2012) found
that Shp2 integrated leptin and estrogen signaling in transgenic female
mice. Transgenic females, but not males, were resistant to high-fat
diet-induced obesity and liver steatosis via enhanced leptin and insulin
sensitivity and downstream ERK activation. SHP2 and estrogen
receptor-alpha (ESR1; 133430) interacted directly in MCF-7 cells and
female mouse tissues, and the interaction was enhanced by estrogen
stimulation. Ovariectomy of transgenic mice reversed their resistance to
high-fat diet-induced obesity.
Nakamura et al. (2007) generated Q79R (176876.0018) transgenic mice in
which the mutated protein was expressed in cardiomyocytes either during
gestation or following birth. Q79R Shp2 embryonic hearts showed altered
cardiomyocyte cell cycling, ventricular noncompaction, and ventricular
septal defects, whereas in the postnatal cardiomyocyte, Q79R Shp2
expression was benign. Fetal expression of Q79R led to the specific
activation of the ERK1/2 pathway (see 176948), and breeding Q79R
transgenics into Erk1/2-null backgrounds confirmed that the pathway was
necessary and sufficient for mediating the effects of mutant Shp2.
Nakamura et al. (2007) concluded that there are developmental
stage-specific effects of Q79R cardiac expression in Noonan syndrome,
and that ablation of subsequent ERK1/2 activation prevents the
development of cardiac abnormalities.
In cultured mouse embryonic cortical precursor cells, Gauthier et al.
(2007) found that Shp2 enhanced neurogenesis and inhibited
cytokine-mediated astrocytosis. Inhibition of Shp2 resulted in decreased
neurogenesis, aberrant migration of neurons, and premature gliogenesis.
Expression of a Noonan syndrome-associated Shp2 mutant with enhanced
activity promoted neurogenesis and inhibited astrogenesis in vitro and
in vivo. Further studies showed that Shp2 promotes neurogenesis via
activation of the MEK-ERK pathway, and inhibits gliogenesis by
suppressing the gp130 (IL6ST; 600694)-JAK-STAT pathway. Gauthier et al.
(2007) suggesting that the cognitive impairment observed in some
patients with Noonan syndrome may result from aberrant neuron cell-fate
and a perturbation in the relative ratios of these brain cell types
during development.
To study the developmental effects of the Y279C and T468M mutations in
the PTPN11 gene, Oishi et al. (2009) generated the equivalent mutations
in the orthologous Drosophila corkscrew (csw) gene. Ubiquitous
expression of the mutant csw alleles resulted in ectopic wing veins and,
for the Y279C allele, rough eyes with increased R7 photoreceptor
numbers. These were gain-of-function phenotypes mediated by increased
RAS/MAPK signaling and requiring the residual phosphatase activity of
the mutant Y279C and T468M alleles.
Princen et al. (2009) created mice with deletion of Shp2 directed to
striated muscle. Homozygous mutant mice were born at the expected
frequency, but developed severe dilated cardiomyopathy, resulting in
heart failure and death within 2 weeks of birth. Development of
cardiomyopathy was associated with insulin resistance, glucose
intolerance, and impaired insulin-stimulated glucose uptake in striated
muscle. No significant abnormalities were observed in other tissues and
organs, including skeletal muscle.
Xu et al. (2010) found that mice with a germline heterozygous D61G
mutation (176876.0010) developed a JMML-like myeloproliferative disorder
with excessive myeloid expansion in the bone marrow and spleen.
Homozygous mutant mice were embryonic lethal due to cardiac
developmental defects. Heterozygous mutant mice had higher levels of
short- and long-term hematopoietic stem cells in the bone marrow and
spleen compared to wildtype mice. Stem cells from heterozygous mutant
mice showed enhanced entry of quiescent stem cells (G0 phase) into the
cell cycle, as well as decreased apoptosis, and showed a greater
long-term repopulating ability in transplanted mice compared to wildtype
cells. Primary and secondary recipient mice transplanted with
D61G-mutant bone marrow cells or purified lineage-negative Sca1+/Kit+
(LSK) cells developed a myeloproliferative disorder, suggesting that the
pathogenic effects of the Ptpn11 mutation are cell autonomous and occur
at the level of the hematopoietic stem cell. D61G-mutant cells also
showed an enhanced response to stimulation with IL3 (147740). Studies
with heterozygous D61G/Gab2 (606203)-null mice and cells showed
attenuation of the increased number of stem cells, indicating that Gab2
is an important mediator of the myeloproliferative disorder induced by
the D61G mutation. Gab2 is a prominent PTPN11-interacting protein with a
role in cell signaling.
To investigate the pathogenesis of metachondromatosis (156250), Yang et
al. (2013) used a conditional knockout (floxed) Ptpn11 allele
(Ptpn11(fl)) and Cre recombinase transgenic mice to delete Ptpn11
specifically in monocytes, macrophages, and osteoclasts (lysozyme
(153450) M-Cre; LysMCre) or in cathepsin K (Ctsk; 601105)-expressing
cells, theretofore thought to be osteoclasts. The LysMCre;Ptpn11(fl/fl)
mice had mild osteopetrosis. However, CtskCre;Ptpn11(fl/fl) mice
developed features very similar to metachondromatosis. Lineage tracing
revealed a novel population of CtskCre-expressing cells in the
perichondrial groove of Ranvier that display markers and functional
properties consistent with mesenchymal progenitors (Ctsk+ chondroid
progenitors, or CCPs). Chondroid neoplasms arise from these cells and
show decreased extracellular signal-regulated kinase (ERK) pathway
activation, increased Indian hedgehog (Ihh; 600726) and parathyroid
hormone-related protein (Pthrp; 168470) expression and excessive
proliferation. Shp2-deficient chondroprogenitors had decreased
fibroblast growth factor (FGF)-evoked ERK activation and enhanced Ihh
and Pthrp expression, whereas fibroblast growth factor receptor (FGFR;
see 136350) or mitogen-activated protein kinase kinase (MEK; see 176872)
inhibitor treatment of chondroid cells increased Ihh and Pthrp
expression. Importantly, smoothened (601500) inhibitor treatment
ameliorated metachondromatosis features in the CtskCre;Ptpn11(fl/fl)
mice. Yang et al. (2013) concluded that thus, in contrast to its
prooncogenic role in hematopoietic and epithelial cells, Ptpn11 is a
tumor suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent
pathway in a novel progenitor cell population to prevent excessive Ihh
production.
*FIELD* AV
.0001
NOONAN SYNDROME 1
PTPN11, ALA72SER
In a family with Noonan syndrome (163950), Tartaglia et al. (2001) found
that affected members had a G-to-T transversion at position 214 in exon
3 of the PTPN11 gene, predicting an ala72-to-ser (A72S) substitution in
the N-SH2 domain. This mutation was also identified by Kosaki et al.
(2002).
.0002
NOONAN SYNDROME 1
PTPN11, ALA72GLY
In a family with Noonan syndrome (163950), Tartaglia et al. (2001) found
that affected members had a C-to-G transversion at nucleotide 215 in
exon 3 of the PTPN11 gene, predicting an ala72-to-gly (A72G) amino acid
substitution.
.0003
NOONAN SYNDROME 1
PTPN11, ASN308ASP
In affected members of 3 families and in a sporadic case of Noonan
syndrome (163950), Tartaglia et al. (2001) found a 922A-G transition in
exon 8 of the PTPN11 gene, predicting an asn308-to-asp (N308D) amino
acid change. This missense mutation affected the phosphotyrosine
phosphatase (PTP) domain.
In a comprehensive study of Tartaglia et al. (2002), about one-third of
the patients who had mutations in the PTPN11 gene had this mutation,
which was by far the most common. This was the mutation present in the
large 3-generation family that was used originally to establish linkage
to the locus on 12q. That codon 308 is a hotspot for Noonan syndrome was
further indicated by the finding of an asn308-to-ser (176876.0004)
missense mutation in 2 families (Tartaglia et al., 2002). In the cohort
of Noonan syndrome patients studied by Tartaglia et al. (2002) noted
that in their cohort, no patient carrying the N308D mutation was
enrolled in special education.
Kosaki et al. (2002) found this mutation in a Japanese patient.
In 13 (23%) of 56 patients with Noonan syndrome, Jongmans et al. (2005)
identified the N308D mutation, confirming the reputation of nucleotide
922 as a mutation hotspot. Among these 13 patients only 3 attended
special school. Except for this suspected correlation with normal
education, the phenotype observed in patients with the mutation at
nucleotide 922 did not differ from the phenotype in patients with other
mutations.
Yoon et al. (2013) calculated that the de novo mutation frequency of the
922A-G (N308D) mutation exceeds the genome average A-G mutation
frequency by more than 2,400-fold. Yoon et al. (2013) examined the
spacial distribution of the mutation in testes of 15 unaffected men and
found that the mutations were not uniformly distributed across each
testis as would be the expected for a mutation hot spot but were highly
clustered and showed an age-dependent germline mosaicism. Computational
modeling that used different stem cell division schemes confirmed that
the data were inconsistent with hypermutation, but consistent with
germline selection: mutated spermatogonial stem cells gained an
advantage that allowed them to increase in frequency. SHP-2, the protein
encoded by PTPN11, interacts with the transcriptional activator STAT3
(102582). Given STAT3's function in mouse spermatogonial stem cells,
Yoon et al. (2013) suggested that this interaction might explain the
mutant's selective advantage by means of repression of stem cell
differentiation signals. Repression of STAT3 activity by cyclin D1
(168461) might also play a role in providing a germline-selective
advantage to spermatogonia for the recurrent mutations in the receptor
tyrosine kinases that cause Apert syndrome (101200) and MEN2B (162300).
