RBCC Red Blood Cell Collection

HRAS (HRAS1) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
GTPase HRas (H-Ras-1; Ha-Ras; Transforming protein p21; c-H-ras; p21ras; GTPase HRas, N-terminally processed; Flags: Precursor)

UniProt P01112
ID RASH_HUMAN Reviewed; 189 AA.
AC P01112; B5BUA0; Q14080; Q6FHV9; Q9BR65; Q9UCE2;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 184.
DE RecName: Full=GTPase HRas;
DE AltName: Full=H-Ras-1;
DE AltName: Full=Ha-Ras;
DE AltName: Full=Transforming protein p21;
DE AltName: Full=c-H-ras;
DE AltName: Full=p21ras;
DE Contains:
DE RecName: Full=GTPase HRas, N-terminally processed;
DE Flags: Precursor;
GN Name=HRAS; Synonyms=HRAS1;
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 [GENOMIC DNA].
RX PubMed=6298635; DOI=10.1038/302033a0;
RA Capon D.J., Chen E.Y., Levinson A.D., Seeburg P.H., Goeddel D.V.;
RT "Complete nucleotide sequences of the T24 human bladder carcinoma
RT oncogene and its normal homologue.";
RL Nature 302:33-37(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6844927; DOI=10.1126/science.6844927;
RA Reddy E.P.;
RT "Nucleotide sequence analysis of the T24 human bladder carcinoma
RT oncogene.";
RL Science 220:1061-1063(1983).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6087347; DOI=10.1073/pnas.81.15.4771;
RA Sekiya T., Fushimi M., Hori H., Hirohashi S., Nishimura S.,
RA Sugimura T.;
RT "Molecular cloning and the total nucleotide sequence of the human c-
RT Ha-ras-1 gene activated in a melanoma from a Japanese patient.";
RL Proc. Natl. Acad. Sci. U.S.A. 81:4771-4775(1984).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, INTERACTION WITH
RP GNB2L1, SUBCELLULAR LOCATION, ALTERNATIVE SPLICING, TISSUE
RP SPECIFICITY, AND MUTAGENESIS OF SER-17.
RX PubMed=14500341;
RA Guil S., de La Iglesia N., Fernandez-Larrea J., Cifuentes D.,
RA Ferrer J.C., Guinovart J.J., Bach-Elias M.;
RT "Alternative splicing of the human proto-oncogene c-H-ras renders a
RT new Ras family protein that trafficks to cytoplasm and nucleus.";
RL Cancer Res. 63:5178-5187(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S.,
RA Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA Korn B., Zuo D., Hu Y., LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=19054851; DOI=10.1038/nmeth.1273;
RA Goshima N., Kawamura Y., Fukumoto A., Miura A., Honma R., Satoh R.,
RA Wakamatsu A., Yamamoto J., Kimura K., Nishikawa T., Andoh T., Iida Y.,
RA Ishikawa K., Ito E., Kagawa N., Kaminaga C., Kanehori K., Kawakami B.,
RA Kenmochi K., Kimura R., Kobayashi M., Kuroita T., Kuwayama H.,
RA Maruyama Y., Matsuo K., Minami K., Mitsubori M., Mori M.,
RA Morishita R., Murase A., Nishikawa A., Nishikawa S., Okamoto T.,
RA Sakagami N., Sakamoto Y., Sasaki Y., Seki T., Sono S., Sugiyama A.,
RA Sumiya T., Takayama T., Takayama Y., Takeda H., Togashi T., Yahata K.,
RA Yamada H., Yanagisawa Y., Endo Y., Imamoto F., Kisu Y., Tanaka S.,
RA Isogai T., Imai J., Watanabe S., Nomura N.;
RT "Human protein factory for converting the transcriptome into an in
RT vitro-expressed proteome.";
RL Nat. Methods 5:1011-1017(2008).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Lung carcinoma;
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 [12]
RP PROTEIN SEQUENCE OF 1-41; 43-117; 129-161 AND 170-185, CLEAVAGE OF
RP INITIATOR METHIONINE, ACETYLATION AT MET-1 AND THR-2, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RA Bienvenut W.V., Calvo F., Kolch W.;
RL Submitted (FEB-2008) to UniProtKB.
RN [13]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-37.
RX PubMed=6290897; DOI=10.1038/300143a0;
RA Tabin C.J., Bradley S.M., Bargmann C.I., Weinberg R.A.,
RA Papageorge A.G., Scolnick E.M., Dhar R., Lowy D.R., Chang E.H.;
RT "Mechanism of activation of a human oncogene.";
RL Nature 300:143-149(1982).
