RBCC

Full text data of KIT

KIT (SCFR) [Confidence: high (a blood group or CD marker)]
Mast/stem cell growth factor receptor Kit; SCFR; 2.7.10.1 (Piebald trait protein; PBT; Proto-oncogene c-Kit; Tyrosine-protein kinase Kit; p145 c-kit; v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog; CD117; Flags: Precursor)

UniProt P10721
ID KIT_HUMAN Reviewed; 976 AA.
AC P10721; B5A956; D5LXN2; D5M931; F5H8F8; Q6IQ28; Q99662; Q9UM99;
read moreDT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1989, sequence version 1.
DT 22-JAN-2014, entry version 174.
DE RecName: Full=Mast/stem cell growth factor receptor Kit;
DE Short=SCFR;
DE EC=2.7.10.1;
DE AltName: Full=Piebald trait protein;
DE Short=PBT;
DE AltName: Full=Proto-oncogene c-Kit;
DE AltName: Full=Tyrosine-protein kinase Kit;
DE AltName: Full=p145 c-kit;
DE AltName: Full=v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog;
DE AltName: CD_antigen=CD117;
DE Flags: Precursor;
GN Name=KIT; Synonyms=SCFR;
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), CATALYTIC ACTIVITY,
RP AUTOPHOSPHORYLATION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Fetal brain, and Term placenta;
RX PubMed=2448137;
RA Yarden Y., Kuang W.-J., Yang-Feng T., Coussens L., Munemitsu S.,
RA Dull T.J., Chen E., Schlessinger J., Francke U., Ullrich A.;
RT "Human proto-oncogene c-kit: a new cell surface receptor tyrosine
RT kinase for an unidentified ligand.";
RL EMBO J. 6:3341-3351(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING (ISOFORMS
RP 1 AND 2).
RX PubMed=1279499;
RA Giebel L.B., Strunk K.M., Holmes S.A., Spritz R.A.;
RT "Organization and nucleotide sequence of the human KIT (mast/stem cell
RT growth factor receptor) proto-oncogene.";
RL Oncogene 7:2207-2217(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9027509; DOI=10.1006/geno.1996.4482;
RA Andre C., Hampe A., Lachaume P., Martin E., Wang X.P., Manus V.,
RA Hu W.X., Galibert F.;
RT "Sequence analysis of two genomic regions containing the KIT and the
RT FMS receptor tyrosine kinase genes.";
RL Genomics 39:216-226(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RX PubMed=18593464; DOI=10.1186/ar2447;
RA Jin P., Zhang J., Sumariwalla P.F., Ni I., Jorgensen B., Crawford D.,
RA Phillips S., Feldmann M., Shepard H.M., Paleolog E.M.;
RT "Novel splice variants derived from the receptor tyrosine kinase
RT superfamily are potential therapeutics for rheumatoid arthritis.";
RL Arthritis Res. Ther. 10:R73-R73(2008).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), SUBCELLULAR LOCATION, AND
RP INDUCTION.
RX PubMed=20658618; DOI=10.1002/pbc.22603;
RA Neumann I., Foell J.L., Bremer M., Volkmer I., Korholz D., Burdach S.,
RA Staege M.S.;
RT "Retinoic acid enhances sensitivity of neuroblastoma cells for
RT imatinib mesylate.";
RL Pediatr. Blood Cancer 55:464-470(2010).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Staege M.S., Neumann I., Volkmer I.;
RT "Sequence of KIT mRNA from all-trans retinoic acid treated
RT neuroblastoma cell lines.";
RL Submitted (MAR-2010) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Trachea;
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].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
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 NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22.
RX PubMed=7506248;
RA Yamamoto K., Tojo A., Aoki N., Shibuya M.;
RT "Characterization of the promoter region of the human c-kit proto-
RT oncogene.";
RL Jpn. J. Cancer Res. 84:1136-1144(1993).
RN [11]
RP FUNCTION IN PHOSPHORYLATION OF PIK3R1; RAF1 AND MAPK1, INTERACTION
RP WITH GRB2; PIK3R1 AND PIK3 CATALYTIC SUBUNIT, ENZYME REGULATION, AND
RP PHOSPHORYLATION.
RX PubMed=7520444;
RA Blume-Jensen P., Ronnstrand L., Gout I., Waterfield M.D., Heldin C.H.;
RT "Modulation of Kit/stem cell factor receptor-induced signaling by
RT protein kinase C.";
RL J. Biol. Chem. 269:21793-21802(1994).
RN [12]
RP PHOSPHORYLATION AT SER-741; SER-746; SER-821 AND SER-959, ENZYME
RP REGULATION, PARTIAL PROTEIN SEQUENCE, AND MUTAGENESIS OF SER-741 AND
RP SER-746.
RX PubMed=7539802; DOI=10.1074/jbc.270.23.14192;
RA Blume-Jensen P., Wernstedt C., Heldin C.H., Ronnstrand L.;
RT "Identification of the major phosphorylation sites for protein kinase
RT C in kit/stem cell factor receptor in vitro and in intact cells.";
RL J. Biol. Chem. 270:14192-14200(1995).
RN [13]
RP INTERACTION WITH PIK3R1; MATK/CHK; FYN AND SHC1, AND PHOSPHORYLATION
RP AT TYR-568; TYR-570 AND TYR-721.
RX PubMed=9038210; DOI=10.1074/jbc.272.9.5915;
RA Price D.J., Rivnay B., Fu Y., Jiang S., Avraham S., Avraham H.;
RT "Direct association of Csk homologous kinase (CHK) with the
RT diphosphorylated site Tyr568/570 of the activated c-KIT in
RT megakaryocytes.";
RL J. Biol. Chem. 272:5915-5920(1997).
RN [14]
RP INTERACTION WITH LYN.
RX PubMed=9341198; DOI=10.1074/jbc.272.43.27450;
RA Linnekin D., DeBerry C.S., Mou S.;
RT "Lyn associates with the juxtamembrane region of c-Kit and is
RT activated by stem cell factor in hematopoietic cell lines and normal
RT progenitor cells.";
RL J. Biol. Chem. 272:27450-27455(1997).
RN [15]
RP INTERACTION WITH PTPN6, AUTOPHOSPHORYLATION, AND FUNCTION IN
RP PHOSPHORYLATION OF PTPN6.
RX PubMed=9528781;
RA Kozlowski M., Larose L., Lee F., Le D.M., Rottapel R.,
RA Siminovitch K.A.;
RT "SHP-1 binds and negatively modulates the c-Kit receptor by
RT interaction with tyrosine 569 in the c-Kit juxtamembrane domain.";
RL Mol. Cell. Biol. 18:2089-2099(1998).
RN [16]
RP INTERACTION WITH GRB2 AND GRB7, PARTIAL PROTEIN SEQUENCE,
RP AUTOPHOSPHORYLATION, AND PHOSPHORYLATION AT TYR-703 AND TYR-936.
RX PubMed=10377264; DOI=10.1042/0264-6021:3410211;
RA Thommes K., Lennartsson J., Carlberg M., Ronnstrand L.;
RT "Identification of Tyr-703 and Tyr-936 as the primary association
RT sites for Grb2 and Grb7 in the c-Kit/stem cell factor receptor.";
RL Biochem. J. 341:211-216(1999).
RN [17]
RP INTERACTION WITH PTPRU, AND FUNCTION IN PHOSPHORYLATION OF PTPRU.
RX PubMed=10397721;
RA Taniguchi Y., London R., Schinkmann K., Jiang S., Avraham H.;
RT "The receptor protein tyrosine phosphatase, PTP-RO, is upregulated
RT during megakaryocyte differentiation and is associated with the c-Kit
RT receptor.";
RL Blood 94:539-549(1999).
RN [18]
RP INTERACTION WITH MPDZ, CHARACTERIZATION OF VARIANT VAL-816, AND
RP MUTAGENESIS OF LYS-623.
RX PubMed=11018522; DOI=10.1016/S0014-5793(00)02036-6;
RA Mancini A., Koch A., Stefan M., Niemann H., Tamura T.;
RT "The direct association of the multiple PDZ domain containing proteins
RT (MUPP-1) with the human c-Kit C-terminus is regulated by tyrosine
RT kinase activity.";
RL FEBS Lett. 482:54-58(2000).
RN [19]
RP INTERACTION WITH LYN; TEC AND DOK1.
RX PubMed=11825908; DOI=10.1074/jbc.M200277200;
RA Liang X., Wisniewski D., Strife A., Shivakrupa R., Clarkson B.,
RA Resh M.D.;
RT "Phosphatidylinositol 3-kinase and Src family kinases are required for
RT phosphorylation and membrane recruitment of Dok-1 in c-Kit
RT signaling.";
RL J. Biol. Chem. 277:13732-13738(2002).
RN [20]
RP INTERACTION WITH SH2B2/APS, FUNCTION IN PHOSPHORYLATION OF SH2B2/APS,
RP AND MUTAGENESIS OF ILE-571 AND LEU-939.
RX PubMed=12444928; DOI=10.1042/BJ20020716;
RA Wollberg P., Lennartsson J., Gottfridsson E., Yoshimura A.,
RA Ronnstrand L.;
RT "The adapter protein APS associates with the multifunctional docking
RT sites Tyr-568 and Tyr-936 in c-Kit.";
RL Biochem. J. 370:1033-1038(2003).
RN [21]
RP PHOSPHORYLATION AT SER-891 AND TYR-900, PARTIAL PROTEIN SEQUENCE,
RP INTERACTION WITH CRK AND PIK3R1, FUNCTION IN PHOSPHORYLATION OF CRK;
RP AKT1 AND MAP KINASES, AND MASS SPECTROMETRY.
RX PubMed=12878163; DOI=10.1016/S0014-4827(03)00206-4;
RA Lennartsson J., Wernstedt C., Engstrom U., Hellman U., Ronnstrand L.;
RT "Identification of Tyr900 in the kinase domain of c-Kit as a Src-
RT dependent phosphorylation site mediating interaction with c-Crk.";
RL Exp. Cell Res. 288:110-118(2003).
RN [22]
RP FUNCTION, AND ALTERNATIVE SPLICING.
RX PubMed=12511554; DOI=10.1074/jbc.M211726200;
RA Voytyuk O., Lennartsson J., Mogi A., Caruana G., Courtneidge S.,
RA Ashman L.K., Ronnstrand L.;
RT "Src family kinases are involved in the differential signaling from
RT two splice forms of c-Kit.";
RL J. Biol. Chem. 278:9159-9166(2003).
RN [23]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-130, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [24]
RP INTERACTION WITH FES/FPS, AND CHARACTERIZATION OF VARIANT VAL-816.
RX PubMed=17595334; DOI=10.1182/blood-2007-02-076471;
RA Voisset E., Lopez S., Dubreuil P., De Sepulveda P.;
RT "The tyrosine kinase FES is an essential effector of KITD816V
RT proliferation signal.";
RL Blood 110:2593-2599(2007).
RN [25]
RP INTERACTION WITH GRB2 AND CBL, UBIQUITINATION, AND FUNCTION IN
RP PHOSPHORYLATION OF CBL.
RX PubMed=17904548; DOI=10.1016/j.yexcr.2007.08.021;
RA Sun J., Pedersen M., Bengtsson S., Ronnstrand L.;
RT "Grb2 mediates negative regulation of stem cell factor receptor/c-Kit
RT signaling by recruitment of Cbl.";
RL Exp. Cell Res. 313:3935-3942(2007).
RN [26]
RP FUNCTION IN ACTIVATION OF SIGNALING PATHWAYS AND CELL SURVIVAL,
RP FUNCTION IN PHOSPHORYLATION OF CBL, PHOSPHORYLATION AT TYR-568;
RP TYR-703; TYR-721 AND TYR-936, UBIQUITINATION, SUBCELLULAR LOCATION,
RP AND CHARACTERIZATION OF VARIANT VAL-816.
RX PubMed=19265199; DOI=10.1074/jbc.M808058200;
RA Sun J., Pedersen M., Ronnstrand L.;
RT "The D816V mutation of c-Kit circumvents a requirement for Src family
RT kinases in c-Kit signal transduction.";
RL J. Biol. Chem. 284:11039-11047(2009).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-959, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [28]
RP SUBCELLULAR LOCATION, ALTERNATIVE SPLICING, AND TISSUE SPECIFICITY.
RX PubMed=20601678; DOI=10.1093/humrep/deq168;
RA Muciaccia B., Sette C., Paronetto M.P., Barchi M., Pensini S.,
RA D'Agostino A., Gandini L., Geremia R., Stefanini M., Rossi P.;
RT "Expression of a truncated form of KIT tyrosine kinase in human
RT spermatozoa correlates with sperm DNA integrity.";
RL Hum. Reprod. 25:2188-2202(2010).
RN [29]
RP PHOSPHORYLATION AT TYR-547; TYR-553; TYR-703; TYR-721; TYR-730;
RP TYR-823 AND TYR-900, MASS SPECTROMETRY, MUTAGENESIS OF TYR-823, AND
RP CHARACTERIZATION OF VARIANT HIS-816.
RX PubMed=20147452; DOI=10.1093/jb/mvq015;
RA DiNitto J.P., Deshmukh G.D., Zhang Y., Jacques S.L., Coli R.,
RA Worrall J.W., Diehl W., English J.M., Wu J.C.;
RT "Function of activation loop tyrosine phosphorylation in the mechanism
RT of c-Kit auto-activation and its implication in sunitinib
RT resistance.";
RL J. Biochem. 147:601-609(2010).
RN [30]
RP FUNCTION, CATALYTIC ACTIVITY, ENZYME REGULATION, AUTOPHOSPHORYLATION,
RP SUBUNIT, AND CHARACTERIZATION OF VARIANT VAL-816.
RX PubMed=21640708; DOI=10.1016/j.bbrc.2011.05.111;
RA Kim S.Y., Kang J.J., Lee H.H., Kang J.J., Kim B., Kim C.G., Park T.K.,
RA Kang H.;
RT "Mechanism of activation of human c-KIT kinase by internal tandem
RT duplications of the juxtamembrane domain and point mutations at
RT aspartic acid 816.";
RL Biochem. Biophys. Res. Commun. 410:224-228(2011).
RN [31]
RP FUNCTION IN ACTIVATION AND PHOSPHORYLATION OF STAT1; STAT3; STAT5A AND
RP STAT5B.
RX PubMed=21135090; DOI=10.1074/jbc.M110.182642;
RA Chaix A., Lopez S., Voisset E., Gros L., Dubreuil P., De Sepulveda P.;
RT "Mechanisms of STAT protein activation by oncogenic KIT mutants in
RT neoplastic mast cells.";
RL J. Biol. Chem. 286:5956-5966(2011).
RN [32]
RP REVIEW.
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 [33]
RP REVIEW ON KIT SIGNALING.
RX PubMed=16129412; DOI=10.1016/j.bbrc.2005.08.055;
RA Roskoski R. Jr.;
RT "Signaling by Kit protein-tyrosine kinase--the stem cell factor
RT receptor.";
RL Biochem. Biophys. Res. Commun. 337:1-13(2005).
RN [34]
RP REVIEW.
RX PubMed=15625120; DOI=10.1634/stemcells.2004-0117;
RA Lennartsson J., Jelacic T., Linnekin D., Shivakrupa R.;
RT "Normal and oncogenic forms of the receptor tyrosine kinase kit.";
RL Stem Cells 23:16-43(2005).
RN [35]
RP REVIEW.
RX PubMed=18381929; DOI=10.1158/1078-0432.CCR-07-5134;
RA Kent D., Copley M., Benz C., Dykstra B., Bowie M., Eaves C.;
RT "Regulation of hematopoietic stem cells by the steel factor/KIT
RT signaling pathway.";
RL Clin. Cancer Res. 14:1926-1930(2008).
RN [36]
RP REVIEW.
RX PubMed=21057534; DOI=10.1038/onc.2010.494;
RA Pittoni P., Piconese S., Tripodo C., Colombo M.P.;
RT "Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the
RT primary off-target of tyrosine kinase inhibitors.";
RL Oncogene 30:757-769(2011).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 549-931 IN COMPLEX WITH ADP
RP AND MAGNESIUM IONS, SUBUNIT, AUTOPHOSPHORYLATION AT TYR-568 AND
RP TYR-570, AND MASS SPECTROMETRY.
RX PubMed=12824176; DOI=10.1074/jbc.C300186200;
RA Mol C.D., Lim K.B., Sridhar V., Zou H., Chien E.Y., Sang B.C.,
RA Nowakowski J., Kassel D.B., Cronin C.N., McRee D.E.;
RT "Structure of a c-kit product complex reveals the basis for kinase
RT transactivation.";
RL J. Biol. Chem. 278:31461-31464(2003).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 565-935 IN COMPLEXES WITH
RP INHIBITOR IMATINIB AND PHOSPHATE, AND ENZYME REGULATION.
RX PubMed=15123710; DOI=10.1074/jbc.M403319200;
RA Mol C.D., Dougan D.R., Schneider T.R., Skene R.J., Kraus M.L.,
RA Scheibe D.N., Snell G.P., Zou H., Sang B.C., Wilson K.P.;
RT "Structural basis for the autoinhibition and STI-571 inhibition of c-
RT Kit tyrosine kinase.";
RL J. Biol. Chem. 279:31655-31663(2004).
RN [39]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 1-519 IN COMPLEX WITH
RP KITLG/SCF, INTERACTION WITH KITLG/SCF, SUBUNIT, DISULFIDE BONDS,
RP CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, MUTAGENESIS OF ARG-381 AND
RP GLU-386, AND GLYCOSYLATION AT ASN-130; ASN-283; ASN-293; ASN-300;
RP ASN-320; ASN-352 AND ASN-367.
RX PubMed=17662946; DOI=10.1016/j.cell.2007.05.055;
RA Yuzawa S., Opatowsky Y., Zhang Z., Mandiyan V., Lax I.,
RA Schlessinger J.;
RT "Structural basis for activation of the receptor tyrosine kinase KIT
RT by stem cell factor.";
RL Cell 130:323-334(2007).
RN [40]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 544-935 IN COMPLEX WITH
RP SUNITINIB, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, CHARACTERIZATION
RP OF VARIANTS HIS-816 AND VAL-816, AND ENZYME REGULATION.
RX PubMed=19164557; DOI=10.1073/pnas.0812413106;
RA Gajiwala K.S., Wu J.C., Christensen J., Deshmukh G.D., Diehl W.,
RA DiNitto J.P., English J.M., Greig M.J., He Y.A., Jacques S.L.,
RA Lunney E.A., McTigue M., Molina D., Quenzer T., Wells P.A., Yu X.,
RA Zhang Y., Zou A., Emmett M.R., Marshall A.G., Zhang H.M.,
RA Demetri G.D.;
RT "KIT kinase mutants show unique mechanisms of drug resistance to
RT imatinib and sunitinib in gastrointestinal stromal tumor patients.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:1542-1547(2009).
RN [41]
RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 564-574 IN COMPLEX WITH
RP SOCS6, AND PHOSPHORYLATION AT TYR-568.
RX PubMed=21030588; DOI=10.1074/jbc.M110.173526;
RA Zadjali F., Pike A.C., Vesterlund M., Sun J., Wu C., Li S.S.,
RA Ronnstrand L., Knapp S., Bullock A.N., Flores-Morales A.;
RT "Structural basis for c-KIT inhibition by the suppressor of cytokine
RT signaling 6 (SOCS6) ubiquitin ligase.";
RL J. Biol. Chem. 286:480-490(2011).
RN [42]
RP VARIANT PBT LYS-583.
RX PubMed=1376329; DOI=10.1172/JCI115772;
RA Fleischman R.A.;
RT "Human piebald trait resulting from a dominant negative mutant allele
RT of the c-kit membrane receptor gene.";
RL J. Clin. Invest. 89:1713-1717(1992).
RN [43]
RP VARIANT PBT LEU-584.
RX PubMed=1370874;
RA Spritz R.A., Giebel L.B., Holmes S.A.;
RT "Dominant negative and loss of function mutations of the c-kit
RT (mast/stem cell growth factor receptor) proto-oncogene in human
RT piebaldism.";
RL Am. J. Hum. Genet. 50:261-269(1992).
RN [44]
RP VARIANT PBT ARG-664.
RX PubMed=1717985; DOI=10.1073/pnas.88.19.8696;
RA Giebel L.B., Spritz R.A.;
RT "Mutation of the KIT (mast/stem cell growth factor receptor)
RT protooncogene in human piebaldism.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:8696-8699(1991).
RN [45]
RP VARIANT MAST CELL LEUKEMIA VAL-816.
RX PubMed=7691885; DOI=10.1172/JCI116761;
RA Furitsu T., Tsujimura T., Tono T., Ikeda H., Kitayama H.,
RA Koshimizu U., Sugahara H., Butterfield J.H., Ashman L.K., Kanayama Y.,
RA Matsuzawa Y., Kitamura Y., Kanakura Y.;
RT "Identification of mutations in the coding sequence of the proto-
RT oncogene c-kit in a human mast cell leukemia cell line causing ligand-
RT independent activation of c-kit product.";
RL J. Clin. Invest. 92:1736-1744(1993).
RN [46]
RP VARIANTS PBT GLY-791 AND VAL-812.
RX PubMed=7687267; DOI=10.1111/1523-1747.ep12358440;
RA Spritz R.A., Holmes S.A., Itin P., Kuester W.;
RT "Novel mutations of the KIT (mast/stem cell growth factor receptor)
RT proto-oncogene in human piebaldism.";
RL J. Invest. Dermatol. 101:22-25(1993).
RN [47]
RP VARIANT PBT 893-GLU--PRO-896 DEL.
RX PubMed=8680409; DOI=10.1002/humu.1380060409;
RA Riva P., Milani N., Gandolfi P., Larizza L.;
RT "A 12-bp deletion (7818del12) in the c-kit protooncogene in a large
RT Italian kindred with piebaldism.";
RL Hum. Mutat. 6:343-345(1995).
RN [48]
RP VARIANT MAST CELL DISEASE GLY-820.
RX PubMed=9029028; DOI=10.1046/j.1365-2141.1997.d01-2042.x;
RA Pignon J.-M., Giraudier S., Duquesnoy P., Jouault H., Imbert M.,
RA Vainchenker W., Vernant J.-P., Tulliez M.;
RT "A new c-kit mutation in a case of aggressive mast cell disease.";
RL Br. J. Haematol. 96:374-376(1997).
RN [49]
RP VARIANT PBT GLY-796.
RX PubMed=9450866;
RX DOI=10.1002/(SICI)1096-8628(19980106)75:1<101::AID-AJMG20>3.0.CO;2-P;
RA Spritz R.A., Beighton P.;
RT "Piebaldism with deafness: molecular evidence for an expanded
RT syndrome.";
RL Am. J. Med. Genet. 75:101-103(1998).
RN [50]
RP VARIANT ACUTE MYELOID LEUKEMIA TYR-816.
RX PubMed=9657776;
RA Beghini A., Larizza L., Cairoli R., Morra E.;
RT "c-kit activating mutations and mast cell proliferation in human
RT leukemia.";
RL Blood 92:701-702(1998).
RN [51]
RP VARIANT PBT PRO-847.
RX PubMed=9699740; DOI=10.1046/j.1523-1747.1998.00269.x;
RA Nomura K., Hatayama I., Narita T., Kaneko T., Shiraishi M.;
RT "A novel KIT gene missense mutation in a Japanese family with
RT piebaldism.";
RL J. Invest. Dermatol. 111:337-338(1998).
RN [52]
RP VARIANT GIST VAL-559 DEL.
RX PubMed=9697690; DOI=10.1038/1209;
RA Nishida T., Hirota S., Taniguchi M., Hashimoto K., Isozaki K.,
RA Nakamura H., Kanakura Y., Tanaka T., Takabayashi A., Matsuda H.,
RA Kitamura Y.;
RT "Familial gastrointestinal stromal tumours with germline mutation of
RT the KIT gene.";
RL Nat. Genet. 19:323-324(1998).
RN [53]
RP VARIANTS GIST ILE-550; 550-LYS--LYS-558 DEL; 551-PRO--VAL-555 DEL;
RP ASP-559 AND 559-VAL-VAL-560 DEL.
RX PubMed=9438854; DOI=10.1126/science.279.5350.577;
RA Hirota S., Isozaki K., Moriyama Y., Hashimoto K., Nishida T.,
RA Ishiguro S., Kawano K., Hanada M., Kurata A., Takeda M.,
RA Muhammad Tunio G., Matsuzawa Y., Kanakura Y., Shinomura Y.,
RA Kitamura Y.;
RT "Gain-of-function mutations of c-kit in human gastrointestinal stromal
RT tumors.";
RL Science 279:577-580(1998).
RN [54]
RP VARIANT HIS-816, AND CHARACTERIZATION OF VARIANT HIS-816.
RX PubMed=10362788;
RA Tian Q., Frierson H.F. Jr., Krystal G.W., Moskaluk C.A.;
RT "Activating c-kit gene mutations in human germ cell tumors.";
RL Am. J. Pathol. 154:1643-1647(1999).
RN [55]
RP VARIANTS MASTOCYTOSIS VAL-816; PHE-816; TYR-816 AND LYS-839, AND
RP CHARACTERIZATION OF VARIANTS MASTOCYTOSIS VAL-816; PHE-816; TYR-816
RP AND LYS-839.
RX PubMed=9990072; DOI=10.1073/pnas.96.4.1609;
RA Longley B.J. Jr., Metcalfe D.D., Tharp M., Wang X., Tyrrell L.,
RA Lu S.-Z., Heitjan D., Ma Y.;
RT "Activating and dominant inactivating c-KIT catalytic domain mutations
RT in distinct clinical forms of human mastocytosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:1609-1614(1999).
RN [56]
RP VARIANTS PBT CYS-584; ARG-601 AND PRO-656.
RX PubMed=11074500;
RX DOI=10.1002/1096-8628(20001106)95:1<79::AID-AJMG16>3.0.CO;2-4;
RA Syrris P., Malik N.M., Murday V.A., Patton M.A., Carter N.D.,
RA Hughes H.E., Metcalfe K.;
RT "Three novel mutations of the proto-oncogene KIT cause human
RT piebaldism.";
RL Am. J. Med. Genet. 95:79-81(2000).
RN [57]
RP VARIANT GIST ALA-559.
RX PubMed=11505412;
RX DOI=10.1002/1097-0142(20010801)92:3<657::AID-CNCR1367>3.0.CO;2-D;
RA Beghini A., Tibiletti M.G., Roversi G., Chiaravalli A.M., Serio G.,
RA Capella C., Larizza L.;
RT "Germline mutation in the juxtamembrane domain of the kit gene in a
RT family with gastrointestinal stromal tumors and urticaria
RT pigmentosa.";
RL Cancer 92:657-662(2001).
RN [58]
RP VARIANT GIST 550-LYS--LYS-558 DEL.
RX PubMed=15824741; DOI=10.1038/sj.onc.1208587;
RA Chen L.L., Sabripour M., Wu E.F., Prieto V.G., Fuller G.N.,
RA Frazier M.L.;
RT "A mutation-created novel intra-exonic pre-mRNA splice site causes
RT constitutive activation of KIT in human gastrointestinal stromal
RT tumors.";
RL Oncogene 24:4271-4280(2005).
RN [59]
RP VARIANTS TYR-816; LYS-822 AND PRO-829.
RX PubMed=16175573; DOI=10.1002/gcc.20265;
RA Bignell G., Smith R., Hunter C., Stephens P., Davies H., Greenman C.,
RA Teague J., Butler A., Edkins S., Stevens C., O'meara S., Parker A.,
RA Avis T., Barthorpe S., Brackenbury L., Buck G., Clements J., Cole J.,
RA Dicks E., Edwards K., Forbes S., Gorton M., Gray K., Halliday K.,
RA Harrison R., Hills K., Hinton J., Jones D., Kosmidou V., Laman R.,
RA Lugg R., Menzies A., Perry J., Petty R., Raine K., Shepherd R.,
RA Small A., Solomon H., Stephens Y., Tofts C., Varian J., Webb A.,
RA West S., Widaa S., Yates A., Gillis A.J.M., Stoop H.J.,
RA van Gurp R.J.H.L.M., Oosterhuis J.W., Looijenga L.H.J., Futreal P.A.,
RA Wooster R., Stratton M.R.;
RT "Sequence analysis of the protein kinase gene family in human
RT testicular germ-cell tumors of adolescents and adults.";
RL Genes Chromosomes Cancer 45:42-46(2006).
RN [60]
RP VARIANTS [LARGE SCALE ANALYSIS] ILE-532; LEU-541; SER-691; ASN-715;
RP ASN-737; TRP-804; TYR-816; LYS-822 AND PRO-829.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Tyrosine-protein kinase that acts as cell-surface
CC receptor for the cytokine KITLG/SCF and plays an essential role in
CC the regulation of cell survival and proliferation, hematopoiesis,
CC stem cell maintenance, gametogenesis, mast cell development,
CC migration and function, and in melanogenesis. In response to
CC KITLG/SCF binding, KIT can activate several signaling pathways.
CC Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the
CC AKT1 signaling pathway by phosphorylation of PIK3R1, the
CC regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT
CC also transmits signals via GRB2 and activation of RAS, RAF1 and
CC the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation
CC of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation
CC of PLCG1 leads to the production of the cellular signaling
CC molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT
CC signaling is modulated by protein phosphatases, and by rapid
CC internalization and degradation of the receptor. Activated KIT
CC promotes phosphorylation of the protein phosphatases PTPN6/SHP-1
CC and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A
CC and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform
CC Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.
CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC [protein]-L-tyrosine phosphate.
CC -!- ENZYME REGULATION: Present in an inactive conformation in the
CC absence of bound ligand. KITLG/SCF binding leads to dimerization
CC and activation by autophosphorylation on tyrosine residues.
CC Activity is down-regulated by PRKCA-mediated phosphorylation on
CC serine residues. Inhibited by imatinib/STI-571 (Gleevec) and
CC sunitinib; these compounds maintain the kinase in an inactive
CC conformation.
CC -!- SUBUNIT: Monomer in the absence of bound KITLG/SCF. Homodimer in
CC the presence of bound KITLG/SCF, forming a heterotetramer with two
CC KITLG/SCF molecules. Interacts (via phosphorylated tyrosine
CC residues) with the adapter proteins GRB2 and GRB7 (via SH2
CC domain), and SH2B2/APS. Interacts (via C-terminus) with MPDZ (via
CC the tenth PDZ domain). Interacts (via phosphorylated tyrosine