.0004
NOONAN SYNDROME 1
PTPN11, ASN308SER
Whereas the very frequent N308D missense mutation (176876.0003) is
caused by a change of nucleotide 922, 2 families with Noonan syndrome
(163950) studied by Tartaglia et al. (2002) showed an asn308-to-ser
(N308S) missense mutation due to an A-to-G transition at the adjacent
nucleotide 923. Thus, codon 308 is a hotspot for Noonan syndrome. One of
the 2 families in which the N308S mutation was observed had typical
features of Noonan syndrome associated with multiple giant cell lesions
in bone.
In a case of fetal demise at 12 weeks' gestation, Becker et al. (2007)
identified compound heterozygosity for the N308S and Y63C (176876.0008)
mutations in the PTPN11 gene. The mother and father, who exhibited
facial features of Noonan syndrome and had both undergone surgical
correction of pulmonary valve stenosis, were heterozygous for N308S and
Y63C, respectively. A second pregnancy resulted in the birth of a boy
with Noonan syndrome carrying the paternal Y63C mutation.
.0005
LEOPARD SYNDROME
PTPN11, TYR279CYS
In 3 patients with LEOPARD syndrome (151100), Digilio et al. (2002)
found an A-to-G transition at nucleotide 836 in exon 7 of the PTPN11
gene resulting in a tyr279-to-cys (Y279C) mutation.
Yoshida et al. (2004) identified heterozygosity for the Y279C mutation
in 2 Japanese patients with LEOPARD syndrome.
Edouard et al. (2010) found that the Y279C mutation caused elevated EGF
(131530)-induced PI3 kinase (see 601232)/AKT (164730) phosphorylation
and activation in LEOPARD syndrome patient fibroblasts and transfected
HEK293 cells compared with normal controls. This upregulation was due to
impaired dephosphorylation of GAB1 (604439), which resulted in enhanced
binding between GAB1 and the PI3 kinase regulatory subunit p85 (see
PIK3R1; 171833). PI3 kinase hyperactivation in Y279C mutant cells also
enhanced myocardin (MYOCD; 606127)/SRF (600589) activity.
.0006
LEOPARD SYNDROME
PTPN11, THR468MET
In 5 unrelated patients and in a mother-daughter pair with LEOPARD
syndrome (151100), Digilio et al. (2002) found a thr468-to-met (T468M)
mutation resulting from a C-to-T transition at nucleotide 1403 in exon
12 of the PTPN11 gene.
Carvajal-Vergara et al. (2010) generated induced pluripotent stem cells
(iPSCs) derived from 2 unrelated LEOPARD patients who were heterozygous
for the T468M mutation in the PTPN11 gene. The iPSCs were extensively
characterized and produced multiple differentiated cell lineages. A
major disease phenotype in patients with LEOPARD syndrome is
hypertrophic cardiomyopathy. Carvajal-Vergara et al. (2010) showed that
in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger,
have a higher degree of sarcomeric organization, and have preferential
localization of NFATC4 (602699) in the nucleus when compared with
cardiomyocytes derived from human embryonic stem cells or wildtype iPSCs
derived from a healthy brother of one of the LEOPARD syndrome patients.
These features correlated with a potential hypertrophic state.
Carvajal-Vergara et al. (2010) also provided molecular insights into
signaling pathways that may promote the disease phenotype.
Carvajal-Vergara et al. (2010) showed that basic fibroblast growth
factor treatment increased the phosphorylation of ERK1/2 levels over
time in several cell lines but did not have a similar effect in the
LEOPARD syndrome iPSCs despite higher basal phosphorylated ERK levels in
the LEOPARD syndrome iPSCs compared with the other cell lines.
Edouard et al. (2010) found that the T468M mutation caused elevated EGF
(131530)-induced PI3 kinase (see 601232)/AKT (164730) phosphorylation
and activation in LEOPARD syndrome patient fibroblasts and transfected
HEK293 cells compared with normal controls. This upregulation was due to
impaired dephosphorylation of GAB1 (604439), which resulted in enhanced
binding between GAB1 and the PI3 kinase regulatory subunit p85 (see
PIK3R1; 171833). PI3 kinase hyperactivation in T468M mutant cells also
enhanced myocardin (MYOCD; 606127)/SRF (600589) activity and promoted
hypertrophic growth in cultured chicken embryo myocardial cushions and
primary human cardiomyocytes.
.0007
NOONAN SYNDROME 1
PTPN11, SER502THR
Maheshwari et al. (2002) found a de novo ser502-to-thr (S502T)
substitution in exon 13 in 2 unrelated subjects with Noonan syndrome
(163950).
Kondoh et al.(2003) described a transient leukemoid reaction and an
apparently spontaneously regressing neuroblastoma in a Japanese infant
with Noonan syndrome and the S502T mutation.
.0008
NOONAN SYNDROME 1
PTPN11, TYR63CYS
In 2 unrelated families, Maheshwari et al. (2002) found that probands
with Noonan syndrome (163950) had a tyr63-to-cys (Y63C) mutation in exon
3. This same mutation was identified by Tartaglia et al. (2001). This
mutation was also identified by Kosaki et al. (2002) in 2 patients.
See 176876.0004 and Becker et al. (2007).
.0009
NOONAN SYNDROME 1
PTPN11, TYR62ASP
In a subject with Noonan syndrome (163950), Maheshwari et al. (2002)
found a tyr62-to-asp (Y62D) substitution in exon 3 of the PTPN11 gene.
This same mutation was identified by Tartaglia et al. (2002).
.0010
NOONAN SYNDROME 1
PTPN11, ASP61GLY
In a Japanese patient with sporadic Noonan syndrome (163950), Kosaki et
al. (2002) found an A-to-G transition at nucleotide 182 in exon 3 of the
PTPN11 gene, which resulted in an asp61-to-gly (D61G) amino acid
substitution.
.0011
NOONAN SYNDROME 1
PTPN11, THR73ILE
In a Japanese patient with sporadic Noonan syndrome (163950), Kosaki et
al. (2002) identified a 218C-T transition in exon 3 of the PTPN11 gene,
resulting in a thr73-to-ile (T73I) substitution.
In 4 children with Noonan syndrome who developed juvenile myelomonocytic
leukemia, Tartaglia et al. (2003) observed a heterozygous germline T73I
mutation, which alters the N-terminal Src homology 2 (SH2) domain. The
T73I mutation was also identified in an individual with growth
retardation, pulmonic stenosis, and JMML. Analysis of germline and
parental DNAs indicated that the mutations were de novo germline events.
Jongmans et al. (2005) described a patient with Noonan syndrome and mild
JMML who carried the T73I mutation.
.0012
NOONAN SYNDROME 1
PTPN11, PHE285SER
In a Japanese patient with sporadic Noonan syndrome (163950), Kosaki et
al. (2002) found a T-to-C transition at nucleotide 854 in exon 8 of the
PTPN11 gene, resulting in a phe285-to-ser (F285S) amino acid
substitution.
.0013
MOVED TO 176876.0011
.0014
LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC
PTPN11, GLU76LYS
Tartaglia et al. (2003) identified somatic missense mutations in PTPN11
in 21 of 62 individuals with JMML (607785) but without Noonan syndrome.
A 226G-A transition predicting a glu76-to-lys (E76K) substitution within
the N-SH2 domain accounted for 25% of the total number of mutations.
Codon 76 was a mutation hotspot for JMML, with 4 different amino acid
substitutions predicted among 8 individuals: in addition to E76K, which
was present in 5 cases, E76V (176876.0015), E76G (176876.0016), and E76A
(176876.0017) were each present in 1 case.
.0015
LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC
PTPN11, GLU76VAL
See 176876.0014 and Tartaglia et al. (2003).
.0016
LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC
PTPN11, GLU76GLY
See 176876.0014 and Tartaglia et al. (2003).
.0017
LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC
PTPN11, GLU76ALA
See 176876.0014 and Tartaglia et al. (2003).
.0018
NOONAN SYNDROME
PTPN11, GLN79ARG
In 10 affected members from a large 4-generation Belgian family with
Noonan syndrome (163950) and some features suggestive of
cardiofaciocutaneous syndrome (115150), Schollen et al. (2003)
identified a 236A-G transition in exon 3 of the PTPN11 gene, resulting
in a gln79-to-arg (Q79R) mutation. The mutation was not found in 7
unaffected relatives or 3 spouses.
.0019
NOONAN SYNDROME
PTPN11, THR411MET
In a 24-year-old female with clinical features of Noonan syndrome
(163950) but with some characteristics of cardiofaciocutaneous syndrome
(CFC; 115150) as well, including prominent ectodermal involvement
(sparse and very coarse hair, and sparse eyebrows and eyelashes),
developmental delay, and mental retardation, Bertola et al. (2004)
identified a T-to-C transition in exon 11 of the PTPN11 gene, resulting
in a thr411-to-met (T411M) substitution. Molecular dynamic studies
indicated that this mutation favors a more active protein conformation.
The mutation was also found in the patient's mother and older sister,
who had subtle clinical findings compatible with the diagnosis of Noonan
syndrome. The mother had 5 miscarriages, 2 of them twinning pregnancies.
.0020
LEOPARD SYNDROME
PTPN11, ALA461THR
In a Japanese patient with LEOPARD syndrome (151100), Yoshida et al.
(2004) identified heterozygosity for a 1381G-A transition in exon 12 of
the PTPN11 gene, resulting in an ala461-to-thr (A461T) substitution.