RN [14]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-16.
RX PubMed=3670300;
RA Honkawa H., Masahashi W., Hashimoto S., Hashimoto-Gotoh T.;
RT "Identification of the principal promoter sequence of the c-H-ras
RT transforming oncogene: deletion analysis of the 5'-flanking region by
RT focus formation assay.";
RL Mol. Cell. Biol. 7:2933-2940(1987).
RN [15]
RP PROTEIN SEQUENCE OF 108-117 AND 132-153.
RX PubMed=8393791; DOI=10.1111/j.1432-1033.1993.tb18056.x;
RA Loew A., Sprinzl M., Faulhammer H.G.;
RT "Affinity labeling of c-H-ras p21 consensus elements with periodate-
RT oxidized GDP and GTP.";
RL Eur. J. Biochem. 215:473-479(1993).
RN [16]
RP MUTAGENESIS OF ALA-83; ASP-119 AND THR-144.
RX PubMed=3088563; DOI=10.1073/pnas.83.13.4607;
RA Feig L.A., Pan B.-T., Roberts T.M., Cooper G.M.;
RT "Isolation of ras GTP-binding mutants using an in situ colony-binding
RT assay.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:4607-4611(1986).
RN [17]
RP MUTAGENESIS OF 164-ARG-GLN-165.
RX PubMed=3011420;
RA Lacal J.C., Anderson P.S., Aaronson S.A.;
RT "Deletion mutants of Harvey ras p21 protein reveal the absolute
RT requirement of at least two distant regions for GTP-binding and
RT transforming activities.";
RL EMBO J. 5:679-687(1986).
RN [18]
RP PALMITOYLATION AT CYS-181 AND CYS-184.
RX PubMed=2661017; DOI=10.1016/0092-8674(89)90054-8;
RA Hancock J.F., Magee A.I., Childs J.E., Marshall C.J.;
RT "All ras proteins are polyisoprenylated but only some are
RT palmitoylated.";
RL Cell 57:1167-1177(1989).
RN [19]
RP PALMITOYLATION AT CYS-181 AND CYS-184, ISOPRENYLATION AT CYS-186,
RP METHYLATION AT CYS-186, AND MUTAGENESIS OF CYS-181 AND CYS-184.
RX PubMed=8626715; DOI=10.1074/jbc.271.19.11541;
RA Dudler T., Gelb M.H.;
RT "Palmitoylation of Ha-Ras facilitates membrane binding, activation of
RT downstream effectors, and meiotic maturation in Xenopus oocytes.";
RL J. Biol. Chem. 271:11541-11547(1996).
RN [20]
RP S-NITROSYLATION AT CYS-118, FUNCTION, MASS SPECTROMETRY, AND
RP MUTAGENESIS OF CYS-118.
RX PubMed=9020151; DOI=10.1074/jbc.272.7.4323;
RA Lander H.M., Hajjar D.P., Hempstead B.L., Mirza U.A., Chait B.T.,
RA Campbell S., Quilliam L.A.;
RT "A molecular redox switch on p21(ras). Structural basis for the nitric
RT oxide-p21(ras) interaction.";
RL J. Biol. Chem. 272:4323-4326(1997).
RN [21]
RP INTERACTION WITH IKZF3.
RX PubMed=10369681; DOI=10.1093/emboj/18.12.3419;
RA Romero F., Martinez-A C., Camonis J., Rebollo A.;
RT "Aiolos transcription factor controls cell death in T cells by
RT regulating Bcl-2 expression and its cellular localization.";
RL EMBO J. 18:3419-3430(1999).
RN [22]
RP INTERACTION WITH RAPGEF2.
RX PubMed=10608844; DOI=10.1074/jbc.274.53.37815;
RA Liao Y., Kariya K., Hu C.-D., Shibatohge M., Goshima M., Okada T.,
RA Watari Y., Gao X., Jin T.-G., Yamawaki-Kataoka Y., Kataoka T.;
RT "RA-GEF, a novel Rap1A guanine nucleotide exchange factor containing a
RT Ras/Rap1A-associating domain, is conserved between nematode and
RT humans.";
RL J. Biol. Chem. 274:37815-37820(1999).