CC residues) with PIK3R1 and PIK3 catalytic subunit. Interacts (via
CC phosphorylated tyrosine) with CRK (isoform Crk-II), FYN, SHC1 and
CC MATK/CHK (via SH2 domain). Interacts with LYN and FES/FPS.
CC Interacts (via phosphorylated tyrosine residues) with the protein
CC phosphatases PTPN6/SHP-1 (via SH2 domain), PTPN11/SHP-2 (via SH2
CC domain) and PTPRU. Interacts with PLCG1. Interacts with DOK1 and
CC TEC.
CC -!- INTERACTION:
CC P62993:GRB2; NbExp=4; IntAct=EBI-1379503, EBI-401755;
CC P21583:KITLG; NbExp=2; IntAct=EBI-1379503, EBI-1379527;
CC P35235:Ptpn11 (xeno); NbExp=2; IntAct=EBI-1379503, EBI-397236;
CC Q92729:PTPRU; NbExp=2; IntAct=EBI-1379503, EBI-7052301;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Cell membrane; Single-pass type I
CC membrane protein.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cell membrane; Single-pass type I
CC membrane protein.
CC -!- SUBCELLULAR LOCATION: Isoform 3: Cytoplasm. Note=Detected in the
CC cytoplasm of spermatozoa, especially in the equatorial and
CC subacrosomal region of the sperm head.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=GNNK(+), Kit(+);
CC IsoId=P10721-1; Sequence=Displayed;
CC Name=2; Synonyms=GNNK(-), KitA(+);
CC IsoId=P10721-2; Sequence=VSP_038385;
CC Name=3; Synonyms=TR-KIT;
CC IsoId=P10721-3; Sequence=VSP_041866, VSP_041867;
CC -!- TISSUE SPECIFICITY: Isoform 1 and isoform 2 are detected in
CC spermatogonia and Leydig cells. Isoform 3 is detected in round
CC spermatids, elongating spermatids and spermatozoa (at protein
CC level). Widely expressed. Detected in the hematopoietic system,
CC the gastrointestinal system, in melanocytes and in germ cells.
CC -!- INDUCTION: Up-regulated by cis-retinoic acid in neuroblastoma cell
CC lines.
CC -!- PTM: Ubiquitinated by SOCS6. KIT is rapidly ubiquitinated after
CC autophosphorylation induced by KITLG/SCF binding, leading to
CC internalization and degradation.
CC -!- PTM: Autophosphorylated on tyrosine residues. KITLG/SCF binding
CC enhances autophosphorylation. Isoform 1 shows low levels of
CC tyrosine phosphorylation in the absence of added KITLG/SCF (in
CC vitro). Kinase activity is down-regulated by phosphorylation on
CC serine residues by protein kinase C family members.
CC Phosphorylation at Tyr-568 is required for interaction with
CC PTPN11/SHP-2, CRK (isoform Crk-II) and members of the SRC
CC tyrosine-protein kinase family. Phosphorylation at Tyr-570 is
CC required for interaction with PTPN6/SHP-1. Phosphorylation at Tyr-
CC 703, Tyr-823 and Tyr-936 is important for interaction with GRB2.
CC Phosphorylation at Tyr-721 is important for interaction with
CC PIK3R1. Phosphorylation at Tyr-823 and Tyr-936 is important for
CC interaction with GRB7.
CC -!- DISEASE: Piebald trait (PBT) [MIM:172800]: Autosomal dominant
CC genetic developmental abnormality of pigmentation characterized by
CC congenital patches of white skin and hair that lack melanocytes.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Gastrointestinal stromal tumor (GIST) [MIM:606764]:
CC Common mesenchymal neoplasms arising in the gastrointestinal
CC tract, most often in the stomach. They are histologically,
CC immunohistochemically, and genetically different from typical
CC leiomyomas, leiomyosarcomas, and schwannomas. Most GISTs are
CC composed of a fairly uniform population of spindle-shaped cells.
CC Some tumors are dominated by epithelioid cells or contain a
CC mixture of spindle and epithelioid morphologies. Primary GISTs in
CC the gastrointestinal tract commonly metastasize in the omentum and
CC mesenteries, often as multiple nodules. However, primary tumors
CC may also occur outside of the gastrointestinal tract, in other
CC intra-abdominal locations, especially in the omentum and
CC mesentery. Note=The gene represented in this entry is involved in
CC disease pathogenesis.
CC -!- DISEASE: Testicular germ cell tumor (TGCT) [MIM:273300]: A common
CC malignancy in males representing 95% of all testicular neoplasms.
CC TGCTs have various pathologic subtypes including: unclassified
CC intratubular germ cell neoplasia, seminoma (including cases with
CC syncytiotrophoblastic cells), spermatocytic seminoma, embryonal
CC carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. Note=The
CC gene represented in this entry may be involved in disease
CC pathogenesis.
CC -!- DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype
CC of acute leukemia, a cancer of the white blood cells. AML is a
CC malignant disease of bone marrow characterized by maturational
CC arrest of hematopoietic precursors at an early stage of
CC development. Clonal expansion of myeloid blasts occurs in bone
CC marrow, blood, and other tissue. Myelogenous leukemias develop
CC from changes in cells that normally produce neutrophils,
CC basophils, eosinophils and monocytes. Note=The gene represented in
CC this entry is involved in disease pathogenesis. Somatic mutations
CC that lead to constitutive activation of KIT are detected in AML
CC patients. These mutations fall into two classes, the most common
CC being in-frame internal tandem duplications of variable length in
CC the juxtamembrane region that disrupt the normal regulation of the
CC kinase activity. Likewise, point mutations in the kinase domain
CC can result in a constitutively activated kinase.
CC -!- MISCELLANEOUS: Numerous proteins are phosphorylated in response to
CC KIT signaling, but it is not evident to determine which are
CC directly phosphorylated by KIT under in vivo conditions.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. CSF-1/PDGF receptor subfamily.
CC -!- SIMILARITY: Contains 5 Ig-like C2-type (immunoglobulin-like)
CC domains.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/KITID127.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/KIT";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=CD117 entry;
CC URL="http://en.wikipedia.org/wiki/CD117";
CC -----------------------------------------------------------------------
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DR EMBL; X06182; CAA29548.1; -; mRNA.
DR EMBL; X69301; CAA49159.1; -; Genomic_DNA.
DR EMBL; X69302; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69303; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69304; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69305; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69306; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69307; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69308; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69309; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69310; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69311; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69312; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69313; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69314; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69315; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; X69316; CAA49159.1; JOINED; Genomic_DNA.
DR EMBL; U63834; AAC50968.1; -; Genomic_DNA.
DR EMBL; U63834; AAC50969.1; -; Genomic_DNA.
DR EMBL; EU826594; ACF47630.1; -; mRNA.
DR EMBL; GU983671; ADF36702.1; -; mRNA.
DR EMBL; HM015525; ADF50068.1; -; mRNA.
DR EMBL; HM015526; ADF50069.1; -; mRNA.
DR EMBL; AK304031; BAG64945.1; -; mRNA.
DR EMBL; AC006552; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC092545; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC071593; AAH71593.1; -; mRNA.
DR EMBL; S67773; AAB29529.1; -; Genomic_DNA.
DR PIR; S01426; TVHUKT.
DR RefSeq; NP_000213.1; NM_000222.2.
DR RefSeq; NP_001087241.1; NM_001093772.1.
DR UniGene; Hs.479754; -.
DR PDB; 1PKG; X-ray; 2.90 A; A/B=549-931.
DR PDB; 1QZJ; Model; -; A=576-932.
DR PDB; 1QZK; Model; -; A=576-932.
DR PDB; 1R01; Model; -; A=576-932.
DR PDB; 1T45; X-ray; 1.90 A; A=547-935.
DR PDB; 1T46; X-ray; 1.60 A; A=565-935.
DR PDB; 2E9W; X-ray; 3.50 A; A/B=26-514.
DR PDB; 2EC8; X-ray; 3.00 A; A=1-519.
DR PDB; 2VIF; X-ray; 1.45 A; P=564-574.
DR PDB; 3G0E; X-ray; 1.60 A; A=544-935.
DR PDB; 3G0F; X-ray; 2.60 A; A/B=544-935.
DR PDB; 4HVS; X-ray; 1.90 A; A=551-934.
DR PDB; 4K94; X-ray; 2.40 A; C=308-518.
DR PDB; 4K9E; X-ray; 2.70 A; C=308-518.
DR PDBsum; 1PKG; -.
DR PDBsum; 1QZJ; -.
DR PDBsum; 1QZK; -.
DR PDBsum; 1R01; -.
DR PDBsum; 1T45; -.
DR PDBsum; 1T46; -.
DR PDBsum; 2E9W; -.
DR PDBsum; 2EC8; -.
DR PDBsum; 2VIF; -.
DR PDBsum; 3G0E; -.
DR PDBsum; 3G0F; -.
DR PDBsum; 4HVS; -.
DR PDBsum; 4K94; -.
DR PDBsum; 4K9E; -.
DR ProteinModelPortal; P10721; -.
DR SMR; P10721; 33-507, 547-931.
DR DIP; DIP-1055N; -.
DR IntAct; P10721; 12.
DR MINT; MINT-146746; -.
DR STRING; 9606.ENSP00000288135; -.
DR BindingDB; P10721; -.
DR ChEMBL; CHEMBL1936; -.
DR DrugBank; DB01254; Dasatinib.
DR DrugBank; DB00619; Imatinib.
DR DrugBank; DB00398; Sorafenib.
DR DrugBank; DB01268; Sunitinib.
DR GuidetoPHARMACOLOGY; 1805; -.
DR PhosphoSite; P10721; -.
DR DMDM; 125472; -.
DR PaxDb; P10721; -.
DR PRIDE; P10721; -.
DR DNASU; 3815; -.
DR Ensembl; ENST00000288135; ENSP00000288135; ENSG00000157404.
DR Ensembl; ENST00000412167; ENSP00000390987; ENSG00000157404.
DR GeneID; 3815; -.
DR KEGG; hsa:3815; -.
DR UCSC; uc010igr.3; human.
DR CTD; 3815; -.
DR GeneCards; GC04P055524; -.
DR HGNC; HGNC:6342; KIT.
DR HPA; CAB003288; -.
DR HPA; HPA004471; -.
DR MIM; 164920; gene.
DR MIM; 172800; phenotype.
DR MIM; 273300; phenotype.
DR MIM; 601626; phenotype.
DR MIM; 606764; phenotype.
DR neXtProt; NX_P10721; -.
DR Orphanet; 98850; Aggressive systemic mastocytosis.
DR Orphanet; 280785; Bullous diffuse cutaneous mastocytosis.
DR Orphanet; 79455; Cutaneous mastocytoma.
DR Orphanet; 44890; Gastrointestinal stromal tumor.
DR Orphanet; 98848; Indolent systemic mastocytosis.
DR Orphanet; 79457; Maculopapular cutaneous mastocytosis.
DR Orphanet; 98851; Mast cell leukemia.
DR Orphanet; 2884; Piebaldism.
DR Orphanet; 280794; Pseudoxanthomatous diffuse cutaneous mastocytosis.
DR Orphanet; 98849; Systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disease.
DR Orphanet; 90389; Telangiectasia macularis eruptiva perstans.
DR PharmGKB; PA30128; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000112008; -.
DR HOVERGEN; HBG104348; -.
DR InParanoid; P10721; -.
DR KO; K05091; -.
DR OMA; YFCPGTE; -.
DR OrthoDB; EOG7S7SCZ; -.
DR PhylomeDB; P10721; -.
DR BRENDA; 2.7.10.1; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P10721; -.
DR EvolutionaryTrace; P10721; -.
DR GeneWiki; CD117; -.
DR GenomeRNAi; 3815; -.
DR NextBio; 14995; -.
DR PRO; PR:P10721; -.
DR ArrayExpress; P10721; -.
DR Bgee; P10721; -.
DR CleanEx; HS_KIT; -.
DR Genevestigator; P10721; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0019955; F:cytokine binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004716; F:receptor signaling protein tyrosine kinase activity; TAS:ProtInc.
DR GO; GO:0005020; F:stem cell factor receptor activity; IEA:Ensembl.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IDA:UniProtKB.
DR GO; GO:0031532; P:actin cytoskeleton reorganization; IDA:UniProtKB.
DR GO; GO:0000187; P:activation of MAPK activity; IDA:UniProtKB.
DR GO; GO:0097067; P:cellular response to thyroid hormone stimulus; IEA:Ensembl.
DR GO; GO:0002371; P:dendritic cell cytokine production; ISS:UniProtKB.
DR GO; GO:0050910; P:detection of mechanical stimulus involved in sensory perception of sound; ISS:UniProtKB.
DR GO; GO:0048565; P:digestive tract development; ISS:UniProtKB.
DR GO; GO:0035162; P:embryonic hemopoiesis; ISS:UniProtKB.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0030218; P:erythrocyte differentiation; ISS:UniProtKB.
DR GO; GO:0038162; P:erythropoietin-mediated signaling pathway; ISS:UniProtKB.
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:0035234; P:germ cell programmed cell death; IEA:Ensembl.
DR GO; GO:0006687; P:glycosphingolipid metabolic process; IEA:Ensembl.
DR GO; GO:0002327; P:immature B cell differentiation; ISS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; ISS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0007243; P:intracellular protein kinase cascade; IEA:Ensembl.
DR GO; GO:0038109; P:Kit signaling pathway; IDA:UniProtKB.
DR GO; GO:0030032; P:lamellipodium assembly; ISS:UniProtKB.
DR GO; GO:0002320; P:lymphoid progenitor cell differentiation; IEA:Ensembl.
DR GO; GO:0008584; P:male gonad development; IEP:UniProtKB.
DR GO; GO:0002551; P:mast cell chemotaxis; IDA:UniProtKB.
DR GO; GO:0032762; P:mast cell cytokine production; IDA:UniProtKB.
DR GO; GO:0043303; P:mast cell degranulation; IMP:UniProtKB.
DR GO; GO:0060374; P:mast cell differentiation; ISS:UniProtKB.
DR GO; GO:0070662; P:mast cell proliferation; TAS:UniProtKB.
DR GO; GO:0035855; P:megakaryocyte development; ISS:UniProtKB.
DR GO; GO:0097326; P:melanocyte adhesion; ISS:UniProtKB.
DR GO; GO:0030318; P:melanocyte differentiation; ISS:UniProtKB.
DR GO; GO:0097324; P:melanocyte migration; ISS:UniProtKB.
DR GO; GO:0002318; P:myeloid progenitor cell differentiation; IEA:Ensembl.
DR GO; GO:0043069; P:negative regulation of programmed cell death; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0001541; P:ovarian follicle development; ISS:UniProtKB.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; TAS:UniProtKB.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase cascade; TAS:UniProtKB.
DR GO; GO:0010863; P:positive regulation of phospholipase C activity; TAS:UniProtKB.
DR GO; GO:0051091; P:positive regulation of sequence-specific DNA binding transcription factor activity; IMP:UniProtKB.
DR GO; GO:0042511; P:positive regulation of tyrosine phosphorylation of Stat1 protein; IMP:UniProtKB.
DR GO; GO:0042517; P:positive regulation of tyrosine phosphorylation of Stat3 protein; IMP:UniProtKB.
DR GO; GO:0042523; P:positive regulation of tyrosine phosphorylation of Stat5 protein; IMP:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0042127; P:regulation of cell proliferation; TAS:UniProtKB.
DR GO; GO:0008360; P:regulation of cell shape; ISS:UniProtKB.
DR GO; GO:0048070; P:regulation of developmental pigmentation; IEA:Ensembl.
DR GO; GO:0009314; P:response to radiation; IEA:Ensembl.
DR GO; GO:0007286; P:spermatid development; IEA:Ensembl.
DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB.
DR GO; GO:0019827; P:stem cell maintenance; TAS:UniProtKB.
DR GO; GO:0030217; P:T cell differentiation; ISS:UniProtKB.
DR Gene3D; 2.60.40.10; -; 5.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR013151; Immunoglobulin.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR027263; SCGF_receptor.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016243; Tyr_kinase_CSF1/PDGF_rcpt.
DR InterPro; IPR001824; Tyr_kinase_rcpt_3_CS.
DR Pfam; PF00047; ig; 1.
DR Pfam; PF07714; Pkinase_Tyr; 1.
DR PIRSF; PIRSF500951; SCGF_recepter; 1.
DR PIRSF; PIRSF000615; TyrPK_CSF1-R; 1.
DR SMART; SM00409; IG; 1.
DR SMART; SM00408; IGc2; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF56112; SSF56112; 2.
DR PROSITE; PS50835; IG_LIKE; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS00240; RECEPTOR_TYR_KIN_III; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Disease mutation; Disulfide bond; Glycoprotein; Immunoglobulin domain;
KW Kinase; Magnesium; Membrane; Metal-binding; Nucleotide-binding;
KW Phosphoprotein; Polymorphism; Proto-oncogene; Receptor;
KW Reference proteome; Repeat; Signal; Transferase; Transmembrane;
KW Transmembrane helix; Tyrosine-protein kinase; Ubl conjugation.
FT SIGNAL 1 25 Potential.
FT CHAIN 26 976 Mast/stem cell growth factor receptor
FT Kit.
FT /FTId=PRO_0000016754.
FT TOPO_DOM 26 524 Extracellular (Potential).
FT TRANSMEM 525 545 Helical; (Potential).
FT TOPO_DOM 546 976 Cytoplasmic (Potential).
FT DOMAIN 27 112 Ig-like C2-type 1.
FT DOMAIN 121 205 Ig-like C2-type 2.
FT DOMAIN 212 308 Ig-like C2-type 3.
FT DOMAIN 317 410 Ig-like C2-type 4.
FT DOMAIN 413 507 Ig-like C2-type 5.
FT DOMAIN 589 937 Protein kinase.
FT NP_BIND 596 603 ATP.
FT NP_BIND 671 677 ATP.
FT REGION 568 570 Important for interaction with
FT phosphotyrosine-binding proteins.
FT ACT_SITE 792 792 Proton acceptor (By similarity).
FT METAL 568 568 Magnesium.
FT METAL 797 797 Magnesium.
FT METAL 810 810 Magnesium.
FT BINDING 623 623 ATP.
FT BINDING 796 796 ATP.
FT SITE 936 936 Important for interaction with
FT phosphotyrosine-binding proteins.
FT MOD_RES 547 547 Phosphotyrosine; by autocatalysis
FT (Probable).
FT MOD_RES 553 553 Phosphotyrosine; by autocatalysis
FT (Probable).
FT MOD_RES 568 568 Phosphotyrosine; by autocatalysis.
FT MOD_RES 570 570 Phosphotyrosine; by autocatalysis.
FT MOD_RES 703 703 Phosphotyrosine; by autocatalysis.
FT MOD_RES 721 721 Phosphotyrosine; by autocatalysis.
FT MOD_RES 730 730 Phosphotyrosine; by autocatalysis
FT (Probable).
FT MOD_RES 741 741 Phosphoserine; by PKC/PRKCA.
FT MOD_RES 746 746 Phosphoserine; by PKC/PRKCA.
FT MOD_RES 821 821 Phosphoserine.
FT MOD_RES 823 823 Phosphotyrosine; by autocatalysis.
FT MOD_RES 891 891 Phosphoserine.
FT MOD_RES 900 900 Phosphotyrosine; by autocatalysis.
FT MOD_RES 936 936 Phosphotyrosine; by autocatalysis.
FT MOD_RES 959 959 Phosphoserine.
FT CARBOHYD 130 130 N-linked (GlcNAc...).
FT CARBOHYD 145 145 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 283 283 N-linked (GlcNAc...).
FT CARBOHYD 293 293 N-linked (GlcNAc...).
FT CARBOHYD 300 300 N-linked (GlcNAc...).
FT CARBOHYD 320 320 N-linked (GlcNAc...).
FT CARBOHYD 352 352 N-linked (GlcNAc...).
FT CARBOHYD 367 367 N-linked (GlcNAc...).
FT CARBOHYD 463 463 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 486 486 N-linked (GlcNAc...) (Potential).
FT DISULFID 58 97
FT DISULFID 136 186
FT DISULFID 151 183
FT DISULFID 233 290
FT DISULFID 428 491
FT VAR_SEQ 412 413 KP -> SL (in isoform 3).
FT /FTId=VSP_041866.
FT VAR_SEQ 414 976 Missing (in isoform 3).
FT /FTId=VSP_041867.
FT VAR_SEQ 510 513 Missing (in isoform 2).
FT /FTId=VSP_038385.
FT VARIANT 532 532 V -> I (in dbSNP:rs55792975).
FT /FTId=VAR_042021.
FT VARIANT 541 541 M -> L (in dbSNP:rs3822214).
FT /FTId=VAR_042022.
FT VARIANT 541 541 M -> V (in dbSNP:rs3822214).
FT /FTId=VAR_061289.
FT VARIANT 550 558 Missing (in GIST; somatic mutation).
FT /FTId=VAR_033124.
FT VARIANT 550 550 K -> I (in GIST; somatic mutation;
FT dbSNP:rs28933968).
FT /FTId=VAR_033123.
FT VARIANT 551 555 Missing (in GIST; somatic mutation).
FT /FTId=VAR_033125.
FT VARIANT 559 560 Missing (in GIST; somatic mutation).
FT /FTId=VAR_033128.
FT VARIANT 559 559 V -> A (in GIST).
FT /FTId=VAR_033126.
FT VARIANT 559 559 V -> D (in GIST; somatic mutation).
FT /FTId=VAR_033127.
FT VARIANT 559 559 Missing (in GIST).
FT /FTId=VAR_007965.
FT VARIANT 583 583 E -> K (in PBT).
FT /FTId=VAR_004104.
FT VARIANT 584 584 F -> C (in PBT; dbSNP:rs28933371).
FT /FTId=VAR_033129.
FT VARIANT 584 584 F -> L (in PBT).
FT /FTId=VAR_004105.
FT VARIANT 601 601 G -> R (in PBT).
FT /FTId=VAR_033130.
FT VARIANT 656 656 L -> P (in PBT).
FT /FTId=VAR_033131.
FT VARIANT 664 664 G -> R (in PBT).
FT /FTId=VAR_004106.
FT VARIANT 691 691 C -> S (in dbSNP:rs35200131).
FT /FTId=VAR_042023.
FT VARIANT 715 715 S -> N (in dbSNP:rs56094246).
FT /FTId=VAR_042024.
FT VARIANT 737 737 D -> N (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_042025.
FT VARIANT 791 791 R -> G (in PBT).
FT /FTId=VAR_004107.
FT VARIANT 796 796 R -> G (in PBT; with sensorineural
FT deafness).
FT /FTId=VAR_033132.
FT VARIANT 804 804 R -> W (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_042026.
FT VARIANT 812 812 G -> V (in PBT).
FT /FTId=VAR_004108.
FT VARIANT 816 816 D -> F (in mastocytosis; requires 2
FT nucleotide substitutions; somatic
FT mutation; constitutively activated and is
FT much more rapidly autophosphorylated than
FT wild type).
FT /FTId=VAR_033133.
FT VARIANT 816 816 D -> H (in a testicular tumor; seminoma;
FT somatic mutation; constitutively
FT activated; dbSNP:rs28933969).
FT /FTId=VAR_033134.
FT VARIANT 816 816 D -> V (in mast cell leukemia and
FT mastocytosis; somatic mutation;
FT constitutively activated; loss of
FT interaction with MPDZ).
FT /FTId=VAR_004109.
FT VARIANT 816 816 D -> Y (in acute myeloid leukemia,
FT mastocytosis and a germ cell tumor of the
FT testis; somatic mutation; constitutively
FT activated).
FT /FTId=VAR_023828.
FT VARIANT 820 820 D -> G (in mast cell disease; systemic).
FT /FTId=VAR_033135.
FT VARIANT 822 822 N -> K (in a germ cell tumor of the
FT testis; somatic mutation).
FT /FTId=VAR_023829.
FT VARIANT 829 829 A -> P (in a germ cell tumor of the
FT testis; somatic mutation).
FT /FTId=VAR_023830.
FT VARIANT 839 839 E -> K (in mastocytosis; somatic
FT mutation; dominant negative mutation;
FT loss of autophosphorylation).
FT /FTId=VAR_033136.
FT VARIANT 847 847 T -> P (in PBT).
FT /FTId=VAR_033137.
FT VARIANT 893 896 Missing (in PBT; severe).
FT /FTId=VAR_004110.
FT MUTAGEN 381 381 R->A: Reduces autophosphorylation in
FT response to KITLG/SCF.
FT MUTAGEN 386 386 E->A: Reduces autophosphorylation in
FT response to KITLG/SCF.
FT MUTAGEN 571 571 I->A: Reduction in SH2B2/APS binding.
FT Abolishes SH2B2/APS binding; when
FT associated with A-939.
FT MUTAGEN 623 623 K->M: Stronger interaction with MPDZ.
FT MUTAGEN 741 741 S->A: Abolishes down-regulation of kinase
FT activity by PKC/PRKCA-mediated
FT phosphorylation; when associated with A-
FT 746.
FT MUTAGEN 746 746 S->A: Abolishes down-regulation of kinase
FT activity by PKC/PRKCA-mediated
FT phosphorylation; when associated with A-
FT 741.
FT MUTAGEN 823 823 Y->F: No decrease in activity. Leads to
FT autophosphorylation at Tyr-900.
FT MUTAGEN 939 939 L->A: Reduction in SH2B2/APS binding.
FT Abolishes SH2B2/APS binding; when
FT associated with A-571.
FT CONFLICT 764 764 L -> I (in Ref. 9; AAH71593).
FT CONFLICT 838 838 P -> H (in Ref. 9; AAH71593).
FT STRAND 38 41
FT STRAND 44 47
FT STRAND 54 59
FT STRAND 63 72
FT STRAND 75 77
FT STRAND 79 86
FT HELIX 89 91
FT STRAND 93 99
FT STRAND 104 110
FT STRAND 125 130
FT STRAND 132 134
FT STRAND 146 149
FT STRAND 151 153
FT STRAND 161 165
FT TURN 166 168
FT STRAND 169 174
FT HELIX 177 179
FT STRAND 183 188
FT STRAND 193 200
FT STRAND 203 205
FT STRAND 213 215
FT STRAND 219 224
FT STRAND 229 239
FT STRAND 243 248
FT STRAND 258 263
FT STRAND 265 267
FT STRAND 269 279
FT TURN 282 284
FT STRAND 286 293
FT STRAND 298 310
FT STRAND 312 319
FT STRAND 321 325
FT STRAND 331 341
FT STRAND 345 352
FT STRAND 356 359
FT STRAND 362 364
FT STRAND 367 369
FT STRAND 372 379
FT HELIX 384 386
FT STRAND 388 395
FT STRAND 400 409
FT STRAND 411 419
FT STRAND 422 424
FT STRAND 426 434
FT STRAND 437 439
FT STRAND 468 470
FT STRAND 472 478
FT STRAND 492 494
FT STRAND 499 501
FT STRAND 558 564
FT STRAND 567 570
FT TURN 573 575
FT HELIX 580 582
FT HELIX 586 588
FT STRAND 589 597
FT STRAND 599 613
FT STRAND 617 625
FT HELIX 631 647
FT STRAND 656 660
FT STRAND 662 665
FT STRAND 667 671
FT HELIX 678 684
FT TURN 685 688
FT STRAND 757 759
FT HELIX 760 762
FT HELIX 766 785
FT STRAND 788 790
FT HELIX 795 797
FT STRAND 798 801
FT TURN 802 804
FT STRAND 805 808
FT HELIX 812 814
FT HELIX 817 819
FT STRAND 823 826
FT STRAND 829 831
FT HELIX 833 835
FT HELIX 838 843
FT HELIX 848 863
FT TURN 864 866
FT HELIX 877 884
FT HELIX 897 906
FT HELIX 911 913
FT HELIX 917 930
SQ SEQUENCE 976 AA; 109865 MW; 81B0CD76817F3454 CRC64;
MRGARGAWDF LCVLLLLLRV QTGSSQPSVS PGEPSPPSIH PGKSDLIVRV GDEIRLLCTD
PGFVKWTFEI LDETNENKQN EWITEKAEAT NTGKYTCTNK HGLSNSIYVF VRDPAKLFLV
DRSLYGKEDN DTLVRCPLTD PEVTNYSLKG CQGKPLPKDL RFIPDPKAGI MIKSVKRAYH
RLCLHCSVDQ EGKSVLSEKF ILKVRPAFKA VPVVSVSKAS YLLREGEEFT VTCTIKDVSS
SVYSTWKREN SQTKLQEKYN SWHHGDFNYE RQATLTISSA RVNDSGVFMC YANNTFGSAN
VTTTLEVVDK GFINIFPMIN TTVFVNDGEN VDLIVEYEAF PKPEHQQWIY MNRTFTDKWE
DYPKSENESN IRYVSELHLT RLKGTEGGTY TFLVSNSDVN AAIAFNVYVN TKPEILTYDR
LVNGMLQCVA AGFPEPTIDW YFCPGTEQRC SASVLPVDVQ TLNSSGPPFG KLVVQSSIDS
SAFKHNGTVE CKAYNDVGKT SAYFNFAFKG NNKEQIHPHT LFTPLLIGFV IVAGMMCIIV
MILTYKYLQK PMYEVQWKVV EEINGNNYVY IDPTQLPYDH KWEFPRNRLS FGKTLGAGAF
GKVVEATAYG LIKSDAAMTV AVKMLKPSAH LTEREALMSE LKVLSYLGNH MNIVNLLGAC
TIGGPTLVIT EYCCYGDLLN FLRRKRDSFI CSKQEDHAEA ALYKNLLHSK ESSCSDSTNE
YMDMKPGVSY VVPTKADKRR SVRIGSYIER DVTPAIMEDD ELALDLEDLL SFSYQVAKGM
AFLASKNCIH RDLAARNILL THGRITKICD FGLARDIKND SNYVVKGNAR LPVKWMAPES
IFNCVYTFES DVWSYGIFLW ELFSLGSSPY PGMPVDSKFY KMIKEGFRML SPEHAPAEMY
DIMKTCWDAD PLKRPTFKQI VQLIEKQISE STNHIYSNLA NCSPNRQKPV VDHSVRINSV
GSTASSSQPL LVHDDV
//