.0021
LEOPARD SYNDROME
PTPN11, GLY464ALA
In a Japanese patient with LEOPARD syndrome (151100), Yoshida et al.
(2004) identified heterozygosity for a 1391G-C transition in exon 12 of
the PTPN11 gene, resulting in a gly464-to-ala (G464A) substitution.
.0022
LEOPARD SYNDROME
PTPN11, GLN510PRO
In the proband of a family with 3 individuals with LEOPARD syndrome
(151100), Kalidas et al. (2005) found a 1529A-C transversion in exon 13
of the PTPN11 gene resulting in a gln510-to-pro (Q510P) substitution.
Edouard et al. (2010) found that PTPN11 with the Q510P mutation elevated
EGF (131530)-induced PI3 kinase (see 601232)/AKT (164730)
phosphorylation and activation in transfected HEK293 cells compared with
wildtype PTPN11. This upregulation was due to impaired dephosphorylation
of GAB1 (604439), which enhanced binding between GAB1 and the PI3 kinase
regulatory subunit p85 (PIK3R1; 171833).
.0023
NOONAN SYNDROME
PTPN11, GLN510ARG
Bertola et al. (2005) described a girl with both neurofibromatosis I
(162200) and Noonan syndrome (163590) who had a de novo mutation in the
NF1 gene (613113.0043) and a mutation in the PTPN11 gene inherited from
her father who was mildly affected with Noonan syndrome. The PTPN11
mutation was a 1909A-G transition, resulting in a gln510-to-arg
substitution.
.0024
NOONAN SYNDROME
PTPN11, 3-BP DEL, 181GTG
In a Japanese patient with Noonan syndrome (163950), Yoshida et al.
(2004) identified a 3-bp deletion in exon 3 of the PTPN11 gene,
181delGTG, that resulted in deletion of the gly60 codon in the N-SH2
domain of the protein. Because gly60 is directly involved in the
N-SH2/PTP interaction, loss of this residue was predicted to disrupt
N-SH2/PTP binding, activating the phosphatase function. Yoshida et al.
(2004) stated that 181delGTG was the sole deletion mutation identified
in the PTPN11 gene to that time.
.0025
METACHONDROMATOSIS
PTPN11, 11-BP DEL, NT514
In affected members of a 5-generation family segregating autosomal
dominant metachondromatosis (METCDS; 156250), Sobreira et al. (2010)
identified heterozygosity for an 11-bp deletion (514del11) in exon 4 of
the PTPN11 gene, predicted to cause a frameshift leading to a new
sequence of 12 codons followed by a premature stop codon. Two apparently
unaffected individuals who carried the deletion were found upon
examination to have manifestations of the disease. The mutation was not
found in 469 controls, 60% of whom were ethnically matched.
.0026
METACHONDROMATOSIS
PTPN11, ARG138TER
In affected members of a 3-generation family segregating autosomal
dominant metachondromatosis (156250), Sobreira et al. (2010) identified
heterozygosity for a C-to-T transition in exon 4 of the PTPN11 gene,
resulting in an arg138-to-ter (R138X) substitution. A brother and
sister, both parents of affected children, were unaffected carriers of
the mutation, indicating incomplete penetrance. The mutation was not
found in 469 controls, 60% of whom were ethnically matched.
.0027
NOONAN SYNDROME
PTPN11, THR2ILE
In a girl with both Noonan syndrome (163950) and neurofibromatosis I
(162200), Thiel et al. (2009) found compound heterozygosity for 2
mutations: a de novo 5C-T transition in the PTPN11 gene, resulting in a
thr2-to-ile (T2I) substitution, and a splice site mutation in the NF1
gene (613113.0044). The PTPN11 mutation was predicted to destabilize the
inactive form of PTPN11, resulting in increased basal activity and a
gain of function. The proband had hypertelorism, low-set ears, short
stature, delayed development, sternal abnormalities, and valvular
pulmonary stenosis. The NF1 mutation was inherited from her mother who
had mild features of neurofibromatosis I. The proband's brother, who
carried the heterozygous NF1 mutation, also had mild features of
neurofibromatosis I. Neither the mother nor the brother had optic
gliomas. However, the girl developed bilateral optic gliomas before age
2 years, suggesting an additive effect of the 2 mutations on the Ras
pathway. Compound heterozygosity for mutations in NF1 and PTPN11 were
also reported by Bertola et al. (2005) in a patient with a combination
of neurofibromatosis I and Noonan syndrome.
.0028
METACHONDROMATOSIS
PTPN11, 5-BP DEL, NT409
In 2 affected members of a family (family A) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous 5-bp deletion in exon 4 of the PTPN11 gene (409_413del5)
resulting in a frameshift (Val137ArgfsX17). The mutation was not found
in an unaffected family member.
.0029
METACHONDROMATOSIS
PTPN11, 11-BP DEL/24-BP INS, NT458
In 2 affected members of a family (family B) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous complex deletion/insertion mutation in exon 4 of the PTPN11
gene (458_468del11ins24), resulting in a frameshift (Thr153LysfsX8). The
mutation was not found in an unaffected family member.
.0030
METACHONDROMATOSIS
PTPN11, 2-BP DEL, NT353
In affected members of a family (family C) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous 2-bp deletion in exon 4 of the PTPN11 gene (353_354del2),
resulting in a frameshift (Ser118TrpfsX10).
.0031
METACHONDROMATOSIS
PTPN11, GLN506TER
In affected members of a family (family E) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous 1516C-T transition in exon 13 of the PTPN11 gene, resulting
in a gln506-to-ter (Q506X) nonsense mutation.
.0032
METACHONDROMATOSIS
PTPN11, 1-BP DEL, NT1315
In affected members of a family (family D) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous 1-bp deletion in exon 11 of the PTPN11 gene (1315del1),
resulting in a frameshift (Leu439TrpfsX33).
.0033
METACHONDROMATOSIS
PTPN11, IVS5AS, A-C, -2
In 2 affected sibs in a family (family F) segregating metachondromatosis
(156250), Bowen et al. (2011) identified a heterozygous acceptor splice
site mutation in intron 5 of the PTPN11 gene (643-2A-C). The mutation
was not found in either parent, including the affected mother. Bowen et
al. (2011) suggested that the mother was mosaic for a PTPN11 mutation.
.0034
METACHONDROMATOSIS
PTPN11, LYS99TER
In affected members of a family (family I) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous 295A-T transversion in exon 3 of the PTPN11 gene, resulting
in a lys99-to-ter (K99X) nonsense mutation.
.0035
METACHONDROMATOSIS
PTPN11, IVS9AS, G-T, -1
In an affected member of a family (family G) segregating
metachondromatosis (156250), Bowen et al. (2011) identified a
heterozygous acceptor splice site mutation in intron 9 of the PTPN11
gene (1093-1G-T).
.0036
METACHONDROMATOSIS
PTPN11, 15-KB DEL
Using copy number analysis of sequencing reads from a second targeted
capture that included the entire PTPN11 gene, Bowen et al. (2011)
identified heterozygosity for a 15-kb deletion spanning exon 7 of the
PTPN11 gene (Thr253LeufsX54) in a patient (patient S) with
metachondromatosis (156250).
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van der Burgt, I.; Brunner, H. G.; Bertola, D. R.; Crosby, A.; Ion,
A.; Kucherlapati, R. S.; Jeffery, S.; Patton, M. A.; Gelb, B. D.:
PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype
correlation, and phenotypic heterogeneity. Am. J. Hum. Genet. 70:
1555-1563, 2002.
43. Tartaglia, M.; Martinelli, S.; Stella, L.; Bocchinfuso, G.; Flex,
E.; Cordeddu, V.; Zampino, G.; van der Burgt, I.; Palleschi, A.; Petrucci,
T. C.; Sorcini, M.; Schoch, C.; Foa, R.; Emanuel, P. D.; Gelb, B.
D.: Diversity and functional consequences of germline and somatic
PTPN11 mutations in human disease. Am. J. Hum. Genet. 78: 279-290,
2006.
44. Tartaglia, M.; Mehler, E. L.; Goldberg, R.; Zampino, G.; Brunner,
H. G.; Kremer, H.; van der Burgt, I.; Crosby, A. H.; Ion, A.; Jeffery,
S.; Kalidas, K.; Patton, M. A.; Kucherlapati, R. S.; Gelb, B. D.:
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2,
cause Noonan syndrome. Nature Genet. 29: 465-468, 2001. Note: Erratum:
Nature Genet. 29: 491 only, 2001; Nature Genet. 30: 123 only, 2002.
45. Tartaglia, M.; Niemeyer, C. M.; Fragale, A.; Song, X.; Buechner,
J.; Jung, A.; Hahlen, K.; Hasle, H.; Licht, J. D.; Gelb, B. D.: Somatic
mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic
syndromes and acute myeloid leukemia. Nature Genet. 34: 148-150,
2003.
46. Thiel, C.; Wilken, M.; Zenker, M.; Sticht, H.; Fahsold, R.; Gusek-Schneider,
G.-C.; Rauch, A.: Independent NF1 and PTPN11 mutations in a family
with neurofibromatosis-Noonan syndrome. Am. J. Med. Genet. 149A:
1263-1267, 2009.
47. Xu, D.; Wang, S.; Yu, W.-M.; Chan, G.; Araki, T.; Bunting, K.
D.; Neel, B. G.; Qu, C.-K.: A germline gain-of-function mutation
in Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by
aberrant activation of hematopoietic stem cells. Blood 116: 3611-3621,
2010.