RN [23]
RP INTERACTION WITH PLCE1, CHARACTERIZATION OF VARIANT VAL-12, AND
RP MUTAGENESIS OF SER-17; ASN-26; VAL-29; TYR-32; PRO-34; THR-35; GLU-37;
RP ASP-38 AND SER-39.
RX PubMed=11022048; DOI=10.1074/jbc.M008324200;
RA Song C., Hu C.-D., Masago M., Kariya K., Yamawaki-Kataoka Y.,
RA Shibatohge M., Wu D., Satoh T., Kataoka T.;
RT "Regulation of a novel human phospholipase C, PLCepsilon, through
RT membrane targeting by Ras.";
RL J. Biol. Chem. 276:2752-2757(2001).
RN [24]
RP INTERACTION WITH RAPGEF2.
RX PubMed=11598133; DOI=10.1074/jbc.M108373200;
RA Pham N., Rotin D.;
RT "Nedd4 regulates ubiquitination and stability of the guanine-
RT nucleotide exchange factor CNrasGEF.";
RL J. Biol. Chem. 276:46995-47003(2001).
RN [25]
RP IDENTIFICATION IN A COMPLEX WITH RASGRP1 AND DGKZ.
RX PubMed=11257115; DOI=10.1083/jcb.152.6.1135;
RA Topham M.K., Prescott S.M.;
RT "Diacylglycerol kinase zeta regulates Ras activation by a novel
RT mechanism.";
RL J. Cell Biol. 152:1135-1143(2001).
RN [26]
RP INTERACTION WITH PDE6D.
RX PubMed=11980706; DOI=10.1093/emboj/21.9.2095;
RA Hanzal-Bayer M., Renault L., Roversi P., Wittinghofer A., Hillig R.C.;
RT "The complex of Arl2-GTP and PDE delta: from structure to function.";
RL EMBO J. 21:2095-2106(2002).
RN [27]
RP LIPID MODIFICATION AT CYS-184, AND MUTAGENESIS OF CYS-184.
RX PubMed=12684535; DOI=10.1073/pnas.0735842100;
RA Oliva J.L., Perez-Sala D., Castrillo A., Martinez N., Canada F.J.,
RA Bosca L., Rojas J.M.;
RT "The cyclopentenone 15-deoxy-delta 12,14-prostaglandin J2 binds to and
RT activates H-Ras.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:4772-4777(2003).
RN [28]
RP CHARACTERIZATION OF FCSS VARIANT VAL-12.
RX PubMed=15546861; DOI=10.1074/jbc.M410775200;
RA Liu F., Iqbal K., Grundke-Iqbal I., Rossie S., Gong C.X.;
RT "Dephosphorylation of tau by protein phosphatase 5: impairment in
RT Alzheimer's disease.";
RL J. Biol. Chem. 280:1790-1796(2005).
RN [29]
RP PALMITOYLATION AT CYS-181 AND CYS-184.
RX PubMed=16000296; DOI=10.1074/jbc.M504113200;
RA Swarthout J.T., Lobo S., Farh L., Croke M.R., Greentree W.K.,
RA Deschenes R.J., Linder M.E.;
RT "DHHC9 and GCP16 constitute a human protein fatty acyltransferase with
RT specificity for H- and N-Ras.";
RL J. Biol. Chem. 280:31141-31148(2005).
RN [30]
RP PALMITOYLATION AT CYS-181 AND CYS-184, MUTAGENESIS OF CYS-181 AND
RP CYS-184, AND SUBCELLULAR LOCATION.
RX PubMed=15705808; DOI=10.1126/science.1105654;
RA Rocks O., Peyker A., Kahms M., Verveer P.J., Koerner C.,
RA Lumbierres M., Kuhlmann J., Waldmann H., Wittinghofer A.,
RA Bastiaens P.I.H.;
RT "An acylation cycle regulates localization and activity of
RT palmitoylated Ras isoforms.";
RL Science 307:1746-1752(2005).
RN [31]
RP INTERACTION WITH TBC1D10C.
RX PubMed=17230191; DOI=10.1038/nature05476;
RA Pan F., Sun L., Kardian D.B., Whartenby K.A., Pardoll D.M., Liu J.O.;
RT "Feedback inhibition of calcineurin and Ras by a dual inhibitory
RT protein Carabin.";
RL Nature 445:433-436(2007).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS).