MIM 164920
*RECORD*
*FIELD* NO
164920
*FIELD* TI
*164920 V-KIT HARDY-ZUCKERMAN 4 FELINE SARCOMA VIRAL ONCOGENE HOMOLOG; KIT
;;KIT ONCOGENE;;
read moreMAST CELL GROWTH FACTOR RECEPTOR;;
STEM CELL FACTOR RECEPTOR; SCFR
*FIELD* TX

DESCRIPTION

The tyrosine kinase receptor KIT and its ligand, KITLG (184745),
function in hematopoiesis, melanogenesis, and gametogenesis (Rothschild
et al., 2003).

CLONING

Kasamatsu et al. (2008) stated that KIT is expressed as a 145-kD
glycosylated transmembrane protein with an extracellular domain, a
transmembrane region, and a tyrosine kinase domain. The extracellular
domain consists of 5 Ig-like domains. A soluble form of KIT (sKIT) is
released from membrane-bound KIT (mKIT) upon stimulation. sKIT is a
glycoprotein of about 100 kD.

GENE STRUCTURE

Vandenbark et al. (1992) demonstrated that the KIT gene spans more than
70 kb of DNA and includes 21 exons. The longest transcript is 5,230 bp
and is alternatively spliced. The overall gene structure of KIT closely
resembles that of the CSF1R gene.

MAPPING

The provirus of the Hardy-Zuckerman 4 feline sarcoma virus was
molecularly cloned. A segment from the middle of the provirus, showing
homology to mammalian genomic DNA, was termed v-Kit. Its human homolog
was assigned to chromosome 4 by Barker et al. (1985) using human-mouse
somatic cell hybrids. By in situ hybridization, Mattei et al. (1987)
mapped the KIT gene to chromosome 4q11-q12, with the largest number of
grains being in the q12 band; see d'Auriol et al. (1988). By the same
method, Yarden et al. (1987) assigned the KIT gene to chromosome
4cen-q21. Brannan et al. (1991) detected a HaeIII polymorphism in the
KIT gene that was linked to other 4q markers. Using pulsed field gel
electrophoresis, Vandenbark et al. (1992) demonstrated that the KIT gene
and the PDGFRA gene (173490), which maps to chromosome 4q12, reside on
the same 700 kb BssHI fragment.

Yarden et al. (1987) demonstrated that the Kit gene is on chromosome 5
in the mouse.

GENE FUNCTION

Packer et al. (1995) found that depletion of Kit in mouse testis via
neutralizing antibody resulted in greatly increased apoptosis in
differentiating type A spermatogonia, as well as in spermatocytes around
the time of meiotic division.

Alternative splicing of mouse Kit ligand (Kl) produces 2 variants, Kl1
and Kl2, both of which encode membrane-bound proteins that can be
processed to generate soluble proteins. Using Western blot and
immunohistochemical analyses, Vincent et al. (1998) found that
membrane-bound Kl2 was expressed on Sertoli cells from the peripheral to
the adluminal compartment of the tubule at stages VII to VIII, when
spermatocytes enter meiosis. Kit was expressed on the surface of germ
cells up to the pachytene stage. Blocking interaction of Kl2 with Kit
via blocking antibody or treatment with soluble Kl protein inhibited the
appearance of haploid cells and completion of meiosis.

Using a knockin strategy, Kissel et al. (2000) mutated the binding site
for the p85 subunit (PIK3R1; 171833) of phosphoinositide 3-kinase (PI3K)
in mouse Kit. Mice homozygous for the Kit mutation, tyr719 to phe
(Y719F), had no pigment deficiency or impairment of steady-state
hematopoiesis, but gametogenesis was affected, and tissue mast cell
numbers were differentially affected. Homozygous mutant males were
sterile due to a block at the premeiotic stages in spermatogenesis, and
adult males developed Leydig cell hyperplasia. In mutant females,
follicle development was impaired at the cuboidal stages, resulting in
reduced fertility. Adult mutant females also developed ovarian cysts and
ovarian tubular hyperplasia. Kissel et al. (2000) concluded that
KIT-mediated PI3K signaling is critical in gametogenesis.

Signaling from the KIT receptor tyrosine kinase is essential for
primordial germ cell growth both in vivo and in vitro. Many downstream
effectors of the KIT signaling pathway have been identified in other
cell types, but how these molecules control primordial germ cell
survival and proliferation are unknown. Determination of the KIT
effectors acting in primordial germ cells has been hampered by the lack
of effective methods to manipulate easily gene expression in these
cells. De Miguel et al. (2002) overcame this problem by testing the
efficacy of retroviral-mediated gene transfer for manipulating gene
expression in mammalian germ cells. They found that primordial germ
cells can successfully be infected with a variety of types of
retroviruses. They used this method to demonstrate an important role of
the AKT1 (164730) in regulating primordial germ cell growth.

Rothschild et al. (2003) found that steroidogenesis in mouse Leydig
cells was dependent on Kitl signaling and involved PI3K. Leydig cells of
mice homozygous for the Kit Y719F mutation were unable to respond
effectively to Kitl stimulation; however, mutant animals had normal
serum testosterone levels. The findings suggested a model in which the
mutant Leydig cells initially produce lower levels of testosterone,
reducing testosterone negative feedback on the hypothalamic-pituitary
axis, which leads to elevated luteinizing hormone (LH; see 152780)
secretion and restoration of normal serum testosterone levels.
Rothschild et al. (2003) concluded that KITL, acting via PI3K, is a
paracrine regulator of Leydig cell steroidogenesis.

Kondo et al. (2007) showed that both ligand-activated wildtype KIT and
KIT carrying the asp816-to-val (D816V; 164920.0009) mutation activated
the stress-related survival factor HSP32 (HMOX1; 141250). Activated KIT
and KIT with the D816V mutation induced HSP32 promoter activity and
expression of HSP32 mRNA and protein. Moreover, pharmacologic inhibitors
of HSP32 inhibited proliferation and induced apoptosis in neoplastic
mast cells. Kondo et al. (2007) concluded that HSP32 supports neoplastic
mast cell survival.

Kasamatsu et al. (2008) stated that the first 3 Ig-like domains of mKIT
are involved in binding SCF (KITLG), and that the fourth Ig-like domain
of KIT is involved in receptor dimerization. Binding and dimerization of
KIT subsequently cause autophosphorylation at tyrosine residues,
followed by the activation of downstream signaling cascades. Kasamatsu
et al. (2008) found that recombinant sKIT inhibited binding of
radiolabeled SCF to mKIT in a dose-dependent manner, and that sKIT
inhibited SCF-induced phosphorylation of mKIT. TACE (ADAM17; 603639) and
some matrix metalloproteases (see MMP1; 120353) activated sKIT release
from human melanocytes and inhibited SCF-induced melanogenesis.
Expression of mKIT was slightly increased, and expression of sKIT was
decreased, after exposure of human melanocytes to ultraviolet B (UVB)
radiation, suggesting a role of mKIT signaling during UBV-induced
melanogenesis. Kasamatsu et al. (2008) concluded that SCF/mKIT signaling
is involved in human skin pigmentation and that this signaling pathway
is regulated by sKIT.

In addition to its role in hematopoietic maintenance, growth, and
differentiation, KIT regulates cell shape, motility, and adhesion via
cytoskeletal changes. Mani et al. (2009) found that Kit ligand-induced
stimulation resulted in tyrosine phosphorylation of Wasp (WASF1;
605035), Wip (WIPF1; 602357), and Arp2/3 (ACTR2; 604221). Kit
ligand-induced filopodia were significantly reduced in size and number,
and Kit ligand-induced calcium influx was impaired in Wasp -/- bone
marrow-derived mast cells (BMMCs). Kit ligand induced outgrowth of
Wasp-positive cells from a mixture of Wasp -/-, Wasp +/-, and wildtype
cells, suggesting a selective advantage for Wasp-expressing cells.
Comparison of the genetic profile of Wasp -/- and wildtype BMMCs
revealed that, of the approximately 1,500 genes that were up- or
downregulated in response to Kit stimulation, about one-third were Wasp
dependent. Mani et al. (2009) concluded that WASP is required for
KIT-mediated signaling, cytoskeletal changes, and gene expression.

Chi et al. (2010) demonstrated that ETV1 (600541) is highly expressed in
the subtypes of interstitial cells of Cajal (ICCs) sensitive to
oncogenic KIT-mediated transformation, and is required for their
development. In addition, ETV1 is universally highly expressed in
gastrointestinal stromal tumors (GISTs; see 606764) and is required for
growth of imatinib-sensitive and -resistant GIST cell lines.
Transcriptome profiling and global analyses of ETV1-binding sites
suggested that ETV1 is a master regulator of an ICC-GIST-specific
transcription network mainly through enhancer binding. The ETV1
transcriptional program is further regulated by activated KIT, which
prolongs ETV1 protein stability and cooperates with ETV1 to promote
tumorigenesis. Chi et al. (2010) proposed that GIST arises from ICCs
with high levels of endogenous ETV1 expression that, when coupled with
an activating KIT mutation, drives an oncogenic ETS transcriptional
program. This model differs from other ETS-dependent tumors such as
prostate cancer, melanoma, and Ewing sarcoma where genomic translocation
or amplification drives aberrant ETS expression. Chi et al. (2010) also
stated that this model of GIST pathogenesis represents a novel mechanism
of oncogenic transcription factor activation.

MOLECULAR GENETICS

Gastrointestinal stromal tumors (GISTs; 606764) are the most common
mesenchymal neoplasms in the human digestive tract. Hirota et al. (1998)
investigated the mutational status of KIT in 58 mesenchymal tumors that
developed in the gastrointestinal wall (4 in the esophagus, 36 in the
stomach, 14 in the small intestine, and 4 in the large intestine). KIT
expression was examined by immunohistochemistry. Eight authentic glial
leiomyomas and an authentic schwannoma did not express KIT. The
remaining 49 mesenchymal tumors were diagnosed as GISTs, and 94% (46 of
49) of these expressed KIT. Examination of these tumors for expression
of CD34 (142230), which is a reliable marker for GISTs, revealed that
82% (40 of 49) were CD34-positive, and 78% (38 of 49) were positive for
both KIT and CD34. Three of 5 KIT-negative GISTs were also
CD34-negative. Hirota et al. (1998) compared the immunohistochemical
characteristic of GISTs with those of interstitial cells of Cajal
(ICCs), which regulate autonomous contraction of the GI tract. They
found that ICCs are double-positive for KIT and CD34. In 5 GISTs, they
found mutations in the region between the transmembrane and tyrosine
kinase domains (e.g., 164920.0011). All of the corresponding mutant KIT
proteins were constitutively activated without the KIT ligand, stem cell
factor (SCF; 184745). Stable transfection of the mutant KIT cDNAs
induced malignant transformation of murine lymphoid cells, suggesting
that the mutations contribute to tumor development. Hirota et al. (1998)
suggested that GISTs may originate from the interstitial cells of Cajal
(ICCs) because the development of ICCs is dependent on the SCF-KIT
interaction and because, like GISTs, these cells express both KIT and
CD34. It is noteworthy that the 5 mutations identified in GISTs lay
between codons 550 and codon 559.

Most GISTs are solitary and the gain-of-function mutations found by
Hirota et al. (1998) were somatic. Nishida et al. (1998) described a
family with multiple GISTs. Affected members all had a KIT mutation
(164920.0017) occurring between the transmembrane and tyrosine kinase
domains, which is also the region where mutations had been demonstrated
in solitary GISTs. The KIT mutation in this family was detected not only
in tumors but also in leukocytes, indicating that GISTs constitute a
familial cancer syndrome. Seven individuals in 5 sibships of 4
generations of the family were affected by either benign and/or
malignant GISTs. Two members of the family reported by Nishida et al.
(1998) were reported to have hyperpigmentation of the perineum.

Lasota et al. (1999) found that mutations in exon 11 of KIT occur
preferentially in malignant versus benign GISTs, and do not occur in
leiomyomas or leiomyosarcomas. Furthermore, the conservation of the KIT
mutation pattern, observed in consecutive lesions from the same
patients, suggested that these mutations may be useful tumor markers in
monitoring recurrence or minimal residual disease.

Beghini et al. (2001) described an Italian family in which the mother
had hyperpigmented spots and developed multiple GISTs with diffuse
hyperplasia of the mysenteric plexus, and her son had urticaria
pigmentosa. Both were found to have a val559-to-ala mutation
(164920.0023) in the KIT gene. The authors commented that 2 previous
families with GIST and germline mutations of the KIT gene had been
reported, one by Nishida et al. (1998) and the other by Isozaki et al.
(2000). The mother and son in the latter family showed no abnormal
pigmentation.

KIT has tyrosine kinase activity. Mutations in KIT result in
ligand-independent tyrosine kinase activity, autophosphorylation of KIT,
uncontrolled cell proliferation, and stimulation of downstream signaling
pathways. Joensuu et al. (2001) demonstrated that STI571, an inhibitor
of tyrosine kinase activity in BCR/ABL-positive leukemia (see 151410),
was effective in treating GISTs. STI571, known as imatinib and by the
trade name Gleevec, was approved by the Food and Drug Administration in
February, 2002, for the treatment of GISTs (Savage and Antman, 2002).

Mastocytosis usually occurs as a sporadic disease that is often
transient and limited in children, but persistent or progressive in
adults. Longley et al. (1999) examined KIT cDNA in skin lesions of 22
patients with sporadic mastocytosis and 3 patients with familial
mastocytosis. All patients with adult sporadic mastocytosis had somatic
KIT mutations in codon 816 causing substitution of valine for aspartate
and spontaneous activation of mast cell growth factor receptor. A subset
of 4 childhood-onset cases with clinically unusual disease also had
codon 816 activating mutations substituting valine, tyrosine, or
phenylalanine for aspartate. Typical pediatric patients, however, lacked
codon 816 mutations, but limited sequencing showed that 3 of 6 had a
novel dominant inactivating mutation substituting lysine for glutamic
acid at position 839, the site of a potential salt bridge that is highly
conserved in receptor tyrosine kinases. No KIT mutations were found in
the entire coding region of 3 patients with familial mastocytosis. Thus,
Longley et al. (1999) concluded that KIT somatic mutations substituting
valine in position 816 of KIT are characteristic of sporadic adult
mastocytosis and may cause this disease. Similar mutations causing
activation of the mast cell growth factor receptor were found in
children apparently at risk for extensive or persistent disease. In
contrast, typical pediatric mastocytosis patients lacked these mutations
and may express inactivating KIT mutations. Familial mastocytosis,
however, may occur in the absence of KIT coding mutations.

Fritsche-Polanz et al. (2001) screened KIT cDNA in bone marrow
mononuclear cells of 28 patients with myelodysplastic syndromes and 12
patients with systemic mastocytosis. All 11 patients with systemic
indolent mastocytosis tested positive for the KIT 2468A-T mutation
(asp816 to val, or D816V; see 164920.0009). In contrast, no mutation was
identified in the 1 case of aggressive mastocytosis. Among patients with
myelodysplastic syndromes, no patient showed a somatic mutation in KIT.

CYTOGENETICS

Spritz et al. (1992) found deletion of both the KIT gene and the PDGFRA
gene in a patient with piebaldism, mental retardation, and multiple
congenital anomalies associated with a 46,XY,del(4)(q12q21.1) karyotype.
The patient was hemizygous for the 2 deleted genes.

ANIMAL MODEL

Mutations at the W locus in the mouse produce changes that include white
coat color, sterility, and anemia that are attributable to failure of
stem cell populations to migrate and/or proliferate effectively during
development. The Kit protooncogene, which encodes a putative
transmembrane tyrosine kinase receptor, maps in the same region as the W
locus. Geissler et al. (1988) showed that the mouse Kit gene was
disrupted in 2 spontaneous mutant W alleles. A strong structural
homology of KIT to the CSF1 receptor (164770) and the platelet-derived
growth factor receptor (173490) suggests a model for the action of the
KIT gene product during differentiation. The phenotypes of W mutants
suggest that 3 cell populations in which KIT function is critical are
the pluripotent hematopoietic stem cell, the migrating melanoblast
during early embryonic development, and the primordial germ cell during
this same period of development. Identification of the ligand for KIT
will help in the understanding of its function. A genetic clue to its
nature may be found through characterization of the Sl ('steel') locus
of the mouse. The phenotypes of mutants at this locus closely resemble
mutants at the W locus; however, unlike W, the defect in Sl is not
intrinsic to the progenitor stem cells of the affected tissues, but
rather lies in the environment in which melanoblast, germ cell, and
hematopoietic progenitors differentiate and proliferate. Chabot et al.
(1988) also related Kit to a W mutation in the mouse. These findings
will prompt search for comparable changes in disorders such as Fanconi
anemia (227650). In the dominant W(42) spotting phenotype in the mouse,
Tan et al. (1990) demonstrated an asp790-to-asparagine mutation in the
KIT protein product. Asp790 is a conserved residue in all protein
kinases. Nocka et al. (1990) identified mutations in other alleles at
the W locus: W(37), E-to-K at position 582; W(v), T-to-M at position
660; and W(41), V-to-M at position 831. The W mutation is the result of
a 78-amino acid deletion that includes the transmembrane of the KIT
protein. Nocka et al. (1990) detected a 125-kD KIT protein in homozygous
W/W mast cells that lacked kinase activity and did not express KIT on
the cell surface. Thus, in mice, the c-Kit receptor tyrosine kinase is
the gene product of the W locus, whereas Sl encodes the ligand for this
growth factor receptor. Microphthalmia (mi/mi) in mice also shows
deficiency in melanocytes and mast cells. In addition, whereas W and Sl
mutants can be anemic and sterile, 'mi' mice are osteopetrotic due to a
monocyte/macrophage defect. Dubreuil et al. (1991) found that the fms
gene (164770) complements the mitogenic defect in mast cells of mutant W
mice but not of mi/mi mice.

The KIT-encoded transmembrane tyrosine kinase receptor for stem cell
factor (SCFR) is required for normal hematopoiesis, melanogenesis, and
gametogenesis. The role of individual KIT/SCFR-induced signaling
pathways in the control of developmental processes in the intact animal
were completely unknown. To examine the function of SCF-induced
phosphatidylinositol (PI) 3-prime-kinase activation in vivo,
Blume-Jensen et al. (2000) employed the Cre-loxP system to mutate the
tyr719 codon, the PI 3-prime-kinase binding site in Kit/Scfr, to phe in
the genome of mice by homologous recombination. Homozygous (Y719F/Y719F)
mutant mice were viable. The mutation completely disrupted PI
3-prime-kinase binding to Kit/Scfr and reduced Scf-induced PI
3-prime-kinase-dependent activation of Akt (164730) by 90%. The mutation
induced a gender- and tissue-specific defect. Although there were no
hematopoietic or pigment defects in homozygous mutant mice, males were
sterile due to a block in spermatogenesis, with initially decreased
proliferation and subsequent extensive apoptosis occurring at the
spermatogonial stem cell level. In contrast, female homozygotes were
fully fertile. This was said to be the first demonstration of the role
of an individual signaling pathway downstream of Kit/Scfr in the intact
animal.

The pacemaker activity in the mammalian gut is responsible for
generating anally propagating phasic contractions. Although the cellular
basis for this intrinsic activity is unknown, the smooth muscle cells of
the external muscle layers and the innervated cellular network of
interstitial cells of Cajal (ICC), which is closely associated with the
external muscle layers, have both been proposed to stimulate pacemaker
activity. The interstitial cells of Cajal were identified in the 19th
century but their developmental origin and function remained unclear
until the studies of Huizinga et al. (1995). Injection of antibodies
directed against the extracellular domain of Kit into newborn mice leads
to changes in the in vitro contraction patterns in the small intestine
and absence of Kit mRNA in the myenteric plexus area. Huizinga et al.
(1995) found that mice with W mutations at the Kit locus lacked the
network of ICC in the myenteric plexus region. Using a polyclonal
antibody directed against the intracellular domain of the Kit receptor
tyrosine kinase, they demonstrated that wildtype and heterozygous mice
showed high levels of Kit expression between the longitudinal and
circular muscle layers at the level of the Auerbach plexus. By contrast,
no Kit immunoreactivity was found in or between the muscle layers of
homozygous W/W mice. Huizinga et al. (1995) suggested that functional
gut abnormalities and megacolon observed in patients with piebaldism
(Bolognia and Pawelek, 1988) reflects an identical function of the KIT
signaling pathway in the development of the interstitial cells of Cajal
in humans; see 172800 for a discussion of megacolon in association with
piebald trait. Mutations in RET (164761), another member of the receptor
tyrosine kinase family that is expressed in neural crest-derived
ganglion cells, are also associated with megacolon.

As outlined earlier, networks of interstitial cells of Cajal embedded in
the musculature of the gastrointestinal tract are involved in the
generation of electrical pacemaker activity for gastrointestinal
motility. This pacemaker activity manifests itself as rhythmic slow
waves in membrane potential, and controls the frequency and propagation
characteristics of gut contractile activity. Mice that lack a functional
Kit receptor failed to develop the network of interstitial cells of
Cajal. Thomsen et al. (1998) provided direct evidence that a single
Cajal cell generates spontaneous contractions and a rhythmic inward
current that is insensitive to L-type calcium channel blockers.

Comparative mapping data suggested that the 'dominant white' coat color
in pigs may be due to a mutation in KIT. Johansson Moller et al. (1996)
reported that dominant white pigs lack melanocytes in the skin, as would
be anticipated for a KIT mutation. They found, furthermore, a complete
association between the dominant white mutation and a duplication of the
KIT gene, or part of it, in samples of unrelated pigs representing 6
different breeds. Duplication was revealed by SSCP analysis and
subsequent sequence analysis showing that white pigs transmitted 2
nonallelic KIT sequences. The presence of a gene duplication in white
pigs was confirmed with quantitative Southern blot, quantitative PCR,
and fluorescence in situ hybridization (FISH) analyses. FISH analysis
showed that KIT and the very closely linked gene encoding
platelet-derived growth factor receptor are located on pig 8p12. The
results of Johansson Moller et al. (1996) demonstrated an extremely low
rate of recombination in the centromeric region of this chromosome since
the closely linked (0.5 cM) serum albumin (103600) locus had previously
been mapped by FISH to 8q12. The authors noted that pig chromosome 8
shares extensive conserved synteny with human chromosome 4, but the gene
order is rearranged.