48. Yang, W.; Wang, J.; Moore, D. C.; Liang, H.; Dooner, M.; Wu, Q.;
Terek, R.; Chen, Q.; Ehrlich, M. G.; Quesenberry, P. J.; Neel, B.
G.: Ptpn11 deletion in a novel progenitor causes metachondromatosis
by inducing hedgehog signalling. Nature 499: 491-495, 2013.
49. Yoon, S.-R.; Choi, S.-K.; Eboreime, J.; Gelb, B. D.; Calabrese,
P.; Arnheim, N.: Age-dependent germline mosaicism of the most common
Noonan syndrome mutation shows the signature of germline selection. Am.
J. Hum. Genet. 92: 917-926, 2013.
50. Yoshida, R.; Hasegawa, T.; Hasegawa, Y.; Nagai, T.; Kinoshita,
E.; Tanaka, Y.; Kanegane, H.; Ohyama, K.; Onishi, T.; Hanew, K.; Okuyama,
T.; Horikawa, R.; Tanaka, T.; Ogata, T.: Protein-tyrosine phosphatase,
nonreceptor type 11 mutation analysis and clinical assessment in 45
patients with Noonan syndrome. J. Clin. Endocr. Metab. 89: 3359-3364,
2004.
51. Yoshida, R.; Nagai, T.; Hasegawa, T.; Kinoshita, E.; Tanaka, T.;
Ogata, T.: Two novel and one recurrent PTPN11 mutations in LEOPARD
syndrome. (Letter) Am. J. Med. Genet. 130A: 432-434, 2004.
52. Zhang, E. E.; Chapeau, E.; Hagihara, K.; Feng, G.-S.: Neuronal
Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc.
Nat. Acad. Sci. 101: 16064-16069, 2004.
53. Zhao, Z. J.; Zhao, R.: Purification and cloning of PZR, a binding
protein and putative physiological substrate of tyrosine phosphatase
SHP-2. J. Biol. Chem. 273: 29367-29372, 1998.
*FIELD* CN
Ada Hamosh - updated: 10/1/2013
Ada Hamosh - updated: 8/26/2013
Patricia A. Hartz - updated: 4/19/2013
Nara Sobreira - updated: 5/15/2012
Patricia A. Hartz - updated: 4/10/2012
Patricia A. Hartz - updated: 3/8/2012
Patricia A. Hartz - updated: 2/13/2012
Cassandra L. Kniffin - updated: 8/1/2011
Cassandra L. Kniffin - updated: 11/8/2010
Ada Hamosh - updated: 8/20/2010
Marla J. F. O'Neill - updated: 6/28/2010
Cassandra L. Kniffin - updated: 12/29/2009
George E. Tiller - updated: 10/23/2009
Marla J. F. O'Neill - updated: 7/10/2009
Marla J. F. O'Neill - updated: 4/9/2008
Marla J. F. O'Neill - updated: 2/1/2008
Marla J. F. O'Neill - updated: 12/21/2007
Marla J. F. O'Neill - updated: 3/9/2007
John A. Phillips, III - updated: 11/17/2006
Patricia A. Hartz - updated: 10/19/2006
Victor A. McKusick - updated: 5/4/2006
Victor A. McKusick - updated: 9/21/2005
Cassandra L. Kniffin - updated: 6/30/2005
Victor A. McKusick - updated: 4/14/2005
Victor A. McKusick - updated: 3/15/2005
Victor A. McKusick - updated: 3/7/2005
Marla J. F. O'Neill - updated: 1/4/2005
Victor A. McKusick - updated: 9/8/2004
Marla J. F. O'Neill - updated: 5/12/2004
Marla J. F. O'Neill - updated: 4/2/2004
Natalie E. Krasikov - updated: 3/29/2004
Victor A. McKusick - updated: 5/13/2003
John A. Phillips, III - updated: 1/21/2003
Victor A. McKusick - updated: 11/13/2002
Victor A. McKusick - updated: 11/1/2002
Victor A. McKusick - updated: 8/16/2002
Victor A. McKusick - updated: 6/12/2002
Ada Hamosh - updated: 1/29/2002
Ada Hamosh - updated: 7/20/2000
Ada Hamosh - updated: 3/30/2000
Victor A. McKusick - updated: 3/1/2000
Paul J. Converse - updated: 12/28/1999
Stylianos E. Antonarakis - updated: 4/25/1998
*FIELD* CD
Victor A. McKusick: 4/28/1993
*FIELD* ED
mgross: 10/04/2013
alopez: 10/1/2013
alopez: 8/26/2013
mgross: 4/19/2013
carol: 7/27/2012
carol: 5/25/2012
mgross: 5/15/2012
terry: 5/15/2012
carol: 5/15/2012
terry: 4/10/2012
mgross: 3/8/2012
mgross: 2/17/2012
terry: 2/13/2012
wwang: 8/11/2011
ckniffin: 8/1/2011
wwang: 5/18/2011
ckniffin: 5/3/2011
wwang: 11/12/2010
ckniffin: 11/8/2010
wwang: 11/5/2010
ckniffin: 10/26/2010
wwang: 10/19/2010
ckniffin: 10/14/2010
wwang: 10/6/2010
alopez: 8/30/2010
terry: 8/20/2010
carol: 6/28/2010
terry: 6/28/2010
wwang: 1/14/2010
ckniffin: 12/29/2009
carol: 11/23/2009
wwang: 11/2/2009
terry: 10/23/2009
wwang: 7/22/2009
terry: 7/10/2009
wwang: 4/9/2008
wwang: 2/6/2008
terry: 2/1/2008
wwang: 1/8/2008
terry: 12/21/2007
wwang: 4/19/2007
wwang: 3/12/2007
terry: 3/9/2007
alopez: 11/17/2006
carol: 10/25/2006
terry: 10/19/2006
alopez: 5/4/2006
carol: 4/25/2006
terry: 9/21/2005
terry: 8/3/2005
wwang: 7/7/2005
wwang: 7/5/2005
ckniffin: 6/30/2005
wwang: 4/27/2005
tkritzer: 4/27/2005
terry: 4/14/2005
wwang: 3/18/2005
terry: 3/15/2005
wwang: 3/9/2005
terry: 3/7/2005
carol: 1/5/2005
terry: 1/4/2005
tkritzer: 11/3/2004
alopez: 9/8/2004
terry: 9/8/2004
carol: 5/13/2004
terry: 5/12/2004
tkritzer: 4/5/2004
terry: 4/2/2004
tkritzer: 3/30/2004
terry: 3/29/2004
alopez: 6/3/2003
alopez: 5/14/2003
terry: 5/13/2003
terry: 2/24/2003
alopez: 1/21/2003
tkritzer: 11/22/2002
tkritzer: 11/18/2002
terry: 11/13/2002
tkritzer: 11/7/2002
tkritzer: 11/4/2002
terry: 11/1/2002
tkritzer: 8/23/2002
tkritzer: 8/21/2002
terry: 8/16/2002
alopez: 6/14/2002
terry: 6/12/2002
alopez: 1/30/2002
terry: 1/29/2002
alopez: 1/7/2002
alopez: 11/27/2001
alopez: 11/21/2001
alopez: 11/13/2001
terry: 11/12/2001
terry: 11/8/2000
mcapotos: 8/1/2000
mcapotos: 7/28/2000
terry: 7/20/2000
alopez: 3/31/2000
terry: 3/30/2000
alopez: 3/1/2000
terry: 3/1/2000
carol: 12/28/1999
alopez: 6/9/1999
psherman: 12/21/1998
terry: 11/13/1998
dkim: 7/23/1998
carol: 6/22/1998
terry: 6/3/1998
carol: 4/25/1998
terry: 3/26/1996
mark: 1/29/1996
jason: 7/26/1994
carol: 6/23/1993
carol: 4/28/1993
MIM
607785
*RECORD*
*FIELD* NO
607785
*FIELD* TI
#607785 JUVENILE MYELOMONOCYTIC LEUKEMIA; JMML
;;LEUKEMIA, JUVENILE MYELOMONOCYTIC
read moreLEUKEMIA, CHRONIC MYELOMONOCYTIC, INCLUDED; CMML, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because juvenile
myelomonocytic leukemia (JMML) can be caused by somatic mutations in
specific genes that result in activation of the RAS signaling pathway,
such as PTPN11 (176876), KRAS (190070), NRAS (164790). Somatic mutation
in the CBL gene (165360) has also been reported.
DESCRIPTION
Juvenile myelomonocytic leukemia is an aggressive pediatric
myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD)
characterized by malignant transformation in the hematopoietic stem cell
compartment with proliferation of differentiated progeny (Loh et al.,
2009). JMML constitutes approximately 30% of childhood cases of
myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999).
Although JMML is a progressive and often rapidly fatal disease without
hematopoietic stem cell transplantation (HSCT), some patients have been
shown to have a prolonged and stable clinical course without HSCT
(Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a
similar disorder with later onset. Both JMML and CMML have a high
frequency of mutations affecting the RAS signaling pathway and show
hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511)
hyperphosphorylation (Loh et al., 2009).
- Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia
In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due
to somatic mutations in the PTPN11, KRAS, and NRAS genes. Additionally,
both germline and somatic mutations in the CBL gene have been found in
patients with JMML, indicating a frequency of 10 to 15% of JMML patients
overall (Loh et al., 2009). Somatic disruptions of the GRAF gene
(ARHGAP26; 605370) have also been found in patients with JMML.
About 10 to 15% of JMML cases arise in children with neurofibromatosis
type I (NF1; 162200) due to germline mutations in the NF1 gene (613113).