RX PubMed=2448879; DOI=10.1126/science.2448879;
RA de Vos A.M., Tong L., Milburn M.V., Matias P.M., Jancarik J.,
RA Noguchi S., Nishimura S., Miura K., Ohtsuka E., Kim S.-H.;
RT "Three-dimensional structure of an oncogene protein: catalytic domain
RT of human c-H-ras p21.";
RL Science 239:888-893(1988).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
RX PubMed=2476675; DOI=10.1038/341209a0;
RA Pai E.F., Kabsch W., Krengel U., Holmes K.C., John J.,
RA Wittinghofer A.;
RT "Structure of the guanine-nucleotide-binding domain of the Ha-ras
RT oncogene product p21 in the triphosphate conformation.";
RL Nature 341:209-214(1989).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS).
RX PubMed=2196171;
RA Pai E.F., Krengel U., Petsko G.A., Goody R.S., Kabsch W.,
RA Wittinghofer A.;
RT "Refined crystal structure of the triphosphate conformation of H-ras
RT p21 at 1.35-A resolution: implications for the mechanism of GTP
RT hydrolysis.";
RL EMBO J. 9:2351-2359(1990).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS).
RX PubMed=1899707; DOI=10.1016/0022-2836(91)90753-S;
RA Tong L.A., de Vos A.M., Milburn M.V., Kim S.H.;
RT "Crystal structures at 2.2-A resolution of the catalytic domains of
RT normal ras protein and an oncogenic mutant complexed with GDP.";
RL J. Mol. Biol. 217:503-516(1991).
RN [36]
RP STRUCTURE BY NMR OF 1-166.
RX PubMed=8142349; DOI=10.1021/bi00178a008;
RA Kraulis P.J., Domaille P.J., Campbell-Burk S.L., van Aken T.,
RA Laue E.D.;
RT "Solution structure and dynamics of ras p21.GDP determined by
RT heteronuclear three- and four-dimensional NMR spectroscopy.";
RL Biochemistry 33:3515-3531(1994).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-166 IN COMPLEX WITH RASGAP.
RX PubMed=9219684; DOI=10.1126/science.277.5324.333;
RA Scheffzek K., Ahmadian M.R., Kabsch W., Wiesmuller L., Lautwein A.,
RA Schmitz F., Wittinghofer A.;
RT "The Ras-RasGAP complex: structural basis for GTPase activation and
RT its loss in oncogenic Ras mutants.";
RL Science 277:333-338(1997).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (1.26 ANGSTROMS).
RX PubMed=10574788; DOI=10.1016/S0969-2126(00)80021-0;
RA Scheidig A.J., Burmester C., Goody R.S.;
RT "The pre-hydrolysis state of p21(ras) in complex with GTP: new
RT insights into the role of water molecules in the GTP hydrolysis
RT reaction of ras-like proteins.";
RL Structure 7:1311-1324(1999).
RN [39]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 1-166 IN COMPLEXES WITH GTP
RP ANALOGS.
RX PubMed=12213964; DOI=10.1073/pnas.192453199;
RA Hall B.E., Bar-Sagi D., Nassar N.;
RT "The structural basis for the transition from Ras-GTP to Ras-GDP.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:12138-12142(2002).
RN [40]
RP STRUCTURE BY NMR OF 1-166, MASS SPECTROMETRY, S-NITROSYLATION,
RP FUNCTION, AND MUTAGENESIS OF CYS-118.
RX PubMed=12740440; DOI=10.1073/pnas.1037299100;
RA Williams J.G., Pappu K., Campbell S.L.;
RT "Structural and biochemical studies of p21Ras S-nitrosylation and
RT nitric oxide-mediated guanine nucleotide exchange.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:6376-6381(2003).
RN [41]
RP X-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS) OF 1-166 IN COMPLEXES WITH GTP
RP ANALOG, CHARACTERIZATION OF VARIANTS LEU-61 AND LYS-61, AND
RP MUTAGENESIS OF GLN-61.
RX PubMed=18073111; DOI=10.1016/j.str.2007.10.011;
RA Buhrman G., Wink G., Mattos C.;
RT "Transformation efficiency of RasQ61 mutants linked to structural
RT features of the switch regions in the presence of Raf.";
RL Structure 15:1618-1629(2007).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1-166 IN COMPLEX WITH RASSF5.
RX PubMed=18596699; DOI=10.1038/emboj.2008.125;
RA Stieglitz B., Bee C., Schwarz D., Yildiz O., Moshnikova A.,
RA Khokhlatchev A., Herrmann C.;
RT "Novel type of Ras effector interaction established between tumour
RT suppressor NORE1A and Ras switch II.";
RL EMBO J. 27:1995-2005(2008).