Marklund et al. (1998) reported that the dominant white phenotype in
domestic pigs is caused by 2 mutations in the KIT gene, 1 gene
duplication associated with a partially dominant phenotype and a splice
mutation in 1 of the copies leading to the fully dominant allele. The
splice mutation is a G-to-A substitution in the first nucleotide of
intron 17, leading to a skipping of exon 17. The duplication is most
likely a regulatory mutation affecting KIT expression, whereas the
splice mutation is expected to cause a receptor with impaired or absent
tyrosine kinase activity. Immunocytochemistry showed that this variant
form is expressed in 17- to 19-day-old pig embryos. Hundreds of millions
of white pigs around the world are assumed to be heterozygous or
homozygous for the 2 mutations.

Giuffra et al. (2002) studied the basis of the dominant white locus
(I/KIT), one of the major coat color loci in the pig. Previous studies
had shown that the 'dominant white' and 'patch' alleles are both
associated with a duplication including the entire KIT coding sequence.
Giuffra et al. (2002) constructed a BAC contig spanning the 3 closely
linked tyrosine kinase receptor genes PDGFRA, KIT, and KDR (191306)
located on chromosome 4q12. The size of the duplication was estimated at
450 kb and included KIT, but not PDGFRA or KDR. Sequence analysis
revealed that the duplication arose by unequal homologous recombination
between 2 LINE elements flanking KIT. Comparative sequence analysis
indicated that the distinct phenotypic effect of the duplication occurs
because the duplicated copy (which is shared by several alleles across
breeds, implying that they are descendants of a single duplication
event) lacks some regulatory elements located more than 150 kb upstream
of KIT exon 1 and necessary for normal KIT expression.

Reinsch et al. (1999) presented evidence suggesting that KIT is a
candidate gene for the degree of spotting in cattle. They did a
quantitative trait loci (QTL) scan over all chromosomes covered by 229
microsatellite marker loci in 665 animals of German Simmental and
Holstein bovine families. On bovine chromosome 6, a QTL for the
proportion of white coat with large effects was found, and a less
important one on bovine chromosome 3 was also identified. Chromosome 6
in cattle was known to harbor the KIT locus. Several groups had mapped
QTL for milk production to chromosome 6 in Holsteins and other breeds.
Some had identified dairy cattle with a higher white percentage as
better producers. Reinsch et al. (1999) raised the possibility that this
result could be caused by linkage disequilibrium between a white
percentage QTL and a QTL for milk production.

By generating mice with mutations at both the W locus and the Nf1 gene
(613113), Ingram et al. (2000) found that mice homozygous for W41 and
heterozygous for Nf1 had 60 to 70% restoration of coat color. However,
Nf1 haploinsufficiency increased peritoneal and cutaneous mast cell
numbers in wildtype and W41 mice, and it increased wildtype and W41/W41
bone marrow mast cells in in vitro cultures containing Steel factor, a
mast cell mitogen (184745).

To create a mouse model for the study of constitutive activation of Kit
in oncogenesis, Sommer et al. (2003) used a knockin strategy to
introduce into the mouse genome a Kit exon 11-activating mutation,
val558del, which corresponds to a val559del mutation (164920.0017) found
in human familial GISTs. Heterozygous male and female mice were fertile,
but fertility was impaired with increasing age. Heterozygous mice
developed symptoms of disease and eventually died from pathology in the
GI tract. Patchy hyperplasia of Kit-positive cells was evident within
the myenteric plexus of the entire GI tract. Neoplastic lesions
indistinguishable from human GISTs were observed in the cecum of the
mutant mice with high penetrance. In addition, mast cell numbers in the
dorsal skin were increased. Sommer et al. (2003) concluded that mice
heterozygous for a val558 deletion in the Kit gene reproduce human
familial GISTs and may be used as a model for studying the role and
mechanisms of Kit in neoplasia. Importantly, these results demonstrated
that constitutive Kit signaling is critical and sufficient for induction
of GIST and hyperplasia of interstitial cells of Cajal.

Rubin et al. (2005) generated a mouse model of GIST using an activating
Kit mutation (K641E) associated with human familial GIST (K642E
(164920.0024) in humans; see Isozaki et al., 2000). Homozygous and
heterozygous Kit K641E mice developed gastrointestinal pathology with
complete penetrance, and all homozygotes died by age 30 weeks due to
gastrointestinal obstruction by hyperplastic interstitial cells of Cajal
(ICC) or GISTs. Heterozygous mice had less extensive ICC hyperplasia and
smaller GISTs, suggesting a dose-response relationship between
oncogenically activated Kit and ICC proliferation. Homozygous Kit K641E
mice also exhibited loss-of-function Kit phenotypes, including white
coat color, decreased numbers of dermal mast cells, and sterility,
indicating that despite oncogenic activity the mutant form cannot
accomplish many activities of the wildtype gene.

Paramutation is a heritable epigenetic modification induced in plants by
crosstalk between allelic loci. Rassoulzadegan et al. (2006) reported a
similar modification of the mouse Kit gene in the progeny of
heterozygotes with the null mutant Kit(tm1Alf) (a lacZ insertion). In
spite of a homozygous wildtype genotype, their offspring maintained, to
a variable extent, the white spots characteristic of Kit mutant animals.
Efficiently inherited from either male or female parents, the modified
phenotype results from a decrease in Kit mRNA levels with the
accumulation of nonpolyadenylated RNA molecules of abnormal sizes.
Sustained transcriptional activity at the postmeiotic stages, at which
time the gene is normally silent, leads to the accumulation of RNA in
spermatozoa. Microinjection into fertilized eggs either of total RNA
from Kit(tm1Alf/+) heterozygotes or of Kit-specific microRNAs induced a
heritable white tail phenotype. Rassoulzadegan et al. (2006) concluded
that their results identified an unexpected mode of epigenetic
inheritance associated with the zygotic transfer of RNA molecules.

*FIELD* AV
.0001
PIEBALDISM
KIT, GLY664ARG

Reasoning that human piebaldism (172800), like mouse dominant white
spotting (W), might be a result of mutation in the KIT gene, Spritz and
Giebel (1991) and Giebel and Spritz (1991) designed primers for PCR
amplification of the 21 coding exons. Studies of DNA from a patient with
classic autosomal dominant piebaldism showed that he was heterozygous
for a single base change, resulting in a glycine-to-arginine
substitution at codon 664, within the ATP-binding site of the tyrosine
kinase domain. This substitution was not found in 40 normal individuals.
A genetic linkage analysis of the mutation in the proband's family,
which could trace its inheritance for 15 generations, yielded a lod
score of 6.02 at theta = 0.0. This substitution was not observed in 3
other unrelated probands with piebaldism.

.0002
PIEBALDISM
KIT, DEL

Fleischman et al. (1991) examined the KIT gene by Southern blot analysis
in 7 unrelated individuals with piebaldism (172800). One subject,
although cytogenetically normal, had a heterozygous deletion of KIT
which involved also the closely linked PDGFRA gene. Fluorescence in situ
hybridization independently confirmed the deletion.

.0003
PIEBALDISM
KIT, PHE584LEU

In a family with severe piebaldism, including white forelock and
extensive nonpigmented patches on the chest, arms, and legs, Spritz et
al. (1992) demonstrated substitution of leucine for phenylalanine at
codon 584 within the tyrosine kinase domain of the KIT gene. They
suggested that this mutation was consistent with 'dominant-negative'
effect of the missense KIT polypeptides on the function of the dimeric
receptor.

.0004
PIEBALDISM
KIT, 2-BP DEL, FS647TER

In a Caucasian family with affected individuals in 3 generations, Spritz
et al. (1992) identified deletion of 2 bases from the AAA triplet of
codon 642 within exon 13 in the tyrosine kinase domain. This resulted in
a frameshift distal to codon 641, terminating only 6 residues downstream
at a novel in-frame TAA. The proband and other members of the family had
no dysmorphia or heterochromia iridis, and hearing was normal. However,
the proband reported chronic severe constipation.

.0005
PIEBALDISM
KIT, 1-BP DUP, FS578TER

In a patient previously reported by Selmanowitz et al. (1977), Spritz et
al. (1992) demonstrated a 1-bp duplication in codon 561 (GAG to GGAG)
within exon 11 in the tyrosine kinase domain. This resulted in a
frameshift distal to codon 560, terminating 18 residues downstream at a
novel in-frame TGA. The proband was a Caucasian male with mild
piebaldism, exhibiting only nonpigmented patches on both legs. Spritz et
al. (1992) commented that the phenotype appeared to be milder in
loss-of-function mutations such as this than in dominant-negative
mutations such as that represented by 164920.0003.

.0006
PIEBALDISM
KIT, GLU583LYS

In 1 of 10 subjects with piebaldism, Fleischman (1992) found a variant
single-strand conformation polymorphism pattern for the first exon
encoding the kinase domain of KIT. DNA sequencing demonstrated a
missense mutation, glu583-to-lys. This mutation is identical to one that
is found in a mouse mutation which abolishes autophosphorylation of the
protein product and causes more extensive depigmentation than do null
mutations. This was interpreted as a 'dominant-negative' effect and
indeed the mutation in the human kindred was associated with unusually
extensive depigmentation. Fleischman (1992) observed that the mouse
mutation was associated with more diffuse and apparently random pattern
of dorsal pigmentation in contrast to the nearly complete sparing of the
central back in the human kindred, an almost invariant feature of human
piebald trait.

.0007
PIEBALDISM
KIT, 1-BP DEL, FS104TER

In affected members of a large family with piebaldism, Spritz et al.
(1992) used combined SSCP/heteroduplex analysis of the 21 KIT exons to
demonstrate an aberrant pattern for exon 2. A subsequent study revealed
heterozygosity for a 1-bp deletion in codon 85 (GAA to AA) near the
beginning of the extracellular ligand-binding domain. This resulted in a
frameshift distal to codon 85, with an 18-amino acid nonsense peptide
terminating at a novel in-frame TAA at codons 103-104.

.0008
PIEBALDISM
KIT, IVS12DS, G-A, +1

In a large family with piebaldism, Spritz et al. (1992) demonstrated an
aberrant SSCP/heteroduplex band pattern for exons 12 and 18. Further
study demonstrated that the atypical exon 18 pattern resulted from a
silent DNA sequence polymorphism. The pathologic KIT mutation was a
guanine-to-adenine substitution at the first base of IVS12. This
mutation abolished the 5-prime splice site of IVS12. Spritz et al.
(1992) demonstrated that the IVS12 mutation cosegregated with the
piebald phenotype in the family, whereas the exon 18 polymorphism did
not.

.0009
MAST CELL LEUKEMIA
MASTOCYTOSIS WITH ASSOCIATED HEMATOLOGIC DISORDER, INCLUDED;;
MASTOCYTOSIS, ADULT SPORADIC, INCLUDED
KIT, ASP816VAL

In a human mast cell leukemia cell line (HMC-1), Furitsu et al. (1993)
found 2 point mutations in KIT that resulted in val560-to-gly and
asp816-to-val substitutions in the cytoplasmic domain. Amino acid
sequences in the regions of the 2 mutations are completely conserved in
all of mouse, rat, and human KIT. To determine the causal role of these
mutations in constitutive activation, murine Kit mutants encoding gly559
and/or val814, corresponding to human gly560 and/or val816, were
constructed by site-directed mutagenesis and expressed in a human
embryonic kidney cell line. In the transfected cells, both KitR (gly559,
val814) and KitR (val814) were abundantly phosphorylated on tyrosine and
activated in immune complex kinase reaction in the absence of SCF,
whereas tyrosine phosphorylation and activation of KitR (gly559) or
wildtype KitR was modest or little, respectively. Furitsu et al. (1993)
suggested that the D816V mutation plays a major role in the constitutive
activation of c-Kit product in HMC-1 cells, while the V560G mutation
plays a minor role.

Nagata et al. (1995) screened for mutations in KIT transcripts expressed
in peripheral blood mononuclear cells of patients with indolent
mastocytosis, mastocytosis with an associated hematologic disorder,
aggressive mastocytosis, and one patient with solitary mastocytoma. In 4
of 4 mastocytosis patients with an associated hematologic disorder with
predominantly myelodysplastic features, they found an A-to-T
transversion at nucleotide 2468 of KIT mRNA that caused an asp816-to-val
substitution. The presence of the mutation in genomic DNA was
established in the 1 patient studied. Identical or similar amino acid
substitutions in mast cell lines result in ligand-independent
autophosphorylation of KIT (mast/stem cell growth factor receptor). The
mutation was not identified in patients in the other disease categories
or in any of 67 controls.

Longley et al. (1996) found heterozygosity for this mutation in a
patient with urticaria pigmentosa and aggressive systemic mastocytosis
with massive splenic involvement. They were able to demonstrate
expression of KIT in mast cells of both skin and spleen. This was said
to be the first in situ demonstration of an activating KIT mutation in
neoplastic cells. That a somatic mutation was involved was indicated by
the fact that ectodermally-derived epithelial cells of the buccal mucosa
and non-mast cell leukocytes did not show the mutation. The patient
studied by Longley et al. (1996) first noted the pigmented macules of
urticaria pigmentosa on his thighs at age 40. The clinical picture
results from discrete mast cell infiltrates associated with increased
epidermal melanin. The lesions were originally asymptomatic, but over
the next 2 years the lesions progressively involved his trunk and upper
limbs. It was during this time the diagnosis of cutaneous mastocytosis
was made. He required antihistamines for pruritus, and at age 42,
splenomegaly was first noted. The following year mild anemia developed,
paratrabecular mast cell infiltrates with fibrosis and eosinophils were
identified in his bone marrow, and he required a gluten-free diet and
type I and II histamine receptor antagonists to control cramps and
diarrhea. Because of hematologic hypersplenism with the progressively
enlarging spleen and his need to travel to remote areas, he successfully
underwent elective splenectomy at age 47 with concurrent biopsies of
liver, mesenteric lymph nodes, and skin, all of which showed
infiltration by mast cells.

Longley et al. (1999) found the D816V mutation in 11 cases of adult
sporadic mastocytosis. In 3 of the patients the disorder presented in
adulthood with progressive urticaria pigmentosa with systemic
involvement. The 8 other cases presented as sporadic, slowly
progressive, or persistent adult urticaria pigmentosa without systemic
involvement. Thus, all patients with adult sporadic mastocytosis had
somatic KIT mutations in codon 816 causing spontaneous activation of
mast cell growth factor receptor. A subset of 4 childhood-onset cases
with a clinically unusual disease also had codon 816 activating
mutations substituting valine, tyrosine, or phenylalanine for aspartate.
Whereas mastocytosis in children is typically transient and limited,
these patients had extensive cutaneous disease with systemic involvement
or progressive cutaneous disease without systemic involvement. Typical
pediatric patients lacked codon 816 mutations, but limited sequencing
showed that 3 of 6 had a novel dominant inactivating mutation
substituting lysine for glutamic acid at position 839 (164920.0020).

To determine whether the asp816-to-val mutation is associated with
identifiable clinical patterns and prognosis of mastocytosis, Worobec et
al. (1998) screened 65 patients with systemic mastocytosis for the
presence of the mutation in peripheral blood mononuclear cells. They
found this mutation in 16 cases (25%): 15 adults and 1 infant, but not
in any children with mastocytosis. Patients with the mutation manifested
a more severe disease pattern and commonly had osteosclerotic bone
involvement as well as immunoglobulin dysregulation and peripheral blood
abnormalities. Pedigree analysis of 3 families provided evidence that
the mutation was somatic.

Fritsche-Polanz et al. (2001) studied 12 patients with systemic
mastocytosis. All 11 patients with systemic indolent mastocytosis tested
positive for the 2468A-T nucleotide substitution in KIT, resulting in an
asp816-to-val amino acid substitution. In contrast, no mutation was
identified in the 1 case of aggressive mastocytosis.

Taylor et al. (2001) demonstrated that the D816V mutation enhances
chemotaxis of CD117(+) cells, offering one explanation for increased
mast cells derived from CD34(+)CD117(+) mast cell precursors observed in
tissues of patients with mastocytosis.

.0010
MAST CELL DISEASE, SYSTEMIC
KIT, ASP820GLY

In a patient with aggressive mast cell disease, Pignon et al. (1997)
failed to find the asp816val mutation (164920.0009) but identified a
'new' KIT mutation, asp820gly, in the mast cells from this patient. The
44-year-old man presented with a 2-month history of asthenia, gastric
pain, and flushes. He was found to have moderate splenomegaly. Although
there were no circulating mast cells, bone marrow aspirates showed 40%
abnormal mast cells, often arranged in clusters. Despite chemotherapy
and followed by a familial HLA-matched bone marrow transplant that
appeared to achieve engraftment, the patient relapsed 4 months later and
died from massive multivisceral involvement of the mastocytosis.

.0011
GASTROINTESTINAL STROMAL TUMOR, SOMATIC
KIT, 6-BP DEL

In a somatic gastrointestinal stromal tumor (606764), Hirota et al.
(1998) found an in-frame deletion of 6 bp, removing codons 559 and 560
(val-val) from the KIT protein.

.0012
GASTROINTESTINAL STROMAL TUMOR, SOMATIC
KIT, 15-BP DEL

In a somatic gastrointestinal stromal tumor (606764), Hirota et al.
(1998) demonstrated an in-frame deletion of 15 bp, removing amino acid
residues 551 to 555 of the KIT protein.

.0013
GASTROINTESTINAL STROMAL TUMOR, SOMATIC
KIT, 15-BP DEL/LYS550ILE

In a somatic gastrointestinal stromal tumor (606764), Hirota et al.
(1998) found the same in-frame deletion of 15 bp, removing amino acid
residues 551 to 555 of the KIT gene as described in 164920.0012. They
also identified an additional point mutation at codon 550 (AAA to ATA)
that resulted in a lys550-to-ile amino acid substitution.

.0014
GASTROINTESTINAL STROMAL TUMOR, SOMATIC
KIT, VAL559ASP

In a somatic gastrointestinal stromal tumor (606764), Hirota et al.
(1998) found a T-to-A transversion that changed codon 559 of the KIT
gene from GTT (val) to GAT (asp).

.0015
GASTROINTESTINAL STROMAL TUMOR, SOMATIC
KIT, 27-BP DEL

In a somatic gastrointestinal stromal tumor (606764), Hirota et al.
(1998) identified an in-frame deletion of 27 bp from the KIT gene,
resulting in deletion of 9 amino acids, 550 to 558, from the KIT
protein.

In 2 GISTs with the 550del27 mutation, which encompasses the noncoding
region in intron 10 and the coding region in exon 11 of the KIT gene,
Chen et al. (2005) elucidated an unusual mechanism of aberrant pre-mRNA
splicing resulting in constitutive activation of the oncoprotein. The
deletion of noncoding and coding regions encompassing the 3-prime
authentic splice site creates a novel intraexonic pre-mRNA 3-prime
splice acceptor site, leading to in-frame loss of 27 nucleotides.
Three-dimensional structural analysis revealed that loss of the 9 amino
acids in this critical location unleashes the protein from
autoinhibition, causing KIT to become constitutively activated and
resulting in the GIST phenotype.

.0016
PIEBALDISM WITH SENSORINEURAL DEAFNESS
KIT, ARG796GLY

In a South African girl of Xhosa stock with severe piebaldism and
profound congenital sensorineural deafness (172800), Spritz and Beighton
(1998) identified a heterozygous A-to-G transition in the KIT gene that
converted codon 796 from AGA (arg) to GGA (gly) (R796G). Although
auditory anomalies have been observed in mice with dominant white
spotting (W) due to KIT mutations, deafness is not typical in human
piebaldism. There was a suggestion that the mother and brother of this
patient may have been similarly affected, but for logistical reasons,
Spritz and Beighton (1998) could not confirm this report.

.0017
GASTROINTESTINAL STROMAL TUMOR, FAMILIAL
KIT, VAL559DEL

In a family with multiple gastrointestinal stromal tumors (606764) in
members of 4 generations, Nishida et al. (1998) identified a deletion of
1 of 2 consecutive valine residues (at codons 559 and 560) due to a 3-bp
deletion, GTT, in the KIT gene.

In mice, Sommer et al. (2003) used deletion of the comparable amino acid
in the Kit gene, val558, to demonstrate the development of GISTs.

.0018
LEUKEMIA, ACUTE MYELOID
KIT, ASP816TYR

In a patient with acute myeloid leukemia of the M2 subtype,
characterized by the massive presence of mast cells in bone marrow and
rapid progression of the disease, Beghini et al. (1998) identified a
G-to-T transversion at nucleotide 2467 of the KIT gene, resulting in an
asp816-to-tyr (D816Y) amino acid substitution. This mutation corresponds
to the D816Y mutation identified and characterized in the murine P815
mastocytoma cell line by Tsujimura et al. (1994).

.0019
PIEBALDISM
KIT, THR847PRO

In a Japanese family in which a mother and daughter had piebaldism
(172800), Nomura et al. (1998) found that the affected individuals had
an A-to-C transition at nucleotide 8447, resulting in substitution of
threonine by proline at codon 847. The patients were heterozygous for
the mutation. The proband was a 5-year-old girl who developed leukoderma
on the forehead 1 week after birth. Examination at 5 years of age showed
a depigmented fleck in the middle of the forehead and various-sized
depigmented patches on the abdomen and anterior legs bilaterally. The
proband's 30-year-old mother exhibited similar but somewhat less
striking changes, which became evident a few weeks after birth. The
proband's maternal grandfather was also affected.

.0020
MASTOCYTOSIS, SPORADIC, CHILDHOOD-ONSET
KIT, GLU839LYS

In children with typical childhood-onset sporadic mastocytosis, which is
often transient and limited, Longley et al. (1999) found a dominant
inactivating mutation of the KIT gene, substituting lysine for glutamic
acid at position 839, the site of a potential salt bridge that is highly
conserved in receptor tyrosine kinases.

.0021
GERM CELL TUMOR, SOMATIC
KIT, ASP816HIS

The KIT gene is required in normal spermatogenesis and is expressed in
seminomas and dysgerminomas, a subset of germ cell tumors (GCTs; see
273300). Tian et al. (1999) studied primary tissue samples of 33
testicular and ovarian tumors for mutations in the juxtamembrane and
phosphotransferase domains of KIT by PCR amplification and DNA
sequencing. Of the 17 seminomas/dysgerminomas studied, 2 GCTs, a
seminoma and a mixed ovarian dysgerminoma/yolk sac tumor, showed a
G-to-C transversion at nucleotide 2467 in exon 17, causing a change from
aspartic acid to histidine at amino acid 816. The mixed ovarian GCT had
the mutation in each tumor component. The KIT alleles in nonneoplastic
tissue from these patients were wildtype, suggesting that the mutant
alleles were acquired and selected for during malignant transformation.
In cell transfection experiments, the D816H mutant protein was a
constitutively activated kinase and was constitutively phosphorylated on
tyrosine residues. This was the first description of an activating KIT
mutation in GCTs and provided evidence that the KIT signal transduction
pathway is important in the pathogenesis of neoplasms with seminoma
differentiation.

.0022
PIEBALDISM
KIT, PHE584CYS

One of 3 novel mutations described by Syrris et al. (2000) as the cause
of piebaldism (172800) was a T-to-G transversion (TTT to TGT) in exon
11, resulting in a phe584-to-cys mutation. A phe-to-leu mutation had
previously been described in the same codon; see 164920.0003.

.0023
GASTROINTESTINAL STROMAL TUMOR, FAMILIAL
KIT, VAL559ALA

Beghini et al. (2001) described an Italian family in which the mother
had hyperpigmented spots and developed multiple GISTs (606764) with
diffuse hyperplasia of the mysenteric plexus, and her son had urticaria
pigmentosa. Both were found to have a heterozygous T-to-C transition at
nucleotide 1697 of the KIT gene, resulting in a val559-to-ala (V559A)
substitution in the juxtamembrane domain of the protein.

.0024
GASTROINTESTINAL STROMAL TUMOR, FAMILIAL
KIT, LYS642GLU

In a French mother and son with multiple GISTs (606764), Isozaki et al.
(2000) identified a heterozygous A-to-G transition in the KIT gene,
resulting in a lys642-to-glu (K642E) substitution in the kinase I
domain. In vitro functional expression studies showed constitutive
activation of the mutant protein.

.0025
PIEBALDISM, PROGRESSIVE
KIT, VAL620ALA

In a mother and her 8-year-old daughter, both of whom had a phenotype of
typical piebaldism but with progressive depigmentation, including total
hair depigmentation in the mother, Richards et al. (2001) identified
heterozygosity for a 1859T-C transition in the KIT gene, resulting in a
val620-to-ala (V620S) substitution in the intracellular tyrosine kinase
domain. The mutation was not found in family members with a localized
patch of white hair but without depigmentation or in 52 control
individuals. Richards et al. (2001) speculated that this mutation may
cause melanocyte instability, leading to progressive loss of
pigmentation as well as the progressive appearance of hyperpigmented
macules.

*FIELD* SA
Spritz et al. (1992); Spritz et al. (1992)
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J. Path. 154: 1643-1647, 1999.

59. Tsujimura, T.; Furitsu, T.; Morimoto, M.; Isozaki, K.; Nomura,
S.; Matsuzawa, Y.; Kitamura, Y.; Kanakura, Y.: Ligand-independent
activation of c-kit receptor tyrosine kinase in a murine mastocytoma
cell line P-815 generated by a point mutation. Blood 83: 2619-2626,
1994.

60. Vandenbark, G. R.; deCastro, C. M.; Taylor, H.; Dew-Knight, S.;
Kaufman, R. E.: Cloning and structural analysis of the human c-kit
gene. Oncogene 7: 1259-1266, 1992.

61. Vincent, S.; Segretain, D.; Nishikawa, S.; Nishikawa, S.; Sage,
J.; Cuzin, F.; Rassoulzadegan, M.: Stage-specific expression of the
Kit receptor and its ligand (KL) during male gametogenesis in the
mouse: a Kit-KL interaction critical for meiosis. Development 125:
4585-4593, 1998.

62. Worobec, A. S.; Semere, T.; Nagata, H.; Metcalfe, D. D.: Clinical
correlates of the presence of the asp816val c-kit mutation in the
peripheral blood mononuclear cells of patients with mastocytosis. Cancer 83:
2120-2129, 1998.

63. Yarden, Y.; Kuang, W.-J.; Yang-Feng, T.; Coussens, L.; Munemitsu,
S.; Dull, T. J.; Chen, E.; Schlessinger, J.; Francke, U.; Ullrich,
A.: Human proto-oncogene c-kit: a new cell surface receptor tyrosine
kinase for an unidentified ligand. EMBO J. 6: 3341-3351, 1987.