In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or
Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations
in the PTPN11, KRAS2, and CBL genes, respectively, also have an
increased risk of developing JMML.
- Genetic Heterogeneity of Chronic Myelomonocytic Leukemia
Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1
(605590) genes have been found in patients with CMML.
CYTOGENETICS
In a patient with chronic myelomonocytic leukemia (CMML) with a
t(5;7)(q33;q11.2) translocation, Ross et al. (1998) found fusion of the
HIP1 gene (601767) to the platelet-derived growth factor-beta receptor
gene (PDGFRB; 173410). They identified a chimeric transcript containing
the HIP1 gene located at 7q11.2 fused to the PDGFRB gene on 5q33. The
fusion gene encoded amino acids 1 to 950 of HIP1 joined in-frame to the
transmembrane and tyrosine kinase domains of the PDGFRB gene. The
reciprocal PDGFRB/HIP1 transcript was not expressed. The fusion protein
product was a 180-kD protein when expressed in a murine hematopoietic
cell line and was constitutively tyrosine phosphorylated. Furthermore,
the fusion gene transformed the same mouse hematopoietic cell line to
interleukin-3-independent growth.
In a patient with CMML and an acquired t(5;17)(q33;p13), Magnusson et
al. (2001) demonstrated rabaptin-5 (RABEP1; 603616) as a novel partner
fused in-frame to the 5-prime portion of the PDGFBR gene (173410). The
fusion protein included more than 85% of the native rabaptin-5 fused to
the transmembrane and intracellular tyrosine kinase domains of PDGFRB.
Rabaptin-5 is an essential and rate-limiting component of early
endosomal fusion. The new fusion protein links 2 important pathways of
growth regulation.
MOLECULAR GENETICS
- Mutations Associated with Noonan Syndrome and JMML
Tartaglia et al. (2003) showed that germline mutations in PTPN11 lead to
Noonan syndrome-1 (NS1; 163950) associated with JMML (T73I;
176876.0011), and that somatic mutations in PTPN11 are associated with
isolated JMML. Jongmans et al. (2005) described a patient with Noonan
syndrome and mild JMML who carried a mutation in the PTPN11 gene
(176876.0011).
Schubbert et al. (2006) described a 3-month-old female with Noonan
syndrome-3 (NS3; 609942) and a severe clinical phenotype who presented
with a JMML-like myeloproliferative disorder. The patient was
heterozygous for a mutation in the KRAS gene (T58I; 190070.0011). This
mutation was also present in her buccal cells, but was absent in
parental DNA.
De Filippi et al. (2009) reported a boy who presented in infancy with
JMML and was later noted to have dysmorphic features suggestive of, but
not diagnostic of, Noonan syndrome (see NS6; 613224). Features included
short stature, relative macrocephaly, high forehead, epicanthal folds,
long eyebrows, low nasal bridge, low-set ears, 2 cafe-au-lait spots, and
low scores on performance tasks. Cardiac studies were normal. Genetic
analysis revealed a de novo germline heterozygous mutation in the NRAS
gene (G13D; 164790.0003).
In 3 unrelated patients with a Noonan syndrome-like disorder (613563)
who developed JMML, Perez et al. (2010) identified a heterozygous
germline mutation in the CBL gene (Y371H; 165360.0005). The mutation
occurred de novo in 2 patients and was inherited from an unaffected
father in 1 patient. Leukemia cells of all patients showed somatic loss
of heterozygosity at chromosome 11q23, including the CBL gene. The
findings indicated that germline heterozygous mutations in the CBL gene
are associated with predisposition for the development of JMML.
In 27 of 159 leukemia samples from patients with JMML, Loh et al. (2009)
identified 25 homozygous and 2 heterozygous mutations in the CBL gene.
The mutations were located throughout the linker and RING finger
domains, and Y371H was the most common mutation. Leukemic cells from 3
patients examined in detail had acquired isodisomy of chromosome 11q
including the CBL gene. Each of these 3 patients had a heterozygous
germline CBL mutation, whereas their tumor cells had homozygous
mutations. Leukemic cells exhibited CFU-GM hypersensitivity and high
levels of STAT5 (601511) in response to GM-CSF. These findings indicated
that reduplication of an inherited CBL mutation in a pluripotent
hematopoietic stem cell confers a selective advantage for the homozygous
state. Loh et al. (2009) estimated the frequency of CBL mutations to be
10 to 15% of JMML patients overall. They did not find CBL mutations in
JMML patients with known PTPN11/RAS mutation, indicating that CBL and
PTPN11/RAS mutations are mutually exclusive. The finding that
heterozygous germline mutations may predispose to development of JMML
suggested that CBL acts as a tumor suppressor gene.
- Isolated Juvenile or Chronic Myelomonocytic Leukemia
Jankowska et al. (2009) identified recurrent areas of somatic copy
number-neutral loss of heterozygosity (LOH) and deletions of chromosome
4q24 in patients with MDS/MPD. Subsequent analysis identified somatic
mutations in the TET2 gene (612839) in 6 of 17 cases of chronic
myelomonocytic leukemia.
Abdel-Wahab et al. (2009) identified somatic mutations in the TET2 gene
in 29 (42%) of 69 CMML.
Gelsi-Boyer et al. (2009) presented evidence that the ASXL1 gene
(612990) may act as a tumor suppressor in myeloid malignancies. They
identified somatic ASXL1 mutations were also found in 19 (43%) of 44
chronic myelomonocytic leukemia samples.
Loh et al. (2009) found isolated CBL mutations in 4 of 44 samples from
patients with CMML, which shares features with JMML.
Muramatsu et al. (2010) identified uniparental disomy of 11q23 in
leukemic cells from 4 of 49 patients with JMML. Mutation analysis of the
CBL gene identified somatic mutations in 5 (10%) of 49 patients.
Mutations in the PTPN11 gene were found in 26 (53%), whereas NRAS and
KRAS mutations were found in 2 (4%) and 1 (2%) patient, respectively.
None of the patients had mutations in the TET2 gene (612839), which had
previously been shown to be present in a significant proportion of
patients with MDS/MPD, including CMML (see Jankowska et al., 2009).
Eighteen (37%) of the 49 patients with JMML studied by Muramatsu et al.
(2010) did not have any of the known pathogenic defects.
Klinakis et al. (2011) identified novel somatic-inactivating Notch (see
190198) pathway mutations in a fraction of patients with CMML.
Inactivation of Notch signaling in mouse hematopoietic stem cells
resulted in aberrant accumulation of granulocyte/monocyte progenitors,
extramedullary hematopoiesis, and the induction of CMML-like disease.
Transcriptome analysis revealed that Notch signaling regulates an
extensive myelomonocytic-specific gene signature, through the direct
suppression of gene transcription by the Notch target Hes1 (139605).
Klinakis et al. (2011) concluded that their studies identified a novel
role for Notch signaling during early hematopoietic stem cell
differentiation and suggested that the Notch pathway can play both
tumor-promoting and -suppressive roles within the same tissue.
Sakaguchi et al. (2013) performed whole-exome sequencing for paired
tumor-normal DNA from 13 individuals with JMML (cases), followed by deep
sequencing of 8 target genes in 92 tumor samples. JMML was characterized
by a paucity of gene mutations (0.85 nonsilent mutations per sample)
with somatic or germline RAS pathway involvement in 82 cases (89%). The
SETBP1 (611060) and JAK3 (600173) mutations were among common targets
for secondary mutations. Mutations in JAK3 were often subclonal, and
Sakaguchi et al. (2013) hypothesized that they may be involved in the
progression rather than the initiation of leukemia; these mutations
associated with poor clinical outcomes.
- Exclusion Studies
Yoshida et al. (2008) excluded mutation in the SIPA1 gene (602180) as a
cause of JMML in 16 specimens obtained from patients with the disorder
who did not have mutations in the KRAS, NRAS, or PTPN11 genes.
GENOTYPE/PHENOTYPE CORRELATIONS
Matsuda et al. (2007) reported 3 with patients with an NRAS or KRAS
gly12-to-ser (G12S) mutation who showed spontaneous improvement of
hematologic abnormalities lasting for 2 to 4 years with neither
intensive therapy nor HSCT. They suggested that the mild course
correlated with the G12S RAS mutation and recommended that patients
found to have this mutation receive close follow-up but no chemotherapy.
Flotho et al. (2008) viewed the recommendation of Matsuda et al. (2007)
as premature. They reviewed 50 patients with JMML who were not given
HSCT within the first 3 years after diagnosis; of these, 17 survived
without treatment from 4 to 21 years. Six of 7 carried a RAS mutation
different from R12S.
*FIELD* RF
1. Abdel-Wahab, O.; Mullally, A.; Hedvat, C.; Garcia-Manero, G.; Patel,
J.; Wadleigh, M.; Malinge, S.; Yao, J.; Kilpivaara, O.; Bhat, R.;
Huberman, K.; Thomas, S.; and 12 others: Genetic characterization
of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114:
144-147, 2009.
2. De Filippi, P.; Zecca, M.; Lisini, D.; Rosti, V.; Cagioni, C.;
Carlo-Stella, C.; Radi, O.; Veggiotti, P.; Mastronuzzi, A.; Acquaviva,
A.; D'Ambrosio, A.; Locatelli, F.; Danesino, C.: Germ-line mutation
of the NRAS gene may be responsible for the development of juvenile
myelomonocytic leukaemia. Brit. J. Haematol. 147: 706-709, 2009.