RN [43]
RP VARIANT OSCC SER-12.
RX PubMed=1459726; DOI=10.1002/ijc.2910520606;
RA Sakai E., Rikimaru K., Ueda M., Matsumoto Y., Ishii N., Enomoto S.,
RA Yamamoto H., Tsuchida N.;
RT "The p53 tumor-suppressor gene and ras oncogene mutations in oral
RT squamous-cell carcinoma.";
RL Int. J. Cancer 52:867-872(1992).
RN [44]
RP VARIANT LYS-61, AND INVOLVEMENT IN SUSCEPTIBILITY TO HURTHLE CELL
RP THYROID CARCINOMA.
RX PubMed=12727991; DOI=10.1210/jc.2002-021907;
RA Nikiforova M.N., Lynch R.A., Biddinger P.W., Alexander E.K.,
RA Dorn G.W. II, Tallini G., Kroll T.G., Nikiforov Y.E.;
RT "RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid
RT tumors: evidence for distinct molecular pathways in thyroid follicular
RT carcinoma.";
RL J. Clin. Endocrinol. Metab. 88:2318-2326(2003).
RN [45]
RP VARIANTS FCSS ALA-12; SER-12; VAL-12 AND ASP-13.
RX PubMed=16170316; DOI=10.1038/ng1641;
RA Aoki Y., Niihori T., Kawame H., Kurosawa K., Ohashi H., Tanaka Y.,
RA Filocamo M., Kato K., Suzuki Y., Kure S., Matsubara Y.;
RT "Germline mutations in HRAS proto-oncogene cause Costello syndrome.";
RL Nat. Genet. 37:1038-1040(2005).
RN [46]
RP VARIANTS FCSS ALA-12; SER-12 AND CYS-13.
RX PubMed=16329078; DOI=10.1002/ajmg.a.31047;
RA Gripp K.W., Lin A.E., Stabley D.L., Nicholson L., Scott C.I. Jr.,
RA Doyle D., Aoki Y., Matsubara Y., Zackai E.H., Lapunzina P.,
RA Gonzalez-Meneses A., Holbrook J., Agresta C.A., Gonzalez I.L.,
RA Sol-Church K.;
RT "HRAS mutation analysis in Costello syndrome: genotype and phenotype
RT correlation.";
RL Am. J. Med. Genet. A 140:1-7(2006).
RN [47]
RP VARIANTS FCSS SER-12; CYS-12; GLU-12; ALA-12 AND ARG-117.
RX PubMed=16443854; DOI=10.1136/jmg.2005.040352;
RA Kerr B., Delrue M.-A., Sigaudy S., Perveen R., Marche M., Burgelin I.,
RA Stef M., Tang B., Eden O.B., O'Sullivan J., De Sandre-Giovannoli A.,
RA Reardon W., Brewer C., Bennett C., Quarell O., M'Cann E., Donnai D.,
RA Stewart F., Hennekam R., Cave H., Verloes A., Philip N., Lacombe D.,
RA Levy N., Arveiler B., Black G.;
RT "Genotype-phenotype correlation in Costello syndrome: HRAS mutation
RT analysis in 43 cases.";
RL J. Med. Genet. 43:401-405(2006).
RN [48]
RP VARIANTS FCSS SER-12 AND THR-146.
RX PubMed=17054105; DOI=10.1002/humu.20431;
RA Zampino G., Pantaleoni F., Carta C., Cobellis G., Vasta I., Neri C.,
RA Pogna E.A., De Feo E., Delogu A., Sarkozy A., Atzeri F., Selicorni A.,
RA Rauen K.A., Cytrynbaum C.S., Weksberg R., Dallapiccola B.,
RA Ballabio A., Gelb B.D., Neri G., Tartaglia M.;
RT "Diversity, parental germline origin, and phenotypic spectrum of de
RT novo HRAS missense changes in Costello syndrome.";
RL Hum. Mutat. 28:265-272(2007).
RN [49]
RP VARIANTS CMEMS VAL-12; SER-12; LYS-22 AND LYS-63.
RX PubMed=17412879; DOI=10.1136/jmg.2007.049270;
RA van der Burgt I., Kupsky W., Stassou S., Nadroo A., Barroso C.,
RA Diem A., Kratz C.P., Dvorsky R., Ahmadian M.R., Zenker