*FIELD* CN
Carol A. Bocchini - updated: 7/16/2012
Patricia A. Hartz - updated: 5/12/2011
Ada Hamosh - updated: 11/11/2010
Patricia A. Hartz - updated: 8/3/2009
Patricia A. Hartz - updated: 12/11/2008
Patricia A. Hartz - updated: 5/27/2008
Cassandra L. Kniffin - updated: 4/4/2008
Ada Hamosh - updated: 7/24/2006
Marla J. F. O'Neill - updated: 4/17/2006
Marla J. F. O'Neill - updated: 10/11/2005
Victor A. McKusick - updated: 6/25/2003
Victor A. McKusick - updated: 3/5/2003
Victor A. McKusick - updated: 9/26/2002
Victor A. McKusick - updated: 3/14/2002
Paul J. Converse - updated: 12/21/2001
Paul J. Converse - updated: 12/11/2001
Victor A. McKusick - updated: 11/6/2001
Victor A. McKusick - updated: 9/12/2001
Victor A. McKusick - updated: 11/10/2000
Victor A. McKusick - updated: 2/9/2000
Victor A. McKusick - updated: 1/28/2000
Victor A. McKusick - updated: 9/20/1999
Victor A. McKusick - updated: 4/28/1999
Victor A. McKusick - updated: 3/24/1999
Victor A. McKusick - updated: 3/18/1999
Victor A. McKusick - updated: 3/2/1999
Victor A. McKusick - updated: 11/4/1998
Victor A. McKusick - updated: 10/13/1998
Victor A. McKusick - updated: 9/4/1998
Victor A. McKusick - updated: 7/27/1998
Victor A. McKusick - updated: 2/24/1998
Victor A. McKusick - updated: 1/26/1998
Victor A. McKusick - updated: 5/16/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
terry: 11/28/2012
carol: 7/16/2012
carol: 11/29/2011
mgross: 6/13/2011
terry: 5/12/2011
alopez: 11/12/2010
terry: 11/11/2010
terry: 11/3/2010
carol: 11/23/2009
mgross: 8/3/2009
terry: 8/3/2009
mgross: 12/15/2008
terry: 12/11/2008
carol: 12/2/2008
mgross: 6/13/2008
terry: 5/27/2008
carol: 4/4/2008
ckniffin: 4/2/2008
alopez: 7/27/2006
terry: 7/24/2006
carol: 4/17/2006
carol: 4/14/2006
terry: 4/11/2006
wwang: 10/14/2005
terry: 10/11/2005
alopez: 3/7/2005
tkritzer: 6/27/2003
tkritzer: 6/25/2003
carol: 3/18/2003
tkritzer: 3/11/2003
terry: 3/5/2003
cwells: 9/30/2002
carol: 9/26/2002
alopez: 3/15/2002
terry: 3/14/2002
mgross: 12/21/2001
terry: 12/11/2001
alopez: 11/12/2001
terry: 11/6/2001
carol: 11/6/2001
carol: 10/10/2001
mcapotos: 9/17/2001
mcapotos: 9/12/2001
mcapotos: 5/2/2001
mcapotos: 4/26/2001
terry: 4/25/2001
carol: 11/17/2000
mcapotos: 11/16/2000
mcapotos: 11/15/2000
terry: 11/10/2000
mcapotos: 8/9/2000
carol: 4/17/2000
mgross: 2/24/2000
terry: 2/9/2000
alopez: 1/31/2000
terry: 1/28/2000
carol: 9/30/1999
jlewis: 9/29/1999
terry: 9/20/1999
alopez: 5/10/1999
terry: 4/28/1999
mgross: 4/2/1999
terry: 3/24/1999
carol: 3/18/1999
terry: 3/18/1999
carol: 3/7/1999
terry: 3/2/1999
carol: 1/4/1999
alopez: 12/22/1998
dkim: 12/18/1998
dkim: 11/13/1998
carol: 11/12/1998
terry: 11/4/1998
carol: 10/18/1998
terry: 10/13/1998
dkim: 9/11/1998
terry: 9/4/1998
terry: 8/21/1998
alopez: 8/3/1998
alopez: 7/31/1998
alopez: 7/30/1998
terry: 7/27/1998
terry: 6/18/1998
terry: 6/3/1998
carol: 5/7/1998
dholmes: 2/24/1998
dholmes: 2/18/1998
mark: 1/28/1998
terry: 1/26/1998
carol: 6/23/1997
alopez: 5/19/1997
terry: 5/16/1997
jamie: 1/16/1997
terry: 1/9/1997
mark: 2/29/1996
terry: 2/27/1996
mark: 12/7/1995
terry: 3/8/1995
carol: 3/7/1995
mimadm: 12/2/1994
carol: 10/29/1993
carol: 4/7/1993
carol: 2/4/1993

MIM 172800
*RECORD*
*FIELD* NO
172800
*FIELD* TI
#172800 PIEBALD TRAIT; PBT
;;PIEBALDISM
*FIELD* TX
A number sign (#) is used with this entry because piebaldism can be
read morecaused by heterozygous mutation in the KIT protooncogene (164920) on
chromosome 4q12.

There is also evidence that piebaldism can be caused by heterozygous
mutation in the gene encoding the zinc finger transcription factor SNAI2
(602150), located on chromosome 8q11.

DESCRIPTION

Piebaldism is a rare autosomal dominant trait characterized by the
congenital absence of melanocytes in affected areas of the skin and
hair. A white forelock of hair, often triangular in shape, may be the
only manifestation, or both the hair and the underlying forehead may be
involved. The eyebrows and eyelashes may be affected. Irregularly shaped
white patches may be observed on the face, trunk, and extremities,
usually in a symmetrical distribution. Typically, islands of
hyperpigmentation are present within and at the border of depigmented
areas (summary by Thomas et al., 2004).

CLINICAL FEATURES

Sundfor (1939) described a family in which many persons had a white
forelock, often with unpigmented patches on the forehead, limbs, and
other areas of the body.

Loewenthal (1959) assigned the name albinoidism to a dominantly
inherited condition characterized by a white 'blaze' in the scalp hair,
usually the forelock, and/or patches of leukoderma. Epitheliomas
occurred with increased frequency. The designation albinoidism is better
reserved for the recessive condition simulating true albinism.

Comings and Odland (1966) found the trait in 6 generations. A genetic
defect in melanoblast differentiation was postulated.

The statement that deafness does not occur in persons with the piebald
trait as a pleiotropic effect of the gene may not be true. Reed et al.
(1967) noted profound deafness with piebaldism in 2 patients. Some of
the patients of Comings and Odland (1966) were deaf.

Winship et al. (1991) described 7 affected persons in 3 generations. Two
other affected individuals were deceased. The disorder seemed distinct
from Waardenburg syndrome (193500). White forelock and patches of
leukoderma occur also in Waardenburg syndrome and in Fanconi anemia
(227650).

From India, Mahakrishnan and Srinivasan (1980) reported Hirschsprung
disease in 2 brothers who had piebaldness (white forelock, patches of
depigmentation over the upper third of the forearms and the lower part
of the arms, diffuse hypopigmentation of the abdomen and chest, and
heterochromia iridis); their father had a white forelock also.

Hulten et al. (1987) reported a presumed homozygote; the severely
affected child was born to heterozygous parents. He had complete absence
of hair and pigmentation and had blue irides.

Richards et al. (2001) described a mother and her 8-year-old daughter
with a phenotype of typical piebaldism but with progressive
depigmentation.

INHERITANCE

Piebaldism is an autosomal dominant disorder (Thomas et al., 2004).

Keeler (1934) described a Louisiana black family in which piebaldism
could be traced back to a woman born in 1853.

Selmanowitz et al. (1977) published a pedigree with at least 10 affected
persons in 4 generations.

Farag et al. (1992) described a Bedouin kindred with 19 affected persons
in 5 generations.

CYTOGENETICS

Funderburk and Crandall (1974) reported a 3-year-old boy with moderate
mental retardation, short stature, and integumentary pigment changes
typical of the autosomal dominant piebald syndrome. The patient's
chromosomes showed a reciprocal translocation and an intercalary
deletion of one chromosome 4. Lacassie et al. (1977) found a similar
case that illustrated the association of piebald trait with interstitial
deletion of the long arm of chromosome 4 (4q13). The deleted segment was
adjacent to centromeric heterochromatin, raising the question of
position effect.

Hoo et al. (1986) described a case of de novo deletion in 4q and pointed
out that several of the patients with comparable deletions have had
abnormal skin pigmentation compatible with the piebald trait. Further
analysis suggested that the piebald trait locus may be situated in band
4q12.

Yamamoto et al. (1989) reported piebald trait in a child with de novo
interstitial deletion of 4q, specifically 4q12-q21.1. Other features
included mental and motor retardation despite normal somatic growth,
aplasia cutis of the scalp, flat nasal root and tip, micrognathia,
widely spaced nipples, and agenesis of the right kidney.

MAPPING

Lyon (1988) pointed out that the location of the W locus on mouse
chromosome 5 supports the location of a piebald trait gene on chromosome
4 of man since there is a large, conserved synteny group on those
chromosomes of the 2 species. Geissler et al. (1988) identified cloned
DNA markers near the W locus and determined the genetic distance from a
number of other loci.

A piebaldism locus in man was mapped to chromosome 4q by the
identification of causative mutations in the KIT gene (Giebel and
Spritz, 1991).

MOLECULAR GENETICS

Giebel and Spritz (1991) identified a heterozygous mutation in the KIT
protooncogene as the cause of piebaldism; see 164920.0001.

Spritz and Beighton (1998) described a South African girl of Xhosa stock
with severe piebaldism and profound congenital sensorineural deafness.
In this patient they identified a novel missense substitution, arg796 to
gly, at a highly conserved residue in the intracellular kinase domain of
the KIT protooncogene (164920.0016).

In 3 of 17 unrelated patients with piebaldism who had no mutations in
the KIT protooncogene, Sanchez-Martin et al. (2003) identified a
heterozygous deletion of the SNAI2 gene (602150.0002). Two of the
patients were sporadic cases and the other had 2 affected sibs and an
affected daughter; all parents were nonconsanguineous and unaffected.

In a mother and her 8-year-old daughter, both of whom had a phenotype of
typical piebaldism but with progressive depigmentation, including total
hair pigmentation in the mother, Richards et al. (2001) identified
heterozygosity for a novel mutation in the intracellular tyrosine kinase
domain of the KIT gene (V630A; 164920.0025). The authors speculated that
the mutation may cause melanocyte instability, leading to progressive
loss of pigmentation as well as the progressive appearance of
hyperpigmented macules.

GENOTYPE/PHENOTYPE CORRELATIONS

The severity of the clinical phenotype in patients with piebaldism
correlates with the site of the mutation with the KIT gene. The most
severe mutations tend to be dominant-negative missense mutations
involving the intracellular tyrosine kinase domain. Mutations leading to
an intermediate severity phenotype have largely been located at or near
the transmembrane region, regardless of whether they are missense,
nonsense, or frameshift mutations. Mutations leading to the mildest
phenotype occur in the N-terminal extracellular ligand-binding domain
with resultant haploinsufficiency (summary by Richards et al., 2001).

ANIMAL MODEL

In mice, aganglionic megacolon is associated with the piebald trait
(Bielschowsky and Schofield, 1962), inherited probably as an autosomal
recessive.

HISTORY

George Catlin (1796-1872), painter of the American Indians, painted an
affected Mandan Indian. Multiple members of the group were said to have
been affected.

*FIELD* SA
Comings and Odland (1965); Cooke (1952); Cromwell (1940); Fitch
(1937); Froggatt (1951); Jahr and McIntyre (1954)
*FIELD* RF
1. Bielschowsky, M.; Schofield, G. C.: Studies on megacolon in piebald
mice. Aust. J. Exp. Biol. Med. Sci. 40: 395-403, 1962.

2. Comings, D. E.; Odland, G. F.: Partial albinism. JAMA 195: 510-523,
1966.

3. Comings, D. E.; Odland, G. F.: Electron microscope study of partial
albinism. (Abstract) Clin. Res. 13: 265, 1965.

4. Cooke, J. V.: Familial white skin spotting (piebaldness) ('partial
albinism') with white forelock. J. Pediat. 4: 1-12, 1952.

5. Cromwell, A. M.: Inheritance of white forelock in a mulatto family. J.
Hered. 31: 94-96, 1940.

6. Farag, T. I.; El-Ramly, M. A.; Sakr, M. F.: A Bedouin kindred
with 19 piebalds in 5 generations. (Letter) Clin. Genet. 42: 326-328,
1992.

7. Fitch, L.: Inheritance of a white forelock: through five successive
generations in the Logsdon family. J. Hered. 28: 413-414, 1937.

8. Froggatt, P.: An outline with bibliography of human piebaldism
and white forelock. Irish J. Med. Sci. 398: 86-94, 1951.

9. Funderburk, S. J.; Crandall, B. F.: Dominant piebald trait in
a retarded child with a reciprocal translocation and small intercalary
deletion. Am. J. Hum. Genet. 26: 715-722, 1974.

10. Geissler, E. N.; Cheng, S. V.; Gusella, J. F.; Housman, D. E.
: Genetic analysis of the dominant white-spotting (W) region on mouse
chromosome 5: identification of cloned DNA markers near W. Proc.
Nat. Acad. Sci. 85: 9635-9639, 1988.

11. Giebel, L. B.; Spritz, R. A.: Mutation of the KIT (mast/stem
cell growth factor receptor) protooncogene in human piebaldism. Proc.
Nat. Acad. Sci. 88: 8696-8699, 1991.

12. Hoo, J. J.; Haslam, R. H. A.; van Orman, C.: Tentative assignment
of piebald trait gene to chromosome band 4q12. Hum. Genet. 73: 230-231,
1986.

13. Hulten, M. A.; Honeyman, M. M.; Mayne, A. J.; Tarlow, M. J.:
Homozygosity in piebald trait. J. Med. Genet. 24: 568-571, 1987.

14. Jahr, H. M.; McIntyre, M. S.: Piebaldness, or familial white
skin spotting (partial albinism). Am. J. Dis. Child. 88: 481-484,
1954.

15. Keeler, C. E.: The heredity of a congenital white spotting in
Negroes. JAMA 103: 179-180, 1934.

16. Lacassie, Y.; Thurmon, T. F.; Tracy, M. C.; Pelias, M. Z.: Piebald
trait in a retarded child with interstitial deletion of chromosome
4. (Letter) Am. J. Hum. Genet. 29: 641-642, 1977.

17. Loewenthal, L. J. A.: Albinoidism with epitheliomatosis. Brit.
J. Derm. 71: 37-38, 1959.

18. Lyon, M. F.: Personal Communication. Harwell, England 6/9/1988.

19. Mahakrishnan, A.; Srinivasan, M. S.: Piebaldness with Hirschsprung's
disease. (Letter) Arch. Derm. 116: 1102, 1980.

20. Reed, W. B.; Stone, V. M.; Boder, E.; Ziprkowski, L.: Pigmentary
disorders in association with congenital deafness. Arch. Derm. 95:
176-186, 1967.

21. Richards, K. A.; Fukai, K.; Oiso, N.; Paller, A. S.: A novel
KIT mutation results in piebaldism with progressive depigmentation. J.
Am. Acad. Derm. 44: 288-292, 2001.

22. Sanchez-Martin, M.; Perez-Losada, J.; Rodriguez-Garcia, A.; Gonzalez-Sanchez,
B.; Korf, B. R.; Kuster, W.; Moss, C.; Spritz, R. A.; Sanchez-Garcia,
I.: Deletion of the SLUG (SNAI2) gene results in human piebaldism. Am.
J. Med. Genet. 122A: 125-132, 2003.

23. Selmanowitz, V. J.; Rabinowitz, A. D.; Orentreich, N.; Went, E.
: Pigmentary correction of piebaldism by autografts. I. Procedures
and clinical findings. J. Derm. Surg. Oncol. 3: 615-622, 1977. Note:
Fig. 1.

24. Spritz, R. A.; Beighton, P.: Piebaldism with deafness: molecular
evidence for an expanded syndrome. Am. J. Med. Genet. 75: 101-103,
1998.

25. Sundfor, H.: A pedigree of skin-spotting in man: 42 piebalds
in a Norwegian family. J. Hered. 30: 67-77, 1939.

26. Thomas, I.; Kihiczak, G. G.; Fox, M. D.; Janniger, C. K.; Schwartz,
R. A.: Piebaldism: an update. Int. J. Derm. 43: 716-719, 2004.

27. Winship, I.; Young, K.; Martell, R.; Ramesar, R.; Curtis, D.;
Beighton, P.: Piebaldism: an autonomous autosomal dominant entity. Clin.
Genet. 39: 330-337, 1991.

28. Yamamoto, Y.; Nishimoto, H.; Ikemoto, S.: Interstitial deletion
of the proximal long arm of chromosome 4 associated with father-child
incompatibility within the Gc-system: probable reduced gene dosage
effect and partial piebald trait. Am. J. Med. Genet. 32: 520-523,
1989.

*FIELD* CS

Skin:
Piebaldism;
White forelock;
Absent pigmentation of medial forehead, eyebrows and chin;
Absent pigmentation of ventral chest, abdomen and limbs;
Hyperpigmented borders of unpigmented areas

Eyes:
Heterochromia iridis

Oncology:
Frequent epitheliomas

Ears:
Occasional deafness

GI:
Rare Hirschsprung disease

Inheritance:
Autosomal dominant (4q11-q12)

*FIELD* CN
Carol A. Bocchini - updated: 7/16/2012
Marla J. F. O'Neill - updated: 8/24/2005

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
terry: 07/25/2012
carol: 7/17/2012
carol: 7/16/2012
terry: 6/3/2009
carol: 8/24/2005
carol: 1/8/2002
carol: 11/15/2000
alopez: 9/16/1998
terry: 9/14/1998
terry: 4/18/1996
mimadm: 1/14/1995
davew: 7/14/1994
warfield: 4/21/1994
carol: 10/5/1993
carol: 2/3/1993
carol: 4/13/1992

MIM 273300
*RECORD*
*FIELD* NO
273300
*FIELD* TI
#273300 TESTICULAR GERM CELL TUMOR; TGCT
;;MALE GERM CELL TUMOR; MGCT
SEMINOMA, INCLUDED;;
read moreNONSEMINOMATOUS GERM CELL TUMORS, INCLUDED;;
TERATOMA, TESTICULAR, INCLUDED;;
EMBRYONAL CELL CARCINOMA, INCLUDED;;
ENDODERMAL SINUS TUMOR, INCLUDED;;
SPERMATOCYTIC SEMINOMA, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because testicular germ cell
tumors have been associated with somatic mutation in several genes; see
MOLECULAR GENETICS.

DESCRIPTION

Testicular germ cell tumors (TGCTs) affect 1 in 500 men and are the most
common cancer in males aged 15 to 40 in western European populations.
The incidence of TGCT rose dramatically during the 20th century. Known
risk factors for TGCT include a history of undescended testis (UDT),
testicular dysgenesis, infertility, previously diagnosed TGCT, and a
family history of the disease. Brothers of men with TGCT have an 8- to
10-fold risk of developing TGCT, whereas the relative risk to fathers
and sons is 4-fold. This familial relative risk is much higher than that
for most other types of cancer (summary by Rapley et al., 2000).

- Genetic Heterogeneity of Testicular Germ Cell Tumors

A locus for testicular germ cell tumors (TGCT1; 300228) has been
identified on chromosome Xq27.

CLINICAL FEATURES

Hutter et al. (1967) reviewed the reports of testicular tumors in
brothers and in twins and reported affected brothers.

Gustavson et al. (1975) reported bilateral testicular teratoma in 2
infant brothers with XXY Klinefelter syndrome. One of them also had
hydrocephalus due to stenosis of the aqueduct of Sylvius. Familial
occurrence of the Klinefelter syndrome is rare. The association of the
Klinefelter syndrome and testicular teratoma may be more than
coincidental because they have been observed together in other cases and
many testicular teratoma are both X-chromatin and Y-chromatin positive
suggesting that they are XXY.

Raghavan et al. (1980) reported a father who had sequential bilateral
seminomas and a son who had embryonal cell carcinoma and seminoma. The
authors reviewed 5 other reports of testicular tumors in father and son,
as well as 7 reports of concordant monozygotic twin pairs and 11 reports
of nontwin brothers. The report of Raghavan et al. (1980) illustrates
the dominant inheritance of hereditary tumors and their bilaterality
(e.g., acoustic neuroma, retinoblastoma, pheochromocytoma, etc.). The
sons (and other first-degree relatives) of men with bilateral tumors may
be at particular risk.

Shinohara et al. (1980) reported mature testicular teratoma in 2 first
cousins. Furthermore, the common grandparents were consanguineous, being
related as first cousins. The parent (i.e., the parent involved in the
consanguinity) of the teratoma-carrying boys was the mother in one case
and the father in the other. In a 10-member sibship in a
Spanish-American family, DiBella (1983) described testicular neoplasm in
3 brothers, benign ovarian neoplasms in 2 sisters, suspected benign
tumors of the uterus in 2 additional sisters, and a suspected testicular
mass in a fourth brother. Lynch et al. (1985) described the infantile
form of embryonal carcinoma of the testis in a 5-year-old boy and in a
23-year-old man who was the maternal half brother of his mother.
Copeland et al. (1986) reported testicular embryonal carcinoma in 2
brothers and a first cousin.

Von der Maase et al. (1986) found carcinoma in situ in the contralateral
testis in 27 of 500 patients (5.4%) with unilateral testicular germ cell
cancer. The estimated risk of developing invasive growth from the
contralateral testicular cancer was 40% within 3 years and 50% within 5
years. None of the 473 patients without carcinoma in situ detected by
screening biopsy developed contralateral testicular cancer after an
observation time ranging from 12 to 96 months. These observations
suggested to the authors that there is a subset of this type of
testicular cancer that is genetic and has a bilateral predisposition.
The authors suggested that all such carcinomas begin as carcinoma in
situ. Von der Maase et al. (1986) recommended that all patients with
unilateral testicular germ cell cancer should be offered biopsy of the
contralateral testis. Of the 27 patients, 16 had a cancer that was
labeled seminoma and 11 had a cancer that was considered to be
nonseminoma. It would be of great interest to know the median age of the
patients with contralateral carcinoma in situ as contrasted with the
others. If these represent a subset who had inherited 1 of the 2
mutations according to the Knudson theory, then the patients with
contralateral carcinoma in situ should have an earlier average age of
development of carcinoma.

Patel et al. (1990) reported 6 cases of familial testicular cancer: 4
father-son pairs, a pair of brothers, and a 23-year-old man who had a
maternal uncle with testicular cancer. In the U.K., according to Forman
et al. (1992), 42 families with 2 or more cases of testicular cancer
were reported to the familial testicular cancer registry. These families
included 2 pairs of identical twins, 27 sets of other brothers (25
pairs, 2 triples), 9 father-son pairs, 2 pairs of first cousins, and 2
uncle-nephew pairs. In all, 91 testicular tumors were described in 86
persons. Pure seminoma was present in 46% and other germ cell tumors in
54%. The median age at diagnosis was significantly younger than in a
comparable series of nonfamilial patients. The cumulative risk of
developing testicular cancer by the age of 50 years for a brother of a
patient was estimated to be 2.2%, which results in a relative risk of
9.8 in comparison with the general population. No significant
peculiarity of class I HLA type was found in a study of 21 affected sib
pairs.

Huddart et al.(1996) studied 3 families suggesting that there is a
familial predisposition to both male and female germ cell tumors. In 1,
the proband presented with a seminoma at the age of 51, his brother had
had a testicular teratoma at the age of 28, and their cousin had an
endodermal sinus tumor of the ovary diagnosed at 32 years. In the second
family, the index case presented with an undifferentiated malignant
teratoma at 28 years of age and his sister was diagnosed with bilateral
mature teratomatous cysts at the age of 39. In the third family, the
index case presented with a retroperitoneal teratoma at 26 years and his
sister was diagnosed with an ovarian dysgerminoma at 45 years. Huddart
et al. (1996) noted that none of these families had any features
indicative of the Li-Fraumeni syndrome (151623) or any other cancer
family syndrome. Trentini and Palmieri (1974) and Yule et al. (1994)
reported single families with ovarian and testicular germ cell tumors
and Jackson (1967) presented a family with multiple cases of
dysgerminoma.

Greene et al. (2010) noted that in familial cases the most common number
of affected family members was 2, that age at diagnosis was 2 to 3 years
younger for familial versus sporadic cases, and that familial TGCT were
more likely to be bilateral than sporadic TGCT.

- Association with Testicular Microlithiasis

Coffey et al. (2007) analyzed the frequency of testicular microlithiasis
(TM; 610441) in 169 patients with testicular germ cell tumor (TGCT), 58
relatives, and 101 controls and found that TM was more frequent in
unaffected male relatives of TGCT cases than controls and that patients
with a history of TGCT had a higher frequency of TM in their
contralateral remaining testis than controls. Coffey et al. (2007) also
demonstrated significant concordance of TM between relatives, raising
the hypothesis that TGCT and TM have a joint etiology.

Korde et al. (2008) performed testicular ultrasound in 48 men with
familial testicular cancer from 31 families with at least 2 cases of
TGCT, and in 33 of their unaffected male relatives. Testicular
microlithiasis (TM) was more frequent in the contralateral testicles of
men with a history of TGCT than in unaffected men (48% vs 24%; p =
0.04). The association appeared stronger for men with 5 or more
microliths than for those with less than 5 microliths. Testicular
microlithiases were bilateral in 6 (75%) of the 8 unaffected men in whom
they were detected. Among affected men, TM was not associated with
histology, age at diagnosis, or cancer treatment. Korde et al. (2008)
noted that TM was more prevalent among unaffected family members in this
study (24%) than previously described in the general population (0.6 to
9%), and that it appeared to cluster in certain families. The findings
suggested both a familial predisposition to TM and an association
between TM and TGCT.

POPULATION GENETICS

Forman et al. (1992) reported an epidemiologic study that showed an 8-
to 10-fold increase in relative risk of testicular cancer to brothers of
patients and a 4-fold increase in risk to fathers and sons. Families
with multiple cases of testicular cancer are rare and almost all those
reported have only 2 affected members.

Heimdal et al. (1996) found that 51 of 922 (5.5%) Norwegian patients
with testicular cancer and 5 of 237 (2.1%) Swedish patients had a
relative with confirmed testicular cancer. It was a first-degree
relative who was affected in the case of 32 of the probands.
Standardized incidence ratios (SIRs) were 10.2 for brothers, 4.3 for
fathers, and 5.7 for sons. The estimate for the risk to brothers in the
Norwegian part of the sample for development of testicular cancer by the
age of 60 was 4.1%. Patients with familial testicular cancer had
bilateral tumors more often than sporadic cases (9.8% bilaterality in
familial vs 2.8% in sporadic cases; P = 0.02). For patients with
seminoma, age of onset was lower in familial than in sporadic cases
(32.9 vs 37.6 years; P = 0.06). Heimdal et al. (1996) stated that the
prevalence of undescended testis did not seem to be higher in familial
than in sporadic testicular cancer.

Einhorn (2002) stated that the highest worldwide incidence of germ cell
tumors is in Scandinavian countries; by contrast, testicular cancer is
rare in African Americans. The primary age group is 15 to 35 years for
nonseminomatous tumors and a decade older for seminomas. Although cases
are few, germ cell tumors are important because they represent the most
common carcinoma in men aged 15 to 35 years and thus have the potential
to greatly shorten productive years of life. Available serum markers
such as alphafetoprotein (104150) and human chorionic gonadotropin have
allowed clinicians to make important and accurate treatment-related
decisions. Testicular cancer is a model for multidisciplinary care, as
surgical resection of postchemotherapy radiographically persistent
disease can improve the cure rate. Germ cell tumors have become an
excellent testing ground for experimental drugs, a number of which were
first approved by the Food and Drug Administration primarily on the
basis of data in testicular cancer.

INHERITANCE

Greene et al. (2010) reviewed the genetic risk factors and clinical
phenotype of familial testicular germ cell tumors in adults, noting that
although linkage analyses had identified several genomic regions of
modest interest, no high-penetrance cancer susceptibility gene had been
mapped to date, suggesting that the combined effects of multiple common
alleles, each conferring modest risk, might underlie familial testicular
cancer.

- L1 Methylation Status

Mirabello et al. (2010) studied global methylation at long interspersed
nuclear elements-1 (L1; 151626) in DNA from 152 patients with TGCT and
314 unaffected family members from 101 multiple-case testicular cancer
families. Analysis of the correlation of L1 methylation levels among
parent-child pairs independent of affection status revealed a strong
positive association only between mother-daughter (r = 0.48; p = 0.0002)
and father-daughter (r = 0.31; p = 0.021) pairs, suggesting
gender-specific inheritance of methylation. Incorporating cancer status
into the analysis revealed a strong correlation in L1 methylation levels
only among affected father-son pairs (r = 0.49; p = 0.03). There was a
marginally significant inverse association between lower L1 methylation
levels and increased risk of TGCT, compared to healthy male relatives (p
= 0.049). Mirabello et al. (2010) stated that their findings suggested
that heritability of L1 methylation might be gender-specific, and that
transgenerational inheritance of L1 methylation levels might be
associated with testicular cancer risk.