3. Flotho, C.; Kratz, C. P.; Bergstrasser, E.; Hasle, H.; Stary, J.;
Trebo, M.; van den Heuvel-Eibrink, M. M.; Wojcik, D.; Zecca, M.; Locatelli,
F.; Niemeyer, C. M.: Genotype-phenotype correlation in cases of juvenile
myelomonocytic leukemia with clonal RAS mutations. (Letter) Blood 111:
966-967, 2008.
4. Gelsi-Boyer, V.; Trouplin, V.; Adelaide, J.; Bonansea, J.; Cervera,
N.; Carbuccia, N.; Lagarde, A.; Prebet, T.; Nezri, M.; Sainty, D.;
Olschwang, S.; Xerri, L.; Chaffanet, M.; Mozziconacci, M.-J.; Vey,
N.; Birnbaum, D.: Mutations of polycomb-associated gene ASXL1 in
myelodysplastic syndromes and chronic myelomonocytic leukaemia. Brit.
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5. Hasle, H.; Arico, M.; Basso, G.; Biondi, A.; Rajnoldi, A. C.; Creutzig,
U.; Fenu, S.; Fonatsch, C.; Haas, O. A.; Harbott, J.; Kardos, G.;
Kerndrup, G.; and 11 others: Myelodysplastic syndrome, juvenile
myelomonocytic leukemia, and acute myeloid leukemia associated with
complete or partial monosomy 7. Leukemia 13: 376-385, 1999.
6. Jankowska, A. M.; Szpurka, H.; Tiu, R. V.; Makishima, H.; Afable,
M.; Huh, J.; O'Keefe, C. L.; Ganetzky, R.; McDevitt, M. A.; Maciejewski,
J. P.: Loss of heterozygosity 4q24 and TET2 mutations associated
with myelodysplastic/myeloproliferative neoplasms. Blood 113: 6403-6410,
2009.
7. Jongmans, M.; Sistermans, E. A.; Rikken, A.; Nillesen, W. M.; Tamminga,
R.; Patton, M.; Maier, E. M.; Tartaglia, M.; Noordam, K.; van der
Burgt, I.: Genotypic and phenotypic characterization of Noonan syndrome:
new data and review of the literature. Am. J. Med. Genet. 134A:
165-170, 2005.
8. Klinakis, A.; Lobry, C.; Abdel-Wahab, O.; Oh, P.; Haeno, H.; Buonamici,
S.; van De Walle, I.; Cathelin, S.; Trimarchi, T.; Araldi, E.; Liu,
C.; Ibrahim, S.; Beran, M.; Zavadil, J.; Efstratiadis, A.; Taghon,
T.; Michor, F.; Levine, R. L.; Aifantis, I.: A novel tumour-suppressor
function for the Notch pathway in myeloid leukaemia. Nature 473:
230-233, 2011.
9. Loh, M. L.; Sakai, D. S.; Flotho, C.; Kang, M.; Fliegauf, M.; Archambeault,
S.; Mullighan, C. G.; Chen, L.; Bergstraesser, E.; Bueso-Ramos, C.
E.; Emanuel, P. D.; Hasle, H.; and 9 others: Mutations in CBL occur
frequently in juvenile myelomonocytic leukemia. Blood 114: 1859-1863,
2009.
10. Magnusson, M. K.; Meade, K. E.; Brown, K. E.; Arthur, D. C.; Krueger,
L. A.; Barrett, A. J.; Dunbar, C. E.: Rabaptin-5 is a novel fusion
partner to platelet-derived growth factor beta receptor in chronic
myelomonocytic leukemia. Blood 98: 2518-2525, 2001.
11. Matsuda, K.; Shimada, A.; Yoshida, N.; Ogawa, A.; Watanabe, A.;
Yajima, S.; Iizuka, S.; Koike, K.; Yanai, F.; Kawasaki, K.; Yanagimachi,
M.; Kikuchi, A.; and 10 others: Spontaneous improvement of hematologic
abnormalities in patients having juvenile myelomonocytic leukemia
with specific RAS mutations. Blood 109: 5477-5480, 2007.
12. Muramatsu, H.; Makishima, H.; Jankowska, A. M.; Cazzolli, H.;
O'Keefe, C.; Yoshida, N.; Xu, Y.; Nishio, N.; Hama, A.; Yagasaki,
H.; Takahashi, Y.; Kato, K.; Manabe, A.; Kojima, S.; Maciejewski,
J. P.: Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations
are pathogenic in juvenile myelomonocytic leukemia. Blood 115: 1969-1975,
2010.
13. Niemeyer, C. M.; Arico, M.; Basso, G.; Biondi, A.; Cantu Rajnoldi,
A.; Creutzig, U.; Haas, O.; Harbott, J.; Hasle, H.; Kerndrup, G.;
Locatelli, F.; Mann, G.; Stollmann-Gibbels, B.; van't Veer-Korthof,
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14. Perez, B.; Mechinaud, F.; Galambrun, C.; Ben Romdhane, N.; Isidor,
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S.; Salmon, A.; Desiree, C.; Pereira, S.; Menot, M. L.; Royer, N.;
Fenneteau, O.; Baruchel, A.; Chomienne, C.; Verloes, A.; Cave, H.
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15. Ross, T. S.; Bernard, O. A.; Berger, R.; Gilliland, D. G.: Fusion
of huntingtin interacting protein 1 to platelet-derived growth factor-beta
receptor (PDGF-beta-R) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood 91:
4419-4426, 1998.
16. Sakaguchi, H.; Okuno, Y.; Muramatsu, H.; Yoshida, K.; Shiraishi,
Y.; Takahashi, M.; Kon, A.; Sanada, M.; Chiba, K.; Tanaka, H.; Makishima,
H.; Wang, X.; and 10 others: Exome sequencing identifies secondary
mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nature
Genet. 45: 937-941, 2013.
17. Schubbert, S.; Zenker, M.; Rowe, S. L.; Boll, S.; Klein, C.; Bollag,
G.; van der Burgt, I.; Musante, L.; Kalscheuer, V.; Wehner, L.-E.;
Nguyen, H.; West, B.; Zhang, K. Y. J.; Sistermans, E.; Rauch, A.;
Niemeyer, C. M.; Shannon, K.; Kratz, C. P.: Germline KRAS mutations
cause Noonan syndrome. Nature Genet. 38: 331-336, 2006. Note: Erratum:
Nature Genet. 38: 598 only, 2006.
18. Tartaglia, M.; Niemeyer, C. M.; Fragale, A.; Song, X.; Buechner,
J.; Jung, A.; Hahlen, K.; Hasle, H.; Licht, J. D.; Gelb, B. D.: Somatic
mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic
syndromes and acute myeloid leukemia. Nature Genet. 34: 148-150,
2003.
19. Yoshida, N.; Yagasaki, H.; Takahashi, Y.; Kudo, K.; Manabe, A.;
Kojima, S.: Mutation analysis of SIPA1 in patients with juvenile
myelomonocytic leukemia. (Letter) Brit. J. Haematol. 142: 845-846,
2008.
*FIELD* CN
Ada Hamosh - updated: 01/28/2014
Cassandra L. Kniffin - updated: 8/1/2011
Cassandra L. Kniffin - updated: 5/25/2011
Ada Hamosh - updated: 5/23/2011
Cassandra L. Kniffin - updated: 5/3/2011
Carol A. Bocchini - updated: 6/1/2009
Cassandra L. Kniffin - updated: 3/9/2009
Victor A. McKusick - updated: 2/24/2006
Victor A. McKusick - updated: 4/14/2005
*FIELD* CD
Victor A. McKusick: 5/14/2003
*FIELD* ED
alopez: 01/28/2014
carol: 12/8/2011
carol: 11/29/2011
ckniffin: 10/24/2011
wwang: 8/9/2011
ckniffin: 8/1/2011
wwang: 6/2/2011
ckniffin: 5/31/2011
ckniffin: 5/25/2011
alopez: 5/24/2011
terry: 5/23/2011
wwang: 5/19/2011
ckniffin: 5/3/2011
carol: 11/23/2009
terry: 6/19/2009
terry: 6/1/2009
carol: 6/1/2009
wwang: 3/18/2009
ckniffin: 3/9/2009
carol: 7/31/2008
alopez: 3/3/2006
terry: 2/24/2006
tkritzer: 4/27/2005
terry: 4/14/2005
terry: 7/30/2003
alopez: 6/3/2003
alopez: 5/15/2003
alopez: 5/14/2003
*RECORD*
*FIELD* NO
607785
*FIELD* TI
#607785 JUVENILE MYELOMONOCYTIC LEUKEMIA; JMML
;;LEUKEMIA, JUVENILE MYELOMONOCYTIC
read moreLEUKEMIA, CHRONIC MYELOMONOCYTIC, INCLUDED; CMML, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because juvenile
myelomonocytic leukemia (JMML) can be caused by somatic mutations in
specific genes that result in activation of the RAS signaling pathway,
such as PTPN11 (176876), KRAS (190070), NRAS (164790). Somatic mutation
in the CBL gene (165360) has also been reported.
DESCRIPTION
Juvenile myelomonocytic leukemia is an aggressive pediatric
myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD)
characterized by malignant transformation in the hematopoietic stem cell
compartment with proliferation of differentiated progeny (Loh et al.,
2009). JMML constitutes approximately 30% of childhood cases of
myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999).
Although JMML is a progressive and often rapidly fatal disease without
hematopoietic stem cell transplantation (HSCT), some patients have been
shown to have a prolonged and stable clinical course without HSCT
(Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a
similar disorder with later onset. Both JMML and CMML have a high
frequency of mutations affecting the RAS signaling pathway and show
hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511)
hyperphosphorylation (Loh et al., 2009).
- Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia
In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due
to somatic mutations in the PTPN11, KRAS, and NRAS genes. Additionally,
both germline and somatic mutations in the CBL gene have been found in
patients with JMML, indicating a frequency of 10 to 15% of JMML patients
overall (Loh et al., 2009). Somatic disruptions of the GRAF gene
(ARHGAP26; 605370) have also been found in patients with JMML.
About 10 to 15% of JMML cases arise in children with neurofibromatosis
type I (NF1; 162200) due to germline mutations in the NF1 gene (613113).
In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or
Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations
in the PTPN11, KRAS2, and CBL genes, respectively, also have an
increased risk of developing JMML.
- Genetic Heterogeneity of Chronic Myelomonocytic Leukemia
Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1
(605590) genes have been found in patients with CMML.
CYTOGENETICS
In a patient with chronic myelomonocytic leukemia (CMML) with a
t(5;7)(q33;q11.2) translocation, Ross et al. (1998) found fusion of the
HIP1 gene (601767) to the platelet-derived growth factor-beta receptor
gene (PDGFRB; 173410). They identified a chimeric transcript containing
the HIP1 gene located at 7q11.2 fused to the PDGFRB gene on 5q33. The
fusion gene encoded amino acids 1 to 950 of HIP1 joined in-frame to the
transmembrane and tyrosine kinase domains of the PDGFRB gene. The
reciprocal PDGFRB/HIP1 transcript was not expressed. The fusion protein
product was a 180-kD protein when expressed in a murine hematopoietic
cell line and was constitutively tyrosine phosphorylated. Furthermore,
the fusion gene transformed the same mouse hematopoietic cell line to
interleukin-3-independent growth.
In a patient with CMML and an acquired t(5;17)(q33;p13), Magnusson et
al. (2001) demonstrated rabaptin-5 (RABEP1; 603616) as a novel partner
fused in-frame to the 5-prime portion of the PDGFBR gene (173410). The
fusion protein included more than 85% of the native rabaptin-5 fused to
the transmembrane and intracellular tyrosine kinase domains of PDGFRB.
Rabaptin-5 is an essential and rate-limiting component of early
endosomal fusion. The new fusion protein links 2 important pathways of
growth regulation.
MOLECULAR GENETICS
- Mutations Associated with Noonan Syndrome and JMML
Tartaglia et al. (2003) showed that germline mutations in PTPN11 lead to
Noonan syndrome-1 (NS1; 163950) associated with JMML (T73I;
176876.0011), and that somatic mutations in PTPN11 are associated with
isolated JMML. Jongmans et al. (2005) described a patient with Noonan
syndrome and mild JMML who carried a mutation in the PTPN11 gene
(176876.0011).
Schubbert et al. (2006) described a 3-month-old female with Noonan
syndrome-3 (NS3; 609942) and a severe clinical phenotype who presented
with a JMML-like myeloproliferative disorder. The patient was
heterozygous for a mutation in the KRAS gene (T58I; 190070.0011). This
mutation was also present in her buccal cells, but was absent in
parental DNA.
De Filippi et al. (2009) reported a boy who presented in infancy with
JMML and was later noted to have dysmorphic features suggestive of, but
not diagnostic of, Noonan syndrome (see NS6; 613224). Features included
short stature, relative macrocephaly, high forehead, epicanthal folds,
long eyebrows, low nasal bridge, low-set ears, 2 cafe-au-lait spots, and
low scores on performance tasks. Cardiac studies were normal. Genetic
analysis revealed a de novo germline heterozygous mutation in the NRAS
gene (G13D; 164790.0003).
In 3 unrelated patients with a Noonan syndrome-like disorder (613563)
who developed JMML, Perez et al. (2010) identified a heterozygous
germline mutation in the CBL gene (Y371H; 165360.0005). The mutation
occurred de novo in 2 patients and was inherited from an unaffected
father in 1 patient. Leukemia cells of all patients showed somatic loss
of heterozygosity at chromosome 11q23, including the CBL gene. The
findings indicated that germline heterozygous mutations in the CBL gene
are associated with predisposition for the development of JMML.
In 27 of 159 leukemia samples from patients with JMML, Loh et al. (2009)
identified 25 homozygous and 2 heterozygous mutations in the CBL gene.
The mutations were located throughout the linker and RING finger
domains, and Y371H was the most common mutation. Leukemic cells from 3
patients examined in detail had acquired isodisomy of chromosome 11q
including the CBL gene. Each of these 3 patients had a heterozygous
germline CBL mutation, whereas their tumor cells had homozygous
mutations. Leukemic cells exhibited CFU-GM hypersensitivity and high
levels of STAT5 (601511) in response to GM-CSF. These findings indicated
that reduplication of an inherited CBL mutation in a pluripotent
hematopoietic stem cell confers a selective advantage for the homozygous
state. Loh et al. (2009) estimated the frequency of CBL mutations to be
10 to 15% of JMML patients overall. They did not find CBL mutations in
JMML patients with known PTPN11/RAS mutation, indicating that CBL and
PTPN11/RAS mutations are mutually exclusive. The finding that
heterozygous germline mutations may predispose to development of JMML
suggested that CBL acts as a tumor suppressor gene.
- Isolated Juvenile or Chronic Myelomonocytic Leukemia
Jankowska et al. (2009) identified recurrent areas of somatic copy
number-neutral loss of heterozygosity (LOH) and deletions of chromosome
4q24 in patients with MDS/MPD. Subsequent analysis identified somatic
mutations in the TET2 gene (612839) in 6 of 17 cases of chronic
myelomonocytic leukemia.
Abdel-Wahab et al. (2009) identified somatic mutations in the TET2 gene
in 29 (42%) of 69 CMML.
Gelsi-Boyer et al. (2009) presented evidence that the ASXL1 gene
(612990) may act as a tumor suppressor in myeloid malignancies. They
identified somatic ASXL1 mutations were also found in 19 (43%) of 44
chronic myelomonocytic leukemia samples.
Loh et al. (2009) found isolated CBL mutations in 4 of 44 samples from
patients with CMML, which shares features with JMML.
Muramatsu et al. (2010) identified uniparental disomy of 11q23 in
leukemic cells from 4 of 49 patients with JMML. Mutation analysis of the
CBL gene identified somatic mutations in 5 (10%) of 49 patients.
Mutations in the PTPN11 gene were found in 26 (53%), whereas NRAS and
KRAS mutations were found in 2 (4%) and 1 (2%) patient, respectively.
None of the patients had mutations in the TET2 gene (612839), which had
previously been shown to be present in a significant proportion of
patients with MDS/MPD, including CMML (see Jankowska et al., 2009).
Eighteen (37%) of the 49 patients with JMML studied by Muramatsu et al.
(2010) did not have any of the known pathogenic defects.
Klinakis et al. (2011) identified novel somatic-inactivating Notch (see
190198) pathway mutations in a fraction of patients with CMML.
Inactivation of Notch signaling in mouse hematopoietic stem cells
resulted in aberrant accumulation of granulocyte/monocyte progenitors,
extramedullary hematopoiesis, and the induction of CMML-like disease.
Transcriptome analysis revealed that Notch signaling regulates an
extensive myelomonocytic-specific gene signature, through the direct
suppression of gene transcription by the Notch target Hes1 (139605).
Klinakis et al. (2011) concluded that their studies identified a novel
role for Notch signaling during early hematopoietic stem cell
differentiation and suggested that the Notch pathway can play both
tumor-promoting and -suppressive roles within the same tissue.
Sakaguchi et al. (2013) performed whole-exome sequencing for paired
tumor-normal DNA from 13 individuals with JMML (cases), followed by deep
sequencing of 8 target genes in 92 tumor samples. JMML was characterized
by a paucity of gene mutations (0.85 nonsilent mutations per sample)
with somatic or germline RAS pathway involvement in 82 cases (89%). The
SETBP1 (611060) and JAK3 (600173) mutations were among common targets
for secondary mutations. Mutations in JAK3 were often subclonal, and
Sakaguchi et al. (2013) hypothesized that they may be involved in the
progression rather than the initiation of leukemia; these mutations
associated with poor clinical outcomes.
- Exclusion Studies
Yoshida et al. (2008) excluded mutation in the SIPA1 gene (602180) as a
cause of JMML in 16 specimens obtained from patients with the disorder
who did not have mutations in the KRAS, NRAS, or PTPN11 genes.
GENOTYPE/PHENOTYPE CORRELATIONS
Matsuda et al. (2007) reported 3 with patients with an NRAS or KRAS
gly12-to-ser (G12S) mutation who showed spontaneous improvement of
hematologic abnormalities lasting for 2 to 4 years with neither
intensive therapy nor HSCT. They suggested that the mild course
correlated with the G12S RAS mutation and recommended that patients
found to have this mutation receive close follow-up but no chemotherapy.
Flotho et al. (2008) viewed the recommendation of Matsuda et al. (2007)
as premature. They reviewed 50 patients with JMML who were not given
HSCT within the first 3 years after diagnosis; of these, 17 survived
without treatment from 4 to 21 years. Six of 7 carried a RAS mutation
different from R12S.
*FIELD* RF
1. Abdel-Wahab, O.; Mullally, A.; Hedvat, C.; Garcia-Manero, G.; Patel,
J.; Wadleigh, M.; Malinge, S.; Yao, J.; Kilpivaara, O.; Bhat, R.;
Huberman, K.; Thomas, S.; and 12 others: Genetic characterization
of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114:
144-147, 2009.