CYTOGENETICS

Studying direct preparations and 24-hr cultures, Atkin and Baker (1982)
found an isochromosome for the short arm of chromosome 12 in all of 10
seminomas, 1 malignant teratoma, and 1 combined seminoma and teratoma of
the testis. (The same workers found a possible isochromosome for 5p in
12 of 18 carcinomas of the cervix.) They also noted a relative excess of
normal chromosomes 12 in 4 of 5 of the seminomas analyzed in detail.
Castedo et al. (1989) found at least 1 copy of a 12p isochromosome in 8
of 10 seminomas. Thus, the authors concluded that amplification of 1 or
more genes on the short arm of chromosome 12 may be important in the
development of malignant testicular tumors. Chromosomal changes
presumably lead to the malignant phenotype by gene loss, gene
modification or gene amplification.

Samaniego et al. (1990) analyzed the karyotype of 24 male germ cell
tumors from both testicular and extragonadal sites and belonging to the
histologic categories seminoma, teratoma, embryonal carcinoma,
choriocarcinoma, and endodermal sinus tumor. In 90% of tumors, including
all histologic subtypes and both gonadal and extragonadal presentation,
they found isochromosome 12p. In contrast, they found del(12)(q13-q22)
exclusively in nonseminomatous GCTs, and mixed GCTs occurring in 44% of
such lesions. They developed a method based on DNA analysis for
detecting i(12p) as increased copy number of 12p. Furthermore, they
detected cytologic evidence of gene amplification in 12p in the form of
homogeneously staining regions (HSRs) and double minute chromosomes in
both treated and untreated primary extragonadal and metastatic GCTs.

Suijkerbuijk et al. (1991, 1992) applied competitive in situ
hybridization (CISH) techniques (Kievits et al., 1990) to show that the
aberrant chromosome in testicular germ cell tumors is indeed an
isochromosome 12p. Other marker chromosomes representing translocation
products that involve chromosome 12 were also identified. In the
studies, DNAs from 2 rodent-human somatic cell hybrids, containing
either a normal chromosome 12 or the p arm of chromosome 12 as their
unique human material, were used as probes. (Competitive in situ
hybridization, also referred to as chromosome painting, employs large
pools of cloned genomic sequences originating from a single human
chromosome as probe and involves a preannealing step in the presence of
an excess of sonicated total human DNA. It results in complete staining
of the particular chromosome in metaphase spreads and in interphase
nuclei. Kievits et al., 1990 stated that the approach permits detection
of hitherto undetectable chromosomal aberrations.)

In a cytogenetic analysis of 65 consecutively ascertained GCTs with
chromosomal abnormalities, Rodriguez et al. (1992) found that an
isochromosome for the short arm of chromosome 12 (i(12p)), monosomy 12,
and deletions in 12q occurred with frequencies of 86%, 11%, and 20%
respectively.

Because a marker chromosome interpreted as isochromosome 12p is present
in most testicular tumors of germ cell origin, Peltomaki et al. (1992)
investigated 22 patients with testicular germ cell tumors by Southern
blot hybridization to characterize changes in chromosome 12. In
comparison with normal DNA, tumor DNA of 18 patients showed increased
dosages of 12p accompanied by a comparable or smaller increase or no
change in the dosage of centromeric sequences of chromosome 12. The
interpretation offered by the authors was that most testicular tumors
had one or several isochromosomes for 12p that were formed by somatic
division of the centromere and that the points of breakage and reunion
in the centromeric region were different in different tumors.
Sex-limited parental imprinting was excluded by the fact that allelic
12p fragments showing increased intensity were paternal in 4 and
maternal in 3 of 7 informative cases. Furthermore, the observed patterns
of allelic fragments suggested that the marker isochromosome was formed
by sister chromatids of 1 homolog number 12 rather than the result of
interchange of genetic material between different homologs.

Ottesen et al. (2004) studied 3 brothers with germ cell tumors. One had
an intracranial tumor in the pineal region and the other 2 had
testicular tumors. No abnormalities were detected in peripheral blood
with karyotyping and molecular marker analysis of selected loci.
High-resolution comparative genomic hybridization (CGH) analysis of
microdissected histologic components of the overt tumors and the
adjacent carcinoma in situ demonstrated a pattern of genomic imbalances
characteristic for sporadic GCTs, including gain of 12p.

Stadler et al. (2012) investigated germline de novo copy number
variations (CNVs) in 382 genomes of 116 early-onset cancer case parent
trios and unaffected sibs. Unique de novo germline CNVs were not
observed in 107 breast or colon cancer trios or controls but were found
in 7% of 43 testicular germ cell tumor trios; this percentage exceeded
background CNV rates and suggested a rare de novo genetic paradigm for
susceptibility to some human malignancies.

MAPPING

- Genomewide Association Studies

Leahy et al. (1995) performed a sib-pair analysis on 35 families in
which there were either 2 or 3 affected brothers. These families were
typed for 220 autosomal microsatellite markers spaced 10-20 cM
throughout the genome. Six regions that gave a lod score of more than
1.0 on formal linkage analysis or a p value of 0.05 or less using a
nonparametric approach were considered as candidate regions for a
susceptibility gene. Of particular interest was one region on chromosome
4. A positive lod score of 2.6 on multipoint analysis was obtained with
2 neighboring probes in the region of 4cen-q13.

Rapley et al. (2009) performed a genomewide association study involving
730 TGCT cases and 1,435 controls, with replication in 571 cases and
1,806 controls, and found the strongest evidence for association with
dbSNP rs995030 (OR, 2.55; p = 1.0 x 10(-31)) and dbSNP rs1508595 (OR,
2.69; p = 2.6 x 10(-30)) that are both located within the same linkage
disequilibrium block on chromosome 12q22. Rapley et al. (2009) noted
that this region contains only 1 annotated protein-coding gene, KITLG
(184745), encoding the ligand for KIT, which has previously been
implicated in the pathogenesis of TGCT. There was also evidence for
susceptibility loci at dbSNP rs4624820 located 10-kb 3-prime of the
SPRY4 gene (607984) on chromosome 5q31.3 (per-allele odds ratio, 1.37; p
= 3.3 x 10(-13)) and at dbSNP rs210138 located in an intron of the BAK1
gene (600516) on chromosome 6p21.3-p21.2 (OR, 1.50; p = 1.1 x 10(-13)).

In a genomewide scan involving 277 TGCT cases and 919 controls, Kanetsky
et al. (2009) found 7 markers at chromosome 12q22 within the KITLG gene
that reached genomewide significance (p less than 5.0 x 10(-8)); in
independent replication using 371 TGCT cases and 860 controls, TGCT risk
increased 3-fold per copy of the major allele at dbSNP rs3782179 and
dbSNP rs4474514. The markers were associated with both seminoma and
nonseminoma TGCT subtypes.

Turnbull et al. (2010) conducted a genomewide association study for
testicular germ cell tumor, genotyping 298,782 SNPs in 979 affected
individuals and 4,947 controls from the U.K. and replicating
associations in a further 664 cases and 3,456 controls. Turnbull et al.
(2010) identified 3 novel susceptibility loci, 2 of which include genes
that are involved in telomere regulation. They identified 2 independent
signals within the TERT (187270)-CLPTM1L (612585) locus on chromosome
5p15.33, which had been associated with multiple other cancers (dbSNP
rs4635969, OR = 1.54, P = 1.14 x 10(-23); dbSNP rs2736100, OR = 1.33, P
= 7.55 x 10(-15)). Turnbull et al. (2010) also identified a locus on
chromosome 12 (dbSNP rs2900333, OR = 1.27, P = 6.16 x 10(-10)) that
contains ATF7IP, a regulator of TERT expression. Finally, Turnbull et
al. (2010) identified a locus on chromosome 9p24.3 (dbSNP rs755383, OR =
1.37, P = 1.12 x 10(-23)), containing the sex determination gene DMRT1
(602424), which has been linked to teratoma susceptibility in mice.

- Other Mapping Studies

Lothe et al. (1989) found loss of heterozygosity (LOH) for 3p or 11p
sequences in 40% of testicular cancers.

Mathew et al. (1994) analyzed chromosome 1 loss of heterozygosity in a
panel of 48 GCTs and observed allelic losses in 46% of cases on 1p and
in 23% of cases on 1q. There were 4 sites of frequent deletions, 3 in
the short arm (1p13, 1p22, and 1p32.2-p31.3) and 1 in the long arm
(1q32). Of the 11 probes on 1p that showed allelic losses, the highest
frequency of LOH was observed for D1S16 at 1p22 (38.5%). Teratomas
showed higher frequency of allelic losses (24.4%) compared to embryonal
carcinomas (9.5%), yolk sac tumors (12.1%), or seminomas (7.6%).

Rodriguez et al. (1992) presented data strongly suggested that loss of
genetic material on 12q characterizes the development of TGCTs. To
define the region of common deletion in GCTs at the molecular level,
Murty et al. (1992) compared germline and tumor genotypes for 8
polymorphic loci in paired normal/tumor DNA samples from 45 GCT
patients. Analysis demonstrated 2 regions of loss of constitutional
heterozygosity, one at 12q13 and the other at 12q22. One tumor exhibited
homozygous deletion of a region of 12q22 which includes the MGF gene
(184745). The MGF and KIT (164920) genes have been shown to play key
roles in embryonal and postnatal development of germ cells. The MGF gene
product constitutes the ligand for the receptor encoded by the KIT
protooncogene. They evaluated the expression of these 2 genes by
Northern blot analysis in a panel of 3 GCT cell lines and 24 fresh GCT
biopsies. Deregulated expression of MGF and KIT, which was discordant
between seminomatous and nonseminomatous lesions, was observed. Murty et
al. (1994) refined their data on the mapping of male germ cell tumors
(MGCTs). Using 5 dinucleotide repeats mapping to 12q22, they found LOH
in approximately 41% of tumors; one of the loci, D12S218, showed LOH in
37% of tumors, suggesting the presence of a tumor suppressor gene in its
vicinity. In this study, a panel of 66 tumor DNA samples and their
corresponding normal cells were investigated.

In a detailed deletion mapping analysis of 67 normal-tumor DNA
comparisons using 20 polymorphic markers mapped to 12q22-q24, Murty et
al. (1996) identified the limit of the minimal region of deletion at
12q22 between D12S377 (proximal) and D12S296 (distal). They constructed
a YAC contig map of a 3-cM region of this band and developed a radiation
hybrid (RH) map of the region. The consensus order developed by RH
mapping was in good agreement with the YAC STS-content map order. The RH
map estimated the distance between the D12S101 and D12S346 to be 246
cR(8000) and the minimal region of deletion to be 141 cR(8000).

Murty and Chaganti (1998) reviewed the genetics of male germ cell
tumors. A characteristic of GCTs is high sensitivity to cisplatin-based
chemotherapy. Chromosomal and molecular cytogenetic studies identified
multiplication of 12p, manifested in i(12p) or tandem duplication of
12p, as a unique change in GCTs which serves as a diagnostic marker.
Ectopic overexpression of cyclin D2 (CCND2; 123833), which maps to 12p,
as early as in carcinoma in situ, identified CCND2 as a candidate gene
in germ cell transformation. Genetic alterations identified in the tumor
suppressor genes DCC (120470), RB1 (614041), and nonmetastatic
protein-23 (NME1; 156490) in GCTs suggested that their inactivation
plays a key role in transformation or differentiation. The exquisite
sensitivity of these tumors to chemotherapy is reflected in their
overexpression of wildtype p53 protein and lack of TP53 mutations.

Zafarana et al. (2002) identified the DADR (609860), SOX5 (604975), and
ETNK1 (609858) genes within a region of chromosome 12p amplified in
testicular seminomas. Although all 3 genes were amplified to the same
level in seminomas with the amplification, only DADR expression was
significantly upregulated. DADR was also highly expressed in
nonseminomas of various histologies and derived cell lines lacking the
12p amplification. Low DADR expression was observed in normal testicular
parenchyma and in parenchyma containing carcinoma in situ. DADR
overexpression in seminomas and nonseminomas correlated with invasive
growth, reduced apoptosis, and earlier clinical manifestation.

In 97 patients with familial TGCT, 22 patients with sporadic bilateral
TGCT, and 871 controls, Kratz et al. (2011) genotyped 106 SNPs in 4
regions, in or near BAK1 on 6p21, DMRT1 on 9p24, KITLG on 12q, and
TERT-CLPTM1L on 5p15, all of which had previously been identified in
genomewide association studies of TGCT. Three previously identified risk
SNPs were replicated in the familial and sporadic bilateral TGCT
patients: dbSNP rs210138 within an intron of BAK1 (OR, 1.80; p = 7.03 x
10(-5)), dbSNP rs755383 near DMRT1 (OR, 1.67; p = 6.70 x 10 (-4)), and
dbSNP rs4635969 near TERT-CLPTM1L (OR, 1.59; p = 4.07 x 10(-3)).
Evidence for a second independent association was found for a SNP within
an intron of TERT, dbSNP rs4975605 (OR, 1.68; p = 1.24 x 10(-3)). In
addition, an association with another SNP in KITLG, dbSNP rs2046971, was
identified (OR 2.33; p = 1.28 x 10(-3)); this SNP is in high linkage
disequilibrium with the previously reported risk variant dbSNP rs995030.
Kratz et al. (2011) suggested that familial TGCT and sporadic bilateral
TGCT are polygenetic diseases caused by the same spectrum of genetic
risk factors.

- Y-Chromosome Microdeletion

A 1.6-Mb deletion of the Y chromosome that removes part of the AZFc
region--known as the gr/gr deletion (see 415000)--has been associated
with infertility. In epidemiologic studies, male infertility has shown
an association with testicular germ cell tumor (TGCT) that is out of
proportion with what can be explained by tumor effects. Thus, Nathanson
et al. (2005) hypothesized that the gr/gr deletion may be associated
with TGCT. They analyzed this deletion in a large series of TGCT cases
with or without a family history of TGCT. The gr/gr deletion was present
in 3% of TGCT cases with a family history. 2% of TGCT cases without a
family history, and 1.3% of unaffected males. The presence of the gr/gr
deletion was associated with a 2-fold increased risk of TGCT and a
3-fold increased risk of TGCT among patients with a positive family
history. The gr/gr deletion was more strongly associated with seminoma
TGCT than with nonseminoma TGCT. Thus, the Y microdeletion gr/gr appears
to be a rare, low penetrance allele that confers susceptibility to TGCT.

MOLECULAR GENETICS

- Variation in the BCL10 Gene and Progression to Advanced
Stage TGCT

Inoue et al. (2006) analyzed 4 SNPs in the BCL10 gene on chromosome
1p22, which had previously been identified in Japanese TGCTs by Kakinuma
et al. (2001), in 73 TGCT patients and 72 controls. No significant
difference in any of the 4 SNPs was observed between patients and
controls. However, GCT patients with metastatic disease were more likely
than patients with only local disease to carry a minor allele of either
of 2 SNPs in exon 1: 13G-T (A5S; adjusted odds ratio, 6.25, and p =
0.040) or 24C-G (L8L; adjusted odds ratio, 4.63 and p = 0.015). Inoue et
al. (2006) concluded that these BCL10 polymorphisms in exon 1 might play
a role in progression to advanced stage TGCTs.

- Somatic Mutation in the BLC10 Gene on Chromosome 1p22

Willis et al. (1999) analyzed 3 male germ cell tumor lines (Tera1,
Tera2, and GCT44) and identified 2, 3, and 1 mutations in the BCL10 gene
(603517), respectively (see, e.g., 603517.0001, 603517.0016, and
603517.0017).

Fakruddin et al. (1999) sequenced BCL10 in the 3 GCT cell lines
previously studied by Willis et al., 1999 but found no mutations.
Fakruddin et al. (1999) noted that their data were at variance with the
results reported by Willis et al. (1999), and concluded that BCL10 is
not a target tumor suppressor gene at 1p22 in GCTs.

Van Schothorst et al. (1999) screened exons 2 and 3 of the BCL10 gene in
a series of TGCT-derived and related cell lines, including the 3 GCT
cell lines previously studied by Willis et al., 1999, as well as primary
tumors. No aberrations were detected by SSCP on genomic DNA or
restriction endonuclease digestion analysis of PCR-amplified fragments,
and van Schothorst et al. (1999) concluded that inactivation of BCL10 by
genomic events in TGCTs is not involved in the majority of cases, if at
all.

Lee et al. (1999) analyzed the BCL10 gene by PCR-SSCP using DNA
extracted from malignant and normal cells of 439 paraffin-embedded tumor
tissue samples, including 78 GCTs. Enrichment and direct sequencing of
aberrantly migrating bands led to the identification of somatic
mutations in 2 (2.6%) of the 78 TGCTs (both were mature teratomas; see,
e.g., 603517.0018). Lee et al. (1999) concluded that BCL10 may
occasionally be involved in the pathogenesis of TGCTs, but that the
absence or low frequency of mutation suggested that either BCL10 is
inactivated by other mechanisms or that it is not the only target of
chromosome 1p22 deletion in human tumors.

Kakinuma et al. (2001) found loss of heterozygosity at chromosome 1p in
21 (42%) of 49 Japanese TGCTs, including 12 (43%) of 28 seminomas and 8
(38%) of 21 nonseminomatous GCTs. No somatic mutations were identified
by SSCP and direct sequencing in any of the tumors, although 4 SNPs were
detected.

- Somatic Mutation in the FGFR3 Gene on Chromosome 4p16

Goriely et al. (2009) screened 30 spermatocytic seminomas for oncogenic
mutations in 17 genes and identified a K650E mutation in FGFR3
(134934.0004) in 2 tumors.

- Somatic Mutation in the KIT Gene on Chromosome 4q12

Tian et al. (1999) identified an asp816-to-his mutation in the KIT gene
(164920.0021) in primary tissue samples from patients with germ cell
tumors.

- Somatic Mutation in the BRAF Gene on Chromosome 7q34

Sommerer et al. (2005) analyzed the BRAF gene (164757) in 30 seminomas
and 32 nonseminomatous GCTs with a mixture of embryonal carcinoma, yolk
sac tumor, choriocarcinoma, and mature teratoma. The activating BRAF
missense mutation 1796T-A (164757.0001) was identified in 3 (9%) of 32
nonseminomatous tumors, within the embryonic carcinoma component; no
BRAF mutations were found in the seminomas. There was no correlation
between BRAF mutation status and tumor stage or grade or other
histopathologic factors.

- Somatic Mutation in the HRAS Gene on Chromosome 11p15.5

Goriely et al. (2009) screened 30 spermatocytic seminomas for oncogenic
mutations in 17 candidate genes and identified apparent homozygosity for
5 mutations in the HRAS gene (190020), 3 182A-G transitions and 2 181C-A
transversions, all involving the Q61 codon (see, e.g., 190020.0002).

- Somatic Mutation in the KRAS Gene on Chromosome 12p12

Sommerer et al. (2005) analyzed the KRAS gene (190070) in 30 seminomas
and 32 nonseminomatous GCTs with a mixture of embryonal carcinoma, yolk
sac tumor, choriocarcinoma, and mature teratoma. KRAS mutations, all
involving codon 12, were identified in 2 (7%) of 30 seminomas and 3 (9%)
of 32 nonseminomas. The KRAS mutations in the nonseminomas occurred
within the embryonal carcinoma component in 2 and within the
choriocarcinoma in 1. No correlation between KRAS mutation pattern and
histopathologic variables was observed.

- Somatic Mutation in the STK11 Gene on Chromosome 19p13

Avizienyte et al. (1998) identified a somatic gly163-to-asp mutation in
the STK11 gene (602216.0011) in a case of sporadic testicular carcinoma.

- Exclusion Studies

Murty et al. (1996) excluded 4 genes on chromosome 12q22 as candidates
for familial testicular cancer: mast cell growth factor (184745), B-cell
translocation gene-1 (109580), thymopoietin (188380), and neural
precursor cell expressed, developmentally down-regulated-1 (600372).

ANIMAL MODEL

In laboratory mice, testicular germ cell tumors (TGCTs) arise from
primordial germ cells (PGC) in only the inbred 129 strain, and
susceptibility is under multigenic control (Stevens and Hummel, 1957).
The spontaneously arising mutation Ter (Stevens, 1973) on mouse
chromosome 18 (Asada et al., 1994; Sakurai et al., 1994) increases TGCT
frequency on a 129/Sv background.

Inbred 129 strain mice are predisposed to developing male germ cell
tumors (GCTs) of the testes. GTC incidence is increased in 129 strain
males that lack functional p53 protein (191170). Muller et al. (2000)
used this finding to facilitate the generation of panels of GCT-bearing
intercross and backcross mice for genetic mapping analysis. A 129 strain
locus, designated pgct1, that segregated with the male GCT phenotype was
identified on mouse chromosome 13 near D13Mit188. This region of mouse
chromosome 13 may have conservation of synteny with a portion of human
chromosome 5q that is implicated in male GCT susceptibility in humans.

Youngren et al. (2005) reported the positional cloning of Ter, revealing
a point mutation that introduces a termination codon in the mouse Dnd1
gene (609385). PGC deficiency was corrected both with BACs containing
Dnd1 and with a Dnd1-encoding transgene. Dnd1 is expressed in fetal
gonads during the critical period when TGCTs originate. Dnd1 has an RNA
recognition motif and is most similar to the apobec (see 600130)
complementation factor, a component of the cytidine to uridine RNA
editing complex. These results suggested that Ter may adversely affect
essential aspects of RNA biology during PGC development. Youngren et al.
(2005) stated that Dnd1 was the first protein known to have an RNA
recognition motif directly implicated as a heritable cause of
spontaneous tumorigenesis, and they suggested that TGCT development in
the 129-Ter mouse strain models pediatric TGCTs in humans.

Collin et al. (1996), in a genome scan of tumor-bearing progeny from
backcrosses between the 129/Sv-Ter/+ and MOLF/Ei strains provided modest
evidence that MOLF-derived alleles on mouse chromosome 19 enhance
development of bilateral TGCTs. To obtain independent evidence for
linkage to the MOLF chromosome, Matin et al. (1999) made an autosomal
chromosome substitution strain (a so-called consomic strain, or CSS), in
which chromosome 19 of 129/Sv +/+ was replaced by its MOLF-derived
homolog. The unusually high frequency of TGCTs in this CSS (even in the
absence of the Ter mutation) provided evidence confirming the genome
survey results, identified linkage for a naturally occurring strain
variant allele that confers susceptibility to TGCTs, and illustrated the
power of CSSs in complex trait analysis.

The agouti (ASIP; 600201)-yellow (Ay) deletion is the only genetic
modifier known to suppress testicular germ cell tumor (TGCT)
susceptibility in mice or human. The Ay mutation deletes Raly and Eif2s2
(603908) and induces the ectopic expression of agouti, all of which are
potential TGCT-modifying mutations. Heaney et al. (2009) reported that
the reduced TGCT incidence of heterozygous Ay male mice and the
recessive embryonic lethality of Ay are caused by the deletion of
Eif2s2, the beta subunit of translation initiation factor eIF2. The
incidence of affected males was reduced 2-fold in mice that were
partially deficient for Eif2s2 and that embryonic lethality occurred
near the time of implantation in mice that were fully deficient for
Eif2s2. In contrast, neither reduced expression of Raly in gene-trap
mice nor ectopic expression of agouti in transgenic or viable-yellow
(Avy) mutants affected TGCT incidence or embryonic viability. Partial
deficiency of Eif2s2 attenuated germ cell proliferation and
differentiation, both of which are important to TGCT formation. Heaney
et al. (2009) concluded that germ cell development and TGCT pathogenesis
are sensitive to the availability of the eIF2 translation initiation
complex and to changes in the rate of translation.

*FIELD* SA
Zevallos et al. (1983)
*FIELD* RF
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*FIELD* CS
INHERITANCE:
Isolated cases

GENITOURINARY:
[Internal genitalia, male];
Painless testicular mass

NEOPLASIA:
Male germ cell tumors (GCT), 2 subtypes -;
Seminoma;
Nonseminoma (embryonal carcinoma, teratoma, choriocarcinoma, endodermal
sinus tumor)

LABORATORY ABNORMALITIES:
Isochromosome 12p (i(12p));
Elevated hCG (choriocarcinoma);
Elevated AFP (endodermal sinus tumor);
Elevated hCG or AFP or both (embryonal carcinoma);
Azoospermia/oligospermia (present at diagnosis)

MISCELLANEOUS:
Two subtypes - seminoma and nonseminoma;
Occasionally germ cell tumor arise from extra gonadal site (e.g.,
mediastinum, retroperitoneum, pineal gland);
Most common cancer in men aged 15-40 years;
Highest incidence in men of European descent;
Risk factors for development of TGCT - family history, cryptorchidism
(219050), testicular feminization (300068), Klinefelter syndrome,
previous TGCT, gonadal dysgenesis

*FIELD* CN
Kelly A. Przylepa - revised: 5/12/2006

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 09/10/2012
joanna: 2/1/2007
joanna: 5/12/2006
alopez: 12/19/2005

*FIELD* CN
Ada Hamosh - updated: 10/15/2013
Marla J. F. O'Neill - updated: 11/29/2011
Marla J. F. O'Neill - updated: 11/23/2011
Marla J. F. O'Neill - updated: 8/3/2011
Ada Hamosh - updated: 11/10/2010
George E. Tiller - updated: 11/25/2009
Marla J. F. O'Neill - updated: 9/10/2009
Marla J. F. O'Neill - updated: 8/10/2009
Patricia A. Hartz - updated: 1/30/2006
Victor A. McKusick - updated: 12/12/2005
Ada Hamosh - updated: 6/3/2005
Victor A. McKusick - updated: 2/25/2004
Victor A. McKusick - updated: 10/11/2002
Victor A. McKusick - updated: 9/29/1999
Victor A. McKusick - updated: 8/21/1998

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 10/15/2013
carol: 11/30/2011
carol: 11/29/2011
carol: 11/23/2011
wwang: 8/8/2011
terry: 8/3/2011
carol: 6/17/2011
alopez: 11/12/2010
terry: 11/10/2010
alopez: 3/2/2010
wwang: 1/6/2010
terry: 11/25/2009
wwang: 9/22/2009
terry: 9/10/2009
wwang: 8/18/2009
terry: 8/10/2009
terry: 6/3/2009
terry: 3/25/2009
carol: 5/3/2007
mgross: 1/30/2006
alopez: 12/19/2005
terry: 12/12/2005
wwang: 6/7/2005
wwang: 6/3/2005
terry: 6/2/2004
carol: 3/17/2004
tkritzer: 2/26/2004
terry: 2/25/2004
tkritzer: 9/17/2003
tkritzer: 10/18/2002
tkritzer: 10/11/2002
terry: 11/24/1999
alopez: 11/4/1999
alopez: 9/30/1999
terry: 9/29/1999
carol: 8/24/1998
terry: 8/21/1998
carol: 6/16/1998
terry: 11/6/1997
mark: 9/10/1996
terry: 8/23/1996
mark: 5/9/1996
terry: 5/2/1996
terry: 3/29/1996
mark: 2/17/1996
mark: 2/12/1996
mark: 9/22/1995
carol: 12/1/1994
terry: 7/27/1994
mimadm: 7/7/1994
jason: 6/27/1994
warfield: 3/10/1994

MIM 601626
*RECORD*
*FIELD* NO
601626
*FIELD* TI
#601626 LEUKEMIA, ACUTE MYELOID; AML
;;LEUKEMIA, ACUTE MYELOGENOUS
LEUKEMIA, ACUTE MYELOID, SUSCEPTIBILITY TO, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that acute
myeloid leukemia (AML) can be caused by mutations in the CEBPA gene
(116897) and the NPM1 gene (164040).

Somatic mutations in several genes have been found in cases of AML,
e.g., in the CEBPA, ETV6 (600618), JAK2 (147796), KRAS2 (190070), HIPK2
(606868), FLT3 (136351), TET2 (612839), ASXL1 (612990), IDH1 (147700),
CBL (165360), DNMT3A (602769), and SF3B1 (605590) genes. Other causes of
AML include fusion genes generated by chromosomal translocations; see,
for example, 600358 and 159555.

Susceptibility to the development of acute myeloid leukemia may be
caused by germline mutations in certain genes, including GATA2 (137295),
TERC (602322), and TERT (187270).

AML may also be part of the phenotypic spectrum of inherited disorders,
including platelet disorder with associated myeloid malignancy (FPDMM;
601399), caused by mutation in the RUNX1 gene (151385), and
telomere-related pulmonary fibrosis and/or bone marrow failure (PFBMFT1,
614742 and PFBMFT2, 614743), caused by mutation in the TERT or the TERC
gene.

CLINICAL FEATURES

Shields et al. (2003) published a case report on acute myeloid leukemia
that presented as bilateral orbital myeloid sarcoma (or chloroma) in a
previously healthy 25-month-old boy. Bone marrow biopsy revealed blasts
and cells with maturing monocytic features. A final diagnosis of M5b AML
was made. The authors reviewed the literature and concluded that
leukemia may be the most likely diagnosis in a child with bilateral soft
tissue orbital tumors.

CLINICAL MANAGEMENT

AML is often treated with allogeneic hematopoietic stem-cell
transplantation (HSCT), and it is most sensitive to natural killer
(NK)-cell reactivity. Venstrom et al. (2012) assessed clinical data, HLA
genotyping results, and donor cell lines or genomic DNA for 1,277
patients with AML who had received HSCT from unrelated donors matched
for HLA-A, -B, -C, -DR, and -DQ or with a single mismatch. They
performed donor KIR genotyping and evaluated the clinical effect of
donor KIR genotype and donor and recipient HLA genotypes. Patients with
AML who received allografts from donors who were positive for KIR2DS1
(604952) had a lower rate of relapse than those with allografts from
donors who were negative for KIR2DS1 (26.5% vs 32.5%; hazard ratio,
0.76; 95% confidence interval, 0.61 to 0.96; P = 0.02). Of allografts
from donors with KIR2DS1, those from donors who were homozygous or
heterozygous for HLA-C1 antigens could mediate this antileukemic effect,
whereas those from donors who were homozygous for HLA-C2 did not provide
any advantage. Recipients of KIR2DS1-positive allografts mismatched for
a single HLA-C locus had a lower relapse rate than recipients of
KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs
35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P = 0.007). KIR3DS1
(see 604946), in positive genetic linkage disequilibrium with KIR2DS1,
had no effect on leukemia relapse but was associated with decreased
mortality (60.1% vs 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI,
0.71 to 0.96; P = 0.01). Venstrom et al. (2012) concluded that
activating KIR genes from donors were associated with distinct outcomes
of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection
against relapse in an HLA-C-dependent manner, and donor KIR3DS1 was
associated with reduced mortality.

BIOCHEMICAL FEATURES

Garzon et al. (2009) provided evidence supporting a tumor suppressor
role for miR29A (610782) and miR29B (610783) in AML. Overexpression of
both microRNAs reduced cell growth and induced apoptosis in AML cell
lines. Injection of miR29B in a xenograft mouse model of AML resulted in
tumor shrinkage. Northern blot analysis showed that the 2 microRNAs
targeted genes involved in apoptosis, the cell cycle, and cell
proliferation. Transfection of leukemic cells with miR29A and miR29B
resulted in specific downregulation of CXXC6 (TET1; 607790), MCL1
(159552), and CDK6 (603368). Studies of 45 samples from patients with
AML showed an inverse correlation between MCL1 and miR29B. Although 42%
of the miR29A-correlated genes were also correlated with miR29B, there
were some differences: genes related to protein metabolism were found
overrepresented in miR29B-correlated genes, and genes related to immune
function were overrepresented in miR29A-correlated genes. Finally, there
was a downregulation of both miR29A and miR29B in primary AML samples
with monosomy 7 (252270).

CYTOGENETICS

Loss of chromosome 5q is observed in 10 to 15% of patients with
myelodysplastic syndrome (MDS) or acute myeloid leukemia and in 40% of
patients with therapy-related MDS or AML. In addition, patients with 5q
deletion syndrome (153550) show hematologic abnormalities, including
refractory anemia and abnormal megakaryocytes. By cytogenetic analysis
and hybridization techniques, Le Beau et al. (1993) identified a common
2.8-Mb critical region containing the EGR1 gene (128990) on chromosome
5q31 that was deleted in 135 patients with hematologic abnormalities and
5q deletions, including 85 patients with de novo MDS or AML, 33 with
therapy-related MDS or AML, and 17 with MDS and the 5q deletion
syndrome. Le Beau et al. (1993) postulated that EGR1 or another
closely-linked gene may act as a tumor suppressor gene.

Baozhang et al. (1999) reported a family with 7 cases of related
leukemias among 22 members in 3 consecutive generations consistent with
autosomal dominant inheritance. One of the patients and her father were
found to have rearrangement and a rearrangement/amplification,
respectively, of the ERBB oncogene (131550).

Horwitz et al. (1996) reported evidence of anticipation in familial
acute myelogenous leukemia. Horwitz et al. (1996) further studied those
pedigrees and others from the literature. In 49 affected individuals
from 9 families transmitting autosomal dominant AML, the mean age of
onset was 57 years in the grandparental generation, 32 years in the
parental generation, and 13 years in the youngest generation (p less
than 0.001). Horwitz et al. (1996) also reported evidence of
anticipation in autosomal dominant chronic lymphocytic leukemia (CLL;
151400) (p = 0.008). In 18 affected individuals from 7 pedigrees with
autosomal dominant CLL, the mean age of onset in the parental generation
was 66 years, versus 51 years in the younger generation. Based on this
evidence of anticipation, Horwitz et al. (1996) suggested that dynamic
mutations of unstable DNA sequence repeats could be a common mechanism
of inherited hematopoietic malignancy. They proposed 3 possible
candidate chromosomal regions for familial leukemia with anticipation:
21q22.1-22.2, 11q23.3 in the vicinity of the CBL2 gene (165360), and
16q22 in the vicinity of the CBFB gene (121360).

MAPPING

Horwitz et al. (1997) presented evidence suggesting that there is a
locus for acute myelogenous leukemia on chromosome 16q22. They studied a
family with 11 relevant meioses transmitting autosomal dominant AML and
myelodysplasia. They excluded linkage to 21q22.1-q22.2 and to 9p22-p21,
and found a maximum 2-point lod score of 2.82 with the microsatellite
marker D16S522 at recombination fraction theta = 0.0. Haplotype analysis
showed a 23.5-cM region of 16q22 that was inherited in common by all
affected family members and extended from D16S451 to D16S289.
Nonparametric linkage analysis gave a p value of 0.00098 for the
conditional probability of linkage. Mutation analysis excluded expansion
of the AT-rich minisatellite repeat FRA16B fragile site and the CAG
trinucleotide repeat in the E2F-4 transcription factor (600659). The
'repeat expansion detection' method, capable of detecting dynamic
mutation associated with anticipation, more generally excluded large CAG
repeat expansion as a cause of leukemia in this family.

MOLECULAR GENETICS

- Mutations in CEBPA

In affected members of a family with acute myeloid leukemia, Smith et
al. (2004) identified a germline 1-bp deletion (212delC; 116897.0007) in
the CEBPA gene. Overt leukemia developed in the father at age 10 years,
in the first-born son at age 30 years, and in the last-born daughter at
age 18 years.

- Mutations in NPM1

NPM, a nucleocytoplasmic shuttling protein with prominent nucleolar
localization, regulates the ARF (103180)/p53 (191170) tumor suppressor
pathway. Chromosomal translocations involving the NPM gene cause
cytoplasmic dislocation of the NPM protein. Falini et al. (2005) used
immunohistochemical methods to study the subcellular localization of NPM
in bone marrow biopsy specimens from 591 patients with primary AML. They
then correlated the presence of cytoplasmic NPM with clinical and
biologic features of the disease. Cytoplasmic NPM was detected in 35.2%
of the 591 specimens from patients with primary AML but not in 135
secondary AML (sAML) specimens or in 980 hematopoietic or
extrahematopoietic neoplasms other than AML. It was associated with a
wide spectrum of morphologic subtypes of the disease, a normal
karyotype, and responsiveness to induction chemotherapy, but not with
recurrent genetic abnormalities. There was a high frequency of internal
tandem duplications of FLT3 (136351) and absence of CD34 (142230) and
CD133 (604365) in AML specimens with a normal karyotype and cytoplasmic
dislocation of NPM, but not in those in which the protein was restricted
to the nucleus. AML specimens with cytoplasmic NPM carried mutations in
the NPM gene (see 164040.0001-164040.0004); this mutant gene caused
cytoplasmic localization of NPM in transfected cells. All 6 NPM mutant
proteins showed mutations in at least 1 of the tryptophan residues at
positions 288 and 290 and shared the same last 5 amino acid residues
(VSLRK). Thus, despite genetic heterogeneity, all NPM gene mutations
resulted in a distinct sequence in the NPM protein C terminus. Falini et
al. (2005) concluded that cytoplasmic NPM is a characteristic feature of
a large subgroup of patients with AML who have a normal karyotype, NPM
gene mutations, and responsiveness to induction chemotherapy. Grisendi
and Pandolfi (2005) noted that NPM staining in cases of AML with
aberrant cytoplasmic localization of the protein is mostly cytoplasmic,
which suggests that the mutant NPM acts dominantly on the product of the
remaining wildtype allele, causing its retention in the cytoplasm by
heterodimerization.

By microRNA (miRNA) expression profiling, Garzon et al. (2008)
identified 36 upregulated and 21 downregulated miRNAs in AML patients
with NPM1 mutations compared with AML patients without NPM1 mutations.
miR10A (MIRN10A; 610173) and miR10B (MIRN10B; 611576) showed the
greatest upregulation, with increases of 20- and 16.67-fold,
respectively. Mir22 (MIRN22; 612077) showed greatest downregulation,
with a reduction of 0.31-fold. Garzon et al. (2008) concluded that AML
with NPM1 mutations has a distinctive miRNA signature.

- Mutations in GATA2

Hahn et al. (2011) analyzed 50 candidate genes in 5 families with a
predisposition to myelodysplastic syndrome (614286) and acute myeloid
leukemia, and in 3 of the families they identified a heritable
heterozygous missense mutation in the GATA2 gene (T354M; 137295.0002)
that segregated with disease and was not found in 695 nonleukemic
ethnically matched controls.

- Mutations in TERT

Calado et al. (2009) found a significantly increased number of germline
mutations in the TERT gene in patients with sporadic acute myeloid
leukemia compared to controls. One mutation in particular, A1062T
(187270.0022), was 3-fold higher among 594 AML patients compared to
1,110 controls (p = 0.0009). In vitro studies showed that the mutations
caused haploinsufficiency of telomerase activity. An abnormal karyotype
was found in 18 of 21 patients with TERT mutations who were tested.
Calado et al. (2009) suggested that telomere attrition may promote
genomic instability and DNA damage, which may contribute to the
development of leukemia.

- Somatic Mutations

In the bone marrow of a 4-year-old child with AML, Bollag et al. (1996)
identified an insertion in the KRAS2 gene (190070.0008). Expression
studies showed that the mutant KRAS2 protein caused cellular
transformation and activated the RAS-mitogen-activated protein kinase
signaling pathway.

Bone marrow minimal residual disease causes relapse after chemotherapy
in patients with acute myelogenous leukemia. Matsunaga et al. (2003)
postulated that the drug resistance is induced by the attachment of very
late antigen-4 (VLA4; see 192975) on leukemic cells to fibronectin
(135600) on bone marrow stromal cells. Matsunaga et al. (2003) found
that VLA4-positive cells acquired resistance to anoikis (loss of
anchorage) or drug-induced apoptosis through the
phosphatidylinositol-3-kinase (see 601232)/AKT (164730)/Bcl2 (151430)
signaling pathway, which is activated by the interaction of VLA4 and
fibronectin. This resistance was negated by VLA4-specific antibodies. In
a mouse model of minimal residual disease, Matsunaga et al. (2003)
achieved a 100% survival rate by combining VLA4-specific antibodies and
cytosine arabinoside, whereas cytosine arabinoside alone prolonged
survival only slightly. In addition, overall survival at 5 years was
100% for 10 VLA4-negative patients and 44.4% for 15 VLA4-positive
patients. Thus, Matsunaga et al. (2003) concluded that the interaction
between VLA4 on leukemic cells and fibronectin on stromal cells may be
crucial in bone marrow minimal residual disease and AML prognosis.

Barjesteh van Waalwijk van Doorn-Khosrovani et al. (2005) analyzed 300
patients newly diagnosed with AML for mutations in the coding region of
the ETV6 gene and identified 5 somatic heterozygous mutations (e.g.,
600618.0001 and 600618.0002). These ETV6 mutant proteins were unable to
repress transcription and showed dominant-negative effects. The authors
also examined ETV6 protein expression in 77 patients with AML and found
that 24 (31%) lacked the wildtype 57- and 50-kD proteins; there was no
correlation between ETV6 mRNA transcript levels and the loss of ETV6
protein, suggesting posttranscriptional regulation of ETV6.

Lee et al. (2006) identified heterozygosity for mutations in the JAK2
gene (147796.0001 and 147796.0002) in bone marrow aspirates from 3
(2.7%) of 113 unrelated patients with AML.

Delhommeau et al. (2009) analyzed the TET2 gene (612839) in bone marrow
cells from 320 patients with myeloid cancers and identified TET2 defects
in 2 patients with primary AML and 5 patients with secondary AML.

Mardis et al. (2009) used massively parallel DNA sequencing to obtain a
very high level of coverage of a primary, cytogenetically normal, de
novo genome for AML with minimal maturation (AML-M1) and a matched
normal skin genome. Mardis et al. (2009) identified 12 somatic mutations
within the coding sequences of genes and 52 somatic point mutations in
conserved or regulatory portions of the genome. All mutations appeared
to be heterozygous and present in nearly all cells in the tumor sample.
Four of the 64 mutations occurred in at least 1 additional AML sample in
188 samples that were tested. Mutations in NRAS (164790) and NPM1
(164040) had been previously identified in patients with AML, but 2
other mutations had not been identified. One of these mutations, in the
IDH1 (147700) gene, was present in 15 of 187 additional AML genomes
tested and was strongly associated with normal cytogenetic status; it
was present in 13 of 80 cytogenetically normal samples (16%). The other
was a nongenic mutation in a genomic region with regulatory potential
and conservation in higher mammals; it is at position 108,115,590 of
chromosome 10. The AML genome that was sequenced contained approximately
750 point mutations, of which only a small fraction are likely to be
relevant to pathogenesis.

Gelsi-Boyer et al. (2009) presented evidence that the ASXL1 gene
(612990) may act as a tumor suppressor in myeloid malignancies. They
identified heterozygous somatic mutations in the ASXL1 gene in 5 (16%)
of 38 myelodysplastic syndrome/acute myeloid leukemia samples. Somatic
ASXL1 mutations were also found in 19 (43%) of 44 chronic myelomonocytic
leukemia (CMML; see 607785) samples. All the mutations were in exon 12
and resulted in truncation of the C-terminal PHD finger of the protein.
The findings suggested that regulators of gene expression via DNA
methylation, histone modification, and chromatin remodeling could be
altered in myelodysplastic syndromes and some leukemias. The same group
(Carbuccia et al., 2009) identified heterozygous somatic truncating
ASXL1 mutations in 5 (7.8%) of 64 myeloproliferative neoplasms,
including 1 essential thrombocythemia (187950), 3 primary myelofibrosis
(254450), and 1 AML.

Harutyunyan et al. (2011) analyzed biopsy specimens of
myeloproliferative neoplastic tissue from 330 patients for chromosomal
aberrations associated with leukemic transformation. Three hundred and
eight of the patients had chronic-phase myeloproliferative neoplasms and
22 had postmyeloproliferative-phase neoplasm secondary acute myeloid
leukemia. Among those 22 patients, 1 carried the MPL W515L mutation and
all others carried the JAK2 V617F mutation. Six of the 22 patients
carried somatic mutations of TP53 (191170). Three of the patients had
independent mutations on both TP53 alleles, and 2 had homozygous
mutations because of an acquired uniparental disomy of chromosome 17p.
None of the patients with TP53 mutations had amplification of chromosome
1q involving the MDM4 gene (604704). Harutyunyan et al. (2011) concluded
that TP53 mutations are strongly associated with transformation to AML
in patients with myeloproliferative neoplasms (p = 0.003). Harutyunyan
et al. (2011) also found amplification of a region of chromosome 1q
harboring the MDM4 gene in 18.18% of patients with secondary AML (p less
than 0.001).

Ding et al. (2012) determined the mutational spectrum associated with
relapse of AML by sequencing the primary tumor and relapse genomes from
8 AML patients, and validated hundreds of somatic mutations using deep
sequencing. This method allowed them to define clonality and clonal
evolution patterns precisely at relapse. In addition to discovering
novel, recurrently mutated genes (e.g., WAC; SMC3, 606062; DIS3, 607533;
DDX41, 608170; and DAXX, 603186) in AML, Ding et al. (2012) identified 2
major clonal evolution patterns during AML relapse: (1) the founding
clone in the primary tumor gained mutations and evolved into the relapse
clone, or (2) a subclone of the founding clone survived initial therapy,
gained additional mutations, and expanded at relapse. In all cases,
chemotherapy failed to eradicate the founding clone. The comparison of
relapse-specific versus primary tumor mutations in all 8 cases revealed
an increase in transversions, probably due to DNA damage caused by
cytotoxic chemotherapy. Ding et al. (2012) concluded that AML relapse is
associated with the addition of new mutations and clonal evolution,
which is shaped, in part, by the chemotherapy that the patients receive
to establish and maintain remissions.

The Cancer Genome Atlas Research Network (2013) analyzed the genomes of
200 clinically annotated adult cases of de novo AML, using either
whole-genome sequencing (50 cases) or whole-exome sequencing (150
cases), along with RNA and microRNA sequencing and DNA methylation
analysis. A total of 23 genes were significantly mutated, and another
237 were mutated in 2 or more samples. Nearly all samples had at least 1
nonsynonymous mutation in 1 of 9 categories of genes that were deemed
relevant for pathogenesis. The authors identified recurrent mutations in
the NPM1 gene in 54/200 (27%) samples, in the FLT3 gene (136351) in
56/200 (28%) samples, in the DNMT3A gene (602769) in 51/200 (26%)
samples, and in the IDH1 or IDH2 (147650) genes in 39/200 (20%) samples.

Brewin et al. (2013) noted that the study of the Cancer Genome Atlas
Research Network (2013) did not reveal which mutations occurred in the
founding clone, as would be expected for an initiator of disease, and
which occurred in minor clones, which subsequently drive disease. Miller
et al. (2013) responded that genes mutated almost exclusively in
founding clones in their study included RUNX1 (151385) (9 of 9 mutations
in founding clones), NPM1 (164040) (3 of 3 clones), U2AF1 (191317) (5 of
5 clones), DNMT3A (38 of 40 clones), IDH2 (13 of 14), IDH1 (147700) (15
of 17 clones), and KIT (164920) (5 of 6). In contrast, mutations in
NRAS, TET2 (612839), CEBPA, WT1 (607102), PTPN11 (176876), and FLT3 were
often found in subclones, suggesting that they were often cooperating
mutations.

GENOTYPE/PHENOTYPE CORRELATIONS

Schlenk et al. (2008) studied 872 patients younger than 60 years of age
with cytogenetically normal AML and compared mutation status of the NPM1
(164040), FLT3 (136351), CEBPA (116897), MLL (159555), and NRAS (164790)
genes in leukemia cells with clinical outcome. There was an overall
complete remission rate of 77%. The genotype of mutant NPM1 without FLT3
internal tandem duplications (FLT3-ITD), the mutant CEBPA genotype, and
younger age were each significantly associated with complete remission.
The authors also found that the benefit of postremission hematopoietic
stem cell transplant was limited to the subgroup of patients with the
prognostically adverse genotype FLT3-ITD or the genotype consisting of
wildtype NPM1 and CEBPA without FLT3-ITD.

Gale et al. (2008) found that 354 (26%) of 1,425 patients with AML had
the FLT3 internal duplication. The median total mutant level for all
patients was 35% of total FLT3, but there was wide variation with levels
ranging from 1 to 96%. There was a significant correlation between worse
overall survival, relapse risk, and increased white blood cell count
with increased mutant level, but the size of the duplication and the
number of mutations had no significant impact on outcome. Those patients
with the FLT3 duplication had a worse risk of relapse than patients
without the FLT3 duplication. Among a subset of 1,217 patients, 503
(41%) had a mutation in the NPM1 gene (164040), and 208 (17%) had
mutations in both genes. The presence of an NPM1 mutation had a
beneficial effect on the remission rate, most likely due to a lower rate
of resistant disease, both in patients with and without FLT3
duplications. Gale et al. (2008) identified 3 prognostic groups among
AML patients: good in those with only a NPM1 mutation; intermediate in
those with either no FLT3 or NPM1 mutations or mutations in both genes;
and poor in those with only FLT3 mutations.

Boissel et al. (2011) reviewed the work of several others and performed
their own analysis of 205 patients with cytogenetically normal AML, and
found that patients with IDH2(R172) mutations had a worse prognosis from
those with IDH2(R140) mutations (e.g., 147650.0001). That patients with
IDH2(R172) mutations had an unfavorable prognosis by comparison had been
noted by Marcucci et al. (2010). The frequency of IDH2(R172) mutations
was lower than that of IDH2(R140) mutations among cytogenetically normal
AML patients. Boissel et al. (2011) cautioned that patients should be
separated by mutation status for prognostic analysis.

Activating internal tandem duplication (ITD) mutations in FLT3
(FLT3-ITD) are detected in approximately 20% of acute myeloid leukemia
patients and are associated with a poor prognosis. Abundant laboratory
and clinical evidence, including the lack of convincing clinical
activity of early FLT3 inhibitors, suggested that FLT3-ITD probably
represents a passenger lesion. Smith et al. (2012) reported point
mutations at 3 residues within the kinase domain of FLT3-ITD that confer
substantial in vitro resistance to AC220 (quizartinib), an active
investigational inhibitor of FLT3, KIT (164920), PDGFRA (173490), PDGFRB
(173410), and RET (164761); evolution of AC220-resistant substitutions
at 2 of these amino acids was observed in 8 of 8 FLT3-ITD-positive AML
patients with acquired resistance to AC220. Smith et al. (2012)
concluded that their findings demonstrated that FLT3-ITD can represent a
driver lesion and valid therapeutic target in human AML.

ANIMAL MODEL

Jin et al. (2006) found that treatment with activating monoclonal
antibodies to CD44 (107269) markedly reduced leukemic repopulation in
nonobese diabetic (NOD)/severe combined immunodeficiency (SCID) mice
challenged with human AML cells. Absence of leukemia following serial
tumor transplantation experiments in mice demonstrated direct targeting
of AML leukemic stem cells (LSCs). Treatment of engrafted mice with
anti-CD44 reduced the number of Cd34 (142230)-positive/Cd38
(107270)-negative primitive stem cells and increased the number of Cd14
(158120)-positive monocytic cells. Anti-CD44 treatment also diminished
the homing capacity of SCID leukemia-initiating cells to bone marrow and
spleen. Jin et al. (2006) concluded that CD44 is a key regulator of AML
LSCs, which require a niche to maintain their stem cell properties. They
suggested that CD44 targeting may help eliminate quiescent AML LSCs.

Mullican et al. (2007) generated Nr4a1 (139139)/Nr4a3 (600542)
double-null mice and observed the development of rapidly lethal acute
myeloid leukemia involving abnormal expansion of hematopoietic stem
cells and myeloid progenitors, decreased expression of JunB (165161) and
c-Jun (165160), and defective extrinsic apoptotic signaling (FASL,
134638; TRAIL, 603598). Leukemic blast cells from 46 AML patients with a
variety of cytogenetic abnormalities all showed downregulation of NR4A1
and NR4A3 compared to CD34+ cells from normal controls, suggesting that
epigenetic silencing of these receptors may be an obligate event in
human AML development.

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Fujimi, A.; Akiyama, T.; Kuroda, H.; Kawano, Y.; Kobune, M.; Kato,
J.; Hirayama, Y.; Sakamaki, S.; Kohda, K.; Miyake, K.; Niitsu, Y.
: Interaction between leukemic-cell VLA-4 and stromal fibronectin
is a decisive factor for minimal residual disease of acute myelogenous
leukemia. Nature Med. 9: 1158-1165, 2003. Note: Erratum: Nature
Med. 11: 578 only, 2005.

28. Miller, C. A.; Wilson, R. K.; Ley, T. J.: Reply to Brewin et
al. (Letter) New Eng. J. Med. 369: 1473 only, 2013.

29. Mullican, S. E.; Zhang, S.; Konopleva, M.; Ruvolo, V.; Andreeff,
M.; Milbrandt, J.; Conneely, O. M.: Abrogation of nuclear receptors
Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nature
Med. 13: 730-735, 2007.

30. Schlenk, R. F.; Dohner, K.; Krauter, J.; Frohling, S.; Corbacioglu,
A.; Bullinger, L.; Habdank, M.; Spath, D.; Morgan, M.; Benner, A.;
Schlegelberger, B.; Heil, G.; Ganser, A.; Dohner, H.: Mutations and
treatment outcome in cytogenetically normal acute myeloid leukemia. New
Eng. J. Med. 358: 1909-1918, 2008.

31. Shields, J. A.; Stopyra, G. A.; Marr, B. P.; Shields, C. L.; Pan,
W.; Eagle, R. C., Jr.; Bernstein, J.: Bilateral orbital myeloid sarcoma
as initial sign of acute myeloid leukemia: case report and review
of the literature. Arch. Ophthal. 121: 138-142, 2003.

32. Smith, C. C.; Wang, Q.; Chin, C.-S.; Salerno, S.; Damon, L. E.;
Levis, M. J.; Perl, A. E.; Travers, K. J.; Wang, S.; Hunt, J. P.;
Zarrinkar, P. P.; Schadt, E. E.; Kasarskis, A.; Kuriyan, J.; Shah,
N. P.: Validation of ITD mutations in FLT3 as a therapeutic target
in human acute myeloid leukaemia. Nature 485: 260-263, 2012.

33. Smith, M. L.; Cavenagh, J. D.; Lister, T. A.; Fitzgibbon, J.:
Mutation of CEBPA in familial acute myeloid leukemia. New Eng. J.
Med. 351: 2403-2407, 2004.

34. Venstrom, J. M.; Pittari, G.; Gooley, T. A.; Chewning, J. H.;
Spellman, S.; Haagenson, M.; Gallagher, M. M.; Malkki, M.; Petersdorf,
E.; Dupont, B.; Hsu, K. C.: HLA-C-dependent prevention of leukemia
relapse by donor activating KIR2DS1. New Eng. J. Med. 367: 805-816,
2012.

*FIELD* CS

Heme:
Familial acute myelogenous leukemia (AML)

Misc:
Evidence of anticipation;
Mean onset age 57 years, 32 years and 13 years in successive generations

Inheritance:
Autosomal dominant

*FIELD* CD
John F. Jackson: 09/23/1998

*FIELD* CN
Ada Hamosh - updated: 11/25/2013
Ada Hamosh - updated: 7/9/2013
Ada Hamosh - updated: 9/6/2012
Cassandra L. Kniffin - updated: 8/2/2012
Ada Hamosh - updated: 6/27/2012
Ada Hamosh - updated: 2/8/2012
Marla J. F. O'Neill - updated: 11/2/2011
Ada Hamosh - updated: 10/4/2011
Cassandra L. Kniffin - updated: 5/4/2011
Ada Hamosh - updated: 2/15/2011
Cassandra L. Kniffin - updated: 12/16/2010
Cassandra L. Kniffin - updated: 10/6/2009
Ada Hamosh - updated: 9/15/2009
Marla J. F. O'Neill - updated: 6/10/2009
Cassandra L. Kniffin - updated: 7/30/2008
Patricia A. Hartz - updated: 6/9/2008
Marla J. F. O'Neill - updated: 5/14/2008
Cassandra L. Kniffin - updated: 3/26/2008
Marla J. F. O'Neill - updated: 7/2/2007
Paul J. Converse - updated: 11/17/2006
Cassandra L. Kniffin - updated: 6/20/2006
Marla J. F. O'Neill - updated: 4/12/2006
Ada Hamosh - updated: 8/26/2003
Victor A. McKusick - updated: 11/17/1999

*FIELD* CD
Moyra Smith: 1/14/1997

*FIELD* ED
carol: 12/06/2013
alopez: 11/25/2013
alopez: 7/9/2013
alopez: 4/15/2013
alopez: 9/10/2012
terry: 9/6/2012
carol: 8/6/2012
ckniffin: 8/2/2012
alopez: 7/3/2012
terry: 6/27/2012
alopez: 2/10/2012
terry: 2/8/2012
carol: 1/30/2012
carol: 11/2/2011
ckniffin: 10/24/2011
alopez: 10/11/2011
terry: 10/7/2011
terry: 10/4/2011
wwang: 5/19/2011
wwang: 5/11/2011
ckniffin: 5/4/2011
ckniffin: 5/2/2011
alopez: 2/17/2011
terry: 2/15/2011
carol: 12/16/2010
ckniffin: 12/16/2010
carol: 7/2/2010
alopez: 1/28/2010
wwang: 10/14/2009
ckniffin: 10/6/2009
alopez: 9/16/2009
terry: 9/15/2009
wwang: 6/12/2009
terry: 6/10/2009
ckniffin: 6/9/2009
wwang: 12/5/2008
ckniffin: 12/3/2008
mgross: 10/9/2008
wwang: 8/1/2008
ckniffin: 7/30/2008
mgross: 6/9/2008
carol: 5/14/2008
wwang: 4/8/2008
ckniffin: 3/26/2008
wwang: 7/5/2007
terry: 7/2/2007
ckniffin: 3/1/2007
mgross: 11/17/2006
wwang: 6/23/2006
ckniffin: 6/20/2006
wwang: 4/12/2006
terry: 4/12/2006
mgross: 5/17/2005
tkritzer: 2/7/2005
alopez: 9/2/2003
alopez: 8/26/2003
terry: 8/26/2003
carol: 11/13/2001
mgross: 12/6/1999
terry: 11/17/1999
mark: 1/14/1997

MIM 606764
*RECORD*
*FIELD* NO
606764
*FIELD* TI
#606764 GASTROINTESTINAL STROMAL TUMOR; GIST
*FIELD* TX
A number sign (#) is used with this entry because gastrointestinal
read morestromal tumors (GISTs) can be caused by heterozygous mutation in the KIT
gene (164920) on chromosome 4q12, the PDGFRA gene (173490) on chromosome
4q12, the SDHB gene (185470) on chromosome 1p36, or the SDHC gene
(602413) on chromosome 1q23.

DESCRIPTION

Gastrointestinal stromal tumors are mesenchymal tumors found in the
gastrointestinal tract that originate from the interstitial cells of
Cajal, the pacemaker cells that regulate peristalsis in the digestive
tract. Approximately 70% of GISTs develop in the stomach, 20% in the
small intestine, and less than 10% in the esophagus, colon, and rectum.
GISTs are typically more cellular than other gastrointestinal sarcomas.
They occur predominantly in patients who are 40 to 70 years old but in
rare cases may occur in younger persons (Miettinen et al., 1999, 1999).

GISTs can also be seen in neurofibromatosis-1 (NF1; 162200) due to
mutations in the NF1 gene, and are thus distinct from the GISTs
described here.

Sandberg and Bridge (2002) reviewed the cytogenetics and molecular
genetics of gastrointestinal stromal tumors. Coffey et al. (2007)
reviewed the clinical features, pathogenesis, and molecular treatments
of Menetrier disease (137280) and GIST, both of which are
hyperproliferative disorders of the stomach caused by dysregulated
receptor tyrosine kinases.

CLINICAL FEATURES

Lipton and Zuckerbrod (1966) described familial intestinal
neurofibromatosis without other features of neurofibromatosis-1.

Verhest et al. (1981) described a Belgian family in which several
individuals had 'intestinal neurofibromatosis.' In a follow-up of this
family, Heimann et al. (1988) reported that onset of symptoms was in
adulthood and that some gene carriers remained asymptomatic into middle
and late adulthood. A reciprocal balanced chromosomal translocation
involving chromosomes 12 and 14 was identified, but did not segregate
completely with the disorder and was thus considered to be a fortuitous
finding (Verhest et al., 1988). Verhest et al. (1988) concluded that the
disorder in this family was phenotypically distinct from NF1. De Raedt
et al. (2006) provided further analysis of the Belgian family reported
by Verhest et al. (1981) and Heimann et al. (1988). There were 5
affected members, including 3 living sisters who were examined. All had
benign intestinal tumors, constipation, large hands, and coarse facies,
and 2 had bowel obstruction necessitating several surgical
interventions. Five tumors from 1 sister were available for pathologic
investigation and showed a moderately cellular spindle cell
proliferation with a typical wavy nature of a collagenous background.
Although the histology was suggestive of neurofibromas, S100 protein
expression was negative. Further studies showed negative staining for
CD34 (142230), DOG1 (605882), and KIT. Genetic analysis revealed a
germline mutation in the PDGFRA gene (173490.0010) in all 3 sisters.

Nishida et al. (1998) reported a Japanese family in which 7 individuals
spanning 4 generations had multiple GISTs. Inheritance was autosomal
dominant. Most tumors were benign, but 1 patient had a malignant GIST.
Two individuals reportedly had hyperpigmentation of the perineum.
Nishida et al. (1998) noted that a woman reported by el-Omar et al.
(1994) with multiple tumors that were probably GISTs also had
hyperpigmentation of the perineal skin. In addition, Marshall et al.
(1990) reported a family in which several members suffered from benign
GISTs associated with either systemic mast cell disease or urticaria
pigmentosa, which is cutaneous mastocytosis.

Isozaki et al. (2000) reported a French mother and son, 67 and 40 years
old, respectively, with multiple macroscopic GISTs, measuring from 1 to
8 cm, in duodenum and jejunum. All tumors examined were of low
malignancy grade and neither patient had metastases.

Beghini et al. (2001) described an Italian family in which the mother
had hyperpigmented spots and developed multiple GISTs with diffuse
hyperplasia of the myenteric plexus, and her son had urticaria
pigmentosa.

Chompret et al. (2004) reported a French family in which 5 individuals
developed multiple GISTs between 40 and 60 years of age. None had
hyperpigmentation, mast cell disorders, or dysphagia, but all 5 had
large hands, which was not present in unaffected family members.

Pasini et al. (2007) reported a woman with GISTs and other mesenchymal
tumors. She developed intestinal obstruction at age 32 years and was
found to have multiple mesenchymal fibroid intestinal tumors. Tumor
tissue showed multiple secondary genetic changes, including loss of
heterozygosity of several chromosomal regions such as 14q. Of note, the
patient had a history of a duodenal lipoma, which had not previously
been reported in patients with GISTs. Genetic analysis identified a
germline mutation in the PDGFRA gene (V561D; 173490.0004).

PATHOGENESIS

Until about 1990, most gastrointestinal sarcomas were considered to be
leiomyosarcomas because they resembled smooth muscle histologically.
However, clinical oncologists observed a distinctly lower rate of
response to standard doxorubicin-based regimens among leiomyosarcomas
that arose in the gut than among those that arose in the uterus, trunk,
or arms and legs. As early as 1983 immunocytochemical studies of
gastrointestinal sarcomas documented their frequent absence of muscle
markers that were typical of leiomyosarcomas located elsewhere in the
body. Tumors in the subgroup without muscle or Schwann-cell (i.e., S100
antigen) markers were eventually termed gastrointestinal stromal tumors.
Almost all of these tumors expressed KIT (164920) and often CD34, both
of which are also expressed on hematopoietic progenitor cells (Miettinen
et al., 1999, 1999).

Chi et al. (2010) demonstrated that ETV1 (600541) is highly expressed in
the subtypes of interstitial cells of Cajal (ICCs) sensitive to
oncogenic KIT-mediated transformation, and is required for their
development. In addition, ETV1 is universally highly expressed in GISTs
and is required for growth of imatinib-sensitive and -resistant GIST
cell lines. Transcriptome profiling and global analyses of ETV1-binding
sites suggested that ETV1 is a master regulator of an ICC-GIST-specific
transcription network mainly through enhancer binding. The ETV1
transcriptional program is further regulated by activated KIT, which
prolongs ETV1 protein stability and cooperates with ETV1 to promote
tumorigenesis. Chi et al. (2010) proposed that GIST arises from ICCs
with high levels of endogenous ETV1 expression that, when coupled with
an activating KIT mutation, drives an oncogenic ETS transcriptional
program. This model differs from other ETS-dependent tumors such as
prostate cancer, melanoma, and Ewing sarcoma where genomic translocation
or amplification drives aberrant ETS expression. Chi et al. (2010) also
stated that this model of GIST pathogenesis represents a novel mechanism
of oncogenic transcription factor activation.

Janeway et al. (2011) evaluated SDHB (185470) expression in 30 GISTs
lacking KIT or PDGFRA mutations, 25 of which were also negative for
associated SDH mutations confirmed by sequence analysis.
Immunohistochemical studies showed lack of SDHB staining in 18 (100%) of
18 pediatric tumors, regardless of SDH mutation status, and in 8 (67%)
of 12 adult tumors and weak expression in 4 (33%) of 12 adult tumors. By
comparison, only 1 of 18 KIT-mutant GISTs and 0 of 5 NF1-associated
GISTs lacked SDHB expression. These findings implicated a defect in
respiration in the pathogenesis of some GIST tumors.

CLINICAL MANAGEMENT

Imatinib, formerly referred to as STI571, is an inhibitor of specific
protein tyrosine kinases. It is highly effective in the treatment of
both chronic myeloid leukemia (CML; 608232) and GISTs (Savage and
Antman, 2002). Joensuu et al. (2001) described a Finnish patient with
metastatic gastrointestinal stromal tumor who had a rapid and sustained
complete response to treatment with imatinib daily for more than 12
months.

Balachandran et al. (2011) found that KIT val558del mice (Sommer et al.,
2003) treated with imatinib had a rapid decrease in tumor weight and
activity. This was associated with an increase in the number of
activated CD8+ T cells and a decrease in the number of regulatory T
cells within the tumor. Gene expression array indicated that these
changes were mediated by reducing expression of the immunosuppressive
enzyme IDO (147435) in tumor cells, whereas the expression of other
immunomodulatory cytokines was not changed. In human GIST cells,
imatinib inhibited KIT activation and IDO expression; IDO expression was
also found to be regulated by mTOR (601231) and ETV4 (600711). In human
GIST specimens, the CD8+ T cell profile correlated with sensitivity to
imatinib and decreased IDO expression. Finally, in mice, concurrent
immunotherapy using CTLA4 (123890) blockade augmented the efficacy of
imatinib in GIST. The findings indicated that T cells are crucial to the
antitumor effects of imatinib in GIST, and suggested that concomitant
immunotherapy may further improve outcomes in human cancers treated with
targeted agents.

MOLECULAR GENETICS

- Germline Mutations

In affected members of a Japanese family with multiple GISTs, Nishida et
al. (1998) identified a germline deletion in the KIT gene (164920.0017).

In a French mother and son with multiple GISTs, Isozaki et al. (2000)
identified a gain-of-function germline mutation in the KIT gene (K642E;
164920.0024).

In an Italian woman with multiple GISTs and hyperpigmented spots,
Beghini et al. (2001) identified a germline mutation in the KIT gene
(V559A; 164920.0023). Her son, who had urticaria pigmentosa, also
carried the mutation.

In affected members of a French family with GISTs, Chompret et al.
(2004) identified a heterozygous germline mutation in the PDGFRA gene
(173490.0009).

Janeway et al. (2011) identified 3 germline mutations in the SDHB gene
(see, e.g., 185470.0004) in 3 different patients with sporadic
occurrence of GIST. The patients were 18, 22, and 21 years old, and none
had a personal or family history of paragangliomas. Tumor tissue
available from 2 of these patients showed lack of SDHB immunostaining. A
fourth patient, who was 16 years old, carried a germline mutation in the
SDHC gene (602413.0004). Overall, mutations in SDH subunit genes
accounted for 4 (12%) of 34 patients with isolated GIST lacking KIT or
PDGFRA mutations.

- Somatic Mutations

Hirota et al. (1998) identified somatic gain-of-function mutations in
the KIT gene (see, e.g., 164920.0011-164920.0015) in 5 of 6 GISTs. Most
GISTs were solitary and the mutations resulted in constitutive
activation of the KIT gene. Miettinen et al. (1999) stated that
gastrointestinal stromal tumors with mutant KIT were more likely to be
high-grade tumors, characterized by more frequent recurrences and a
higher mortality rate compared to gastrointestinal stromal tumors with
normal KIT.

Heinrich et al. (2003) found that approximately 35% (14 of 40) of GISTs
lacking KIT mutations had somatic intragenic activation mutations in the
PDGFRA gene (see, e.g., 173490.0001-173490.0007). Tumors expressing KIT
or PDGFRA oncoproteins were indistinguishable with respect to activation
of downstream signaling intermediates and cytogenetic changes associated
with tumor progression. Heinrich et al. (2003) concluded that KIT and
PDGFRA mutations appear to be alternative and mutually exclusive
oncogenic mechanisms in GISTs.

- Modifier Genes

Delahaye et al. (2011) found an association between alternatively
spliced exon 4 isoforms of the NCR3 gene (611550) and prognosis in GIST.
In a study of 44 GIST tumors, tumor-infiltrating NK cells showed
downregulation of NCR3 compared to circulating cells of healthy
volunteers. The density of the NK cell infiltrate was inversely
correlated with the presence of metastasis at diagnosis, suggesting an
NK cell-mediated immunosurveillance mechanism in these tumors. RT-PCR
studies of peripheral blood from 80 patients with GIST showed
preferential expression of the immunosuppressive NCR3c isoform in 53%,
compared to healthy volunteers, of whom only 30% expressed isoform NCR3c
(p = 0.02). NK cells from GIST patients with the NCR3c isoform showed a
defect in NCR3-driven NK effector functions. A retrospective analysis of
80 GIST patients treated with imatinib showed decreased overall survival
in those with the NRC3c isoform compared to those with NRC3a and NRC3b
isoforms (p = 0.001). Delahaye et al. (2011) also found an association
between a 3790T-C SNP (dbSNP rs986475) in the promoter region of the
NCR3 gene, as well as other SNPs, and expression of the NCR3c isoform.
The findings suggested that the genetically determined NCR3 status may
predict clinical outcome in patients with GIST.

GENOTYPE/PHENOTYPE CORRELATIONS

Patients with familial GISTs usually have multiple tumors; those with
germline mutations in the KIT gene may also have hyperpigmentation, mast
cell tumors, or dysphagia, whereas those with mutations in the PDGFRA
gene often have large hands (Chompret et al., 2004).

NOMENCLATURE

The form of familial GIST previously referred to as 'intestinal
neurofibromatosis' and symbolized NF3B (or NF3) should not be confused
with neurofibromatosis type III of Riccardi (162260), designated NF3A
(or NF3).

ANIMAL MODEL

In a review, Coffey et al. (2007) stated that gain-of-function mutations
in Kit lead to GIST in mice.

Sommer et al. (2003) generated a mouse model of GIST by knockin of a Kit
exon 11-activating mutation, val558del, which corresponds to a val559del
mutation (164920.0017) found in human familial GISTs. Heterozygous male
and female mice were fertile, but fertility was impaired with increasing
age. Heterozygous mice developed symptoms of disease and eventually died
from pathology in the GI tract. Patchy hyperplasia of Kit-positive cells
was evident within the myenteric plexus of the entire GI tract.
Neoplastic lesions indistinguishable from human GISTs were observed in
the cecum of the mutant mice with high penetrance. In addition, mast
cell numbers in the dorsal skin were increased. Sommer et al. (2003)
concluded that mice heterozygous for a val558 deletion in the Kit gene
reproduce human familial GISTs and may be used as a model for studying
the role and mechanisms of Kit in neoplasia. Importantly, these results
demonstrated that constitutive Kit signaling is critical and sufficient
for induction of GIST and hyperplasia of interstitial cells of Cajal.

*FIELD* RF
1. Balachandran, V. P.; Cavnar, M. J.; Zeng, S.; Bamboat, Z. M.; Ocuin,
L. M.; Obaid, H.; Sorenson, E. C.; Popow, R.; Ariyan, C.; Rossi, F.;
Besmer, P.; Guo, T.; Antonescu, C. R.; Taguchi, T.; Yuan, J.; Wolchok,
J. D.; Allison, J. P.; DeMatteo, R. P.: Imatinib potentiates antitumor
T cell responses in gastrointestinal stromal tumor through the inhibition
of Ido. Nature Med. 17: 1094-1100, 2011.

2. Beghini, A.; Tibiletti, M.; Roversi, G.; Chiaravalli, A.; Serio,
G.; Capella, C.; Larizza, L.: Germline mutation in the juxtamembrane
domain of the KIT gene in a family with gastrointestinal stromal tumors
and urticaria pigmentosa. Cancer 92: 657-662, 2001.

3. Chi, P.; Chen, Y.; Zhang, L.; Guo, X.; Wongvipat, J.; Shamu, T.;
Fletcher, J. A.; Dewell, S.; Maki, R. G.; Zheng, D.; Antonescu, C.
R.; Allis, C. D.; Sawyers, C. L.: ETV1 is a lineage survival factor
that cooperates with KIT in gastrointestinal stromal tumours. Nature 467:
849-853, 2010.

4. Chompret, A.; Kannengiesser, C.; Barrois, M.; Terrier, P.; Dahan,
P.; Tursz, T.; Lenoir, G. M.; Bressac-De Paillerets, B.: PDGFRA germline
mutation in a family with multiple cases of gastrointestinal stromal
tumor. Gastroenterology 126: 318-321, 2004.

5. Coffey, R. J.; Washington, M. K.; Corless, C. L.; Heinrich, M.
C.: Menetrier disease and gastrointestinal stromal tumors: hyperproliferative
disorders of the stomach. J. Clin. Invest. 117: 70-80, 2007.

6. Delahaye, N. F.; Rusakiewicz, S.; Martins, I.; Menard, C.; Roux,
S.; Lyonnet, L.; Pascale, P.; Sarabi, M.; Chaput, N.; Semeraro, M.;
Minard-Colin, V.; Poirier-Colame, V.; and 29 others: Alternatively
spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal
tumors. Nature Med. 17: 700-707, 2011.

7. De Raedt, T.; Cools, J.; Debiec-Rychter, M.; Brems, H.; Mentens,
N.; Sciot, R.; Himpens, J.; De Wever, I.; Schoffski, P.; Marynen,
P.; Legius, E.: Intestinal neurofibromatosis is a subtype of familial
GIST and results from a dominant activating mutation in PDGFRA. Gastroenterology 131:
1907-1912, 2006.

8. el-Omar, M.; Davies, J.; Gupta, S.; Ross, H.; Thompson, R.: Leiomyosarcoma
in leiomyomatosis of the small intestine. Postgrad. Med. J. 70:
661-664, 1994.

9. Heimann, R.; Verhest, A.; Verschraegen, J.; Grosjean, W.; Draps,
J. P.; Hecht, F.: Hereditary intestinal neurofibromatosis. I. A distinctive
genetic disease. Neurofibromatosis 1: 26-32, 1988.

10. Heinrich, M. C.; Corless, C. L.; Duensing, A.; McGreevey, L.;
Chen, C.-J.; Joseph, N.; Singer, S.; Griffith, D. J.; Haley, A.; Town,
A.; Demetri, G. D.; Fletcher, C. D. M.; Fletcher, J. A.: PDGFRA activating
mutations in gastrointestinal stromal tumors. Science 299: 708-710,
2003.

11. Hirota, S.; Isozaki, K.; Moriyama, Y.; Hashimoto, K.; Nishida,
T.; Ishiguro, S.; Kawano, K.; Hanada, M.; Kurata, A.; Takeda, M.;
Tunio, G. M.; Matsuzawa, Y.; Kanakura, Y.; Shinomura, Y.; Kitamura,
Y.: Gain-of-function mutations of c-kit in human gastrointestinal
stromal tumors. Science 279: 577-580, 1998.

12. Isozaki, K.; Terris, B.; Belghiti, J.; Schiffmann, S.; Hirota,
S.; Vanderwinden, J.-M.: Germline-activating mutation in the kinase
domain of KIT gene in familial gastrointestinal stromal tumors. Am.
J. Path. 157: 1581-1585, 2000.

13. Janeway, K. A.; Kim, S. Y.; Lodish, M.; Nose, V.; Rustin, P.;
Gaal, J.; Dahia, P. L. M.; Liegl, B.; Ball, E. R.; Raygada, M.; Lai,
A. H.; Kelly, L.; and 10 others: Defects in succinate dehydrogenase
in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc.
Nat. Acad. Sci. 108: 314-318, 2011.

14. Joensuu, H.; Roberts, P. J.; Sarlomo-Rikala, M.; Andersson, L.
C.; Tervahartiala, P.; Tuveson, D.; Silberman, S. L.; Capdeville,
R.; Dimitrijevic, S.; Druker, B.; Demetri, G. D.: Effect of the tyrosine
kinase inhibitor STI571 in a patient with a metastatic gastrointestinal
stromal tumor. New Eng. J. Med. 344: 1052-1056, 2001.

15. Lipton, S.; Zuckerbrod, M.: Familial enteric neurofibromatosis. Med.
Times 94: 544-548, 1966.

16. Marshall, J. B.; Diaz-Arias, A. A.; Bochna, G. S.; Vogele, K.
A.: Achalasia due to diffuse esophageal leiomyomatosis and inherited
as an autosomal dominant disorder. Gastroenterology 98: 1358-1365,
1990.

17. Miettinen, M.; Monihan, J. M.; Sarlomo-Rikala, M.; Kovatich, A.
J.; Carr, N. J.; Emory, T. S.; Sobin, L. H.: Gastrointestinal stromal
tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery:
clinicopathologic and immunohistochemical study of 26 cases. Am.
J. Surg. Path. 23: 1109-1118, 1999.

18. Miettinen, M.; Sarlomo-Rikala, M.; Lasota, J.: Gastrointestinal
stromal tumors: recent advances in understanding of their biology. Hum.
Path. 30: 1213-1220, 1999.

19. Nishida, T.; Hirota, S.; Taniguchi, M.; Hashimoto, K.; Isozaki,
K.; Nakamura, H.; Kanakura, Y.; Tanaka, T.; Takabayashi, A.; Matsuda,
H.; Kitamura, Y.: Familial gastrointestinal stromal tumours with
germline mutation of the KIT gene. (Letter) Nature Genet. 19: 323-324,
1998.

20. Pasini, B.; Matyakhina, L.; Bei, T.; Muchow, M.; Boikos, S.; Ferrando,
B.; Carney, J. A.; Stratakis, C. A.: Multiple gastrointestinal stromal
and other tumors caused by platelet-derived growth factor receptor-alpha
gene mutations: a case associated with a germline V561D defect. J.
Clin. Endocr. Metab. 92: 3728-3732, 2007.

21. Sandberg, A. A.; Bridge, J. A.: Updates on the cytogenetics and
molecular genetics of bone and soft tissue tumors: gastrointestinal
stromal tumors. Cancer Genet. Cytogenet. 135: 1-22, 2002. Note:
Erratum: Cancer Genet. Cytogenet. 137: 156 only, 2002.

22. Savage, D. G.; Antman, K. H.: Imatinib mesylate--a new oral targeted
therapy. New Eng. J. Med. 346: 683-693, 2002.

23. Sommer, G.; Agosti, V.; Ehlers, I.; Rossi, F.; Corbacioglu, S.;
Farkas, J.; Moore, M.; Manova, K.; Antonescu, C. R.; Besmer, P.:
Gastrointestinal stromal tumors in a mouse model by targeted mutation
of the Kit receptor tyrosine kinase. Proc. Nat. Acad. Sci. 100:
6706-6711, 2003.

24. Verhest, A.; Verschraegen, J.; Grosjean, W.; Draps, J. P.; Vamos,
E.; Heimann, R.; Hecht, F.: Hereditary intestinal neurofibromatosis.
II. Translocation between chromosomes 12 and 14. Neurofibromatosis 1:
33-36, 1988.

25. Verhest, A.; Verschraegen, J.; Grosjean, W.; Heimann, R.: Transmissible
chromosome abnormality in familial intestinal neurofibromatosis. (Abstract) Sixth
Int. Cong. Hum. Genet., Jerusalem 176 only, 1981.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Isolated cases

ABDOMEN:
[Gastrointestinal];
Gastrointestinal stromal tumors;
Pathology resembles neurofibromas;
Hyperplasia of the myenteric plexus;
Intestinal obstruction;
Constipation (reported in 1 family with a PDFGRA mutation);
Dysphagia

SKELETAL:
[Hands];
Large hands (in patients with PDGFRA mutations)

SKIN, NAILS, HAIR:
[Skin];
Hyperpigmentation (in patients with KIT mutations);
Urticaria pigmentosa or cutaneous mastocytosis (in patients with KIT
mutations)

MISCELLANEOUS:
Tumors usually develop between 40 and 60 years of age;
Both germline (familial) and somatic (sporadic) mutation in KIT (164920)
and PDGFRA (173490) have been found

MOLECULAR BASIS:
Caused by mutation in the V-KIT Hardy-Zuckerman 4 feline sarcoma viral
oncogene homolog gene (KIT, 164920.0011);
Caused by mutation in the platelet-derived growth factor receptor
alpha gene (PDGFRA, 173490.0001)

*FIELD* CD
Cassandra L. Kniffin: 4/2/2008

*FIELD* ED
joanna: 09/24/2011
wwang: 6/9/2011
joanna: 1/28/2009
ckniffin: 4/2/2008

*FIELD* CN
Cassandra L. Kniffin - updated: 12/15/2011
Cassandra L. Kniffin - updated: 9/6/2011
Cassandra L. Kniffin - updated: 6/2/2011
Ada Hamosh - updated: 11/11/2010
Cassandra L. Kniffin - updated: 4/2/2008
Marla J. F. O'Neill - updated: 4/11/2006
Ada Hamosh - updated: 2/13/2003
Victor A. McKusick - updated: 10/17/2002

*FIELD* CD
Victor A. McKusick: 3/15/2002

*FIELD* ED
terry: 12/20/2012
carol: 3/21/2012
terry: 3/21/2012
ckniffin: 12/15/2011
carol: 9/7/2011
ckniffin: 9/6/2011
wwang: 6/9/2011
ckniffin: 6/2/2011
alopez: 11/12/2010
terry: 11/11/2010
carol: 4/4/2008
ckniffin: 4/2/2008
mgross: 4/12/2007
carol: 4/13/2006
terry: 4/11/2006
alopez: 11/17/2003
tkritzer: 6/25/2003
alopez: 2/19/2003
terry: 2/13/2003
carol: 10/17/2002
terry: 6/26/2002
alopez: 3/15/2002

RBCC Red Blood Cell Collection

Full text data of KIT