2. De Filippi, P.; Zecca, M.; Lisini, D.; Rosti, V.; Cagioni, C.;
Carlo-Stella, C.; Radi, O.; Veggiotti, P.; Mastronuzzi, A.; Acquaviva,
A.; D'Ambrosio, A.; Locatelli, F.; Danesino, C.: Germ-line mutation
of the NRAS gene may be responsible for the development of juvenile
myelomonocytic leukaemia. Brit. J. Haematol. 147: 706-709, 2009.
3. Flotho, C.; Kratz, C. P.; Bergstrasser, E.; Hasle, H.; Stary, J.;
Trebo, M.; van den Heuvel-Eibrink, M. M.; Wojcik, D.; Zecca, M.; Locatelli,
F.; Niemeyer, C. M.: Genotype-phenotype correlation in cases of juvenile
myelomonocytic leukemia with clonal RAS mutations. (Letter) Blood 111:
966-967, 2008.
4. Gelsi-Boyer, V.; Trouplin, V.; Adelaide, J.; Bonansea, J.; Cervera,
N.; Carbuccia, N.; Lagarde, A.; Prebet, T.; Nezri, M.; Sainty, D.;
Olschwang, S.; Xerri, L.; Chaffanet, M.; Mozziconacci, M.-J.; Vey,
N.; Birnbaum, D.: Mutations of polycomb-associated gene ASXL1 in
myelodysplastic syndromes and chronic myelomonocytic leukaemia. Brit.
J. Haemat. 145: 788-800, 2009.
5. Hasle, H.; Arico, M.; Basso, G.; Biondi, A.; Rajnoldi, A. C.; Creutzig,
U.; Fenu, S.; Fonatsch, C.; Haas, O. A.; Harbott, J.; Kardos, G.;
Kerndrup, G.; and 11 others: Myelodysplastic syndrome, juvenile
myelomonocytic leukemia, and acute myeloid leukemia associated with
complete or partial monosomy 7. Leukemia 13: 376-385, 1999.
6. Jankowska, A. M.; Szpurka, H.; Tiu, R. V.; Makishima, H.; Afable,
M.; Huh, J.; O'Keefe, C. L.; Ganetzky, R.; McDevitt, M. A.; Maciejewski,
J. P.: Loss of heterozygosity 4q24 and TET2 mutations associated
with myelodysplastic/myeloproliferative neoplasms. Blood 113: 6403-6410,
2009.
7. Jongmans, M.; Sistermans, E. A.; Rikken, A.; Nillesen, W. M.; Tamminga,
R.; Patton, M.; Maier, E. M.; Tartaglia, M.; Noordam, K.; van der
Burgt, I.: Genotypic and phenotypic characterization of Noonan syndrome:
new data and review of the literature. Am. J. Med. Genet. 134A:
165-170, 2005.
8. Klinakis, A.; Lobry, C.; Abdel-Wahab, O.; Oh, P.; Haeno, H.; Buonamici,
S.; van De Walle, I.; Cathelin, S.; Trimarchi, T.; Araldi, E.; Liu,
C.; Ibrahim, S.; Beran, M.; Zavadil, J.; Efstratiadis, A.; Taghon,
T.; Michor, F.; Levine, R. L.; Aifantis, I.: A novel tumour-suppressor
function for the Notch pathway in myeloid leukaemia. Nature 473:
230-233, 2011.
9. Loh, M. L.; Sakai, D. S.; Flotho, C.; Kang, M.; Fliegauf, M.; Archambeault,
S.; Mullighan, C. G.; Chen, L.; Bergstraesser, E.; Bueso-Ramos, C.
E.; Emanuel, P. D.; Hasle, H.; and 9 others: Mutations in CBL occur
frequently in juvenile myelomonocytic leukemia. Blood 114: 1859-1863,
2009.
10. Magnusson, M. K.; Meade, K. E.; Brown, K. E.; Arthur, D. C.; Krueger,
L. A.; Barrett, A. J.; Dunbar, C. E.: Rabaptin-5 is a novel fusion
partner to platelet-derived growth factor beta receptor in chronic
myelomonocytic leukemia. Blood 98: 2518-2525, 2001.
11. Matsuda, K.; Shimada, A.; Yoshida, N.; Ogawa, A.; Watanabe, A.;
Yajima, S.; Iizuka, S.; Koike, K.; Yanai, F.; Kawasaki, K.; Yanagimachi,
M.; Kikuchi, A.; and 10 others: Spontaneous improvement of hematologic
abnormalities in patients having juvenile myelomonocytic leukemia
with specific RAS mutations. Blood 109: 5477-5480, 2007.
12. Muramatsu, H.; Makishima, H.; Jankowska, A. M.; Cazzolli, H.;
O'Keefe, C.; Yoshida, N.; Xu, Y.; Nishio, N.; Hama, A.; Yagasaki,
H.; Takahashi, Y.; Kato, K.; Manabe, A.; Kojima, S.; Maciejewski,
J. P.: Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations
are pathogenic in juvenile myelomonocytic leukemia. Blood 115: 1969-1975,
2010.
13. Niemeyer, C. M.; Arico, M.; Basso, G.; Biondi, A.; Cantu Rajnoldi,
A.; Creutzig, U.; Haas, O.; Harbott, J.; Hasle, H.; Kerndrup, G.;
Locatelli, F.; Mann, G.; Stollmann-Gibbels, B.; van't Veer-Korthof,
E. T.; van Wering, E.; Zimmermann, M.; European Working Group on
Myelodysplastic Syndromes in Childhood (EWOG-MDS): Chronic myelomonocytic
leukemia in childhood: a retrospective analysis of 110 cases. Blood 89:
3534-3543, 1997.
14. Perez, B.; Mechinaud, F.; Galambrun, C.; Ben Romdhane, N.; Isidor,
B.; Philip, N.; Derain-Court, J.; Cassinat, B.; Lachenaud, J.; Kaltenbach,
S.; Salmon, A.; Desiree, C.; Pereira, S.; Menot, M. L.; Royer, N.;
Fenneteau, O.; Baruchel, A.; Chomienne, C.; Verloes, A.; Cave, H.
: Germline mutations of the CBL gene define a new genetic syndrome
with predisposition to juvenile myelomonocytic leukaemia. J. Med.
Genet. 47: 686-691, 2010.
15. Ross, T. S.; Bernard, O. A.; Berger, R.; Gilliland, D. G.: Fusion
of huntingtin interacting protein 1 to platelet-derived growth factor-beta
receptor (PDGF-beta-R) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood 91:
4419-4426, 1998.
16. Sakaguchi, H.; Okuno, Y.; Muramatsu, H.; Yoshida, K.; Shiraishi,
Y.; Takahashi, M.; Kon, A.; Sanada, M.; Chiba, K.; Tanaka, H.; Makishima,
H.; Wang, X.; and 10 others: Exome sequencing identifies secondary
mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nature
Genet. 45: 937-941, 2013.
17. Schubbert, S.; Zenker, M.; Rowe, S. L.; Boll, S.; Klein, C.; Bollag,
G.; van der Burgt, I.; Musante, L.; Kalscheuer, V.; Wehner, L.-E.;
Nguyen, H.; West, B.; Zhang, K. Y. J.; Sistermans, E.; Rauch, A.;
Niemeyer, C. M.; Shannon, K.; Kratz, C. P.: Germline KRAS mutations
cause Noonan syndrome. Nature Genet. 38: 331-336, 2006. Note: Erratum:
Nature Genet. 38: 598 only, 2006.
18. Tartaglia, M.; Niemeyer, C. M.; Fragale, A.; Song, X.; Buechner,
J.; Jung, A.; Hahlen, K.; Hasle, H.; Licht, J. D.; Gelb, B. D.: Somatic
mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic
syndromes and acute myeloid leukemia. Nature Genet. 34: 148-150,
2003.
19. Yoshida, N.; Yagasaki, H.; Takahashi, Y.; Kudo, K.; Manabe, A.;
Kojima, S.: Mutation analysis of SIPA1 in patients with juvenile
myelomonocytic leukemia. (Letter) Brit. J. Haematol. 142: 845-846,
2008.
*FIELD* CN
Ada Hamosh - updated: 01/28/2014
Cassandra L. Kniffin - updated: 8/1/2011
Cassandra L. Kniffin - updated: 5/25/2011
Ada Hamosh - updated: 5/23/2011
Cassandra L. Kniffin - updated: 5/3/2011
Carol A. Bocchini - updated: 6/1/2009
Cassandra L. Kniffin - updated: 3/9/2009
Victor A. McKusick - updated: 2/24/2006
Victor A. McKusick - updated: 4/14/2005
*FIELD* CD
Victor A. McKusick: 5/14/2003
*FIELD* ED
alopez: 01/28/2014
carol: 12/8/2011
carol: 11/29/2011
ckniffin: 10/24/2011
wwang: 8/9/2011
ckniffin: 8/1/2011
wwang: 6/2/2011
ckniffin: 5/31/2011
ckniffin: 5/25/2011
alopez: 5/24/2011
terry: 5/23/2011
wwang: 5/19/2011
ckniffin: 5/3/2011
carol: 11/23/2009
terry: 6/19/2009
terry: 6/1/2009
carol: 6/1/2009
wwang: 3/18/2009
ckniffin: 3/9/2009
carol: 7/31/2008
alopez: 3/3/2006
terry: 2/24/2006
tkritzer: 4/27/2005
terry: 4/14/2005
terry: 7/30/2003
alopez: 6/3/2003
alopez: 5/15/2003
alopez: 5/14/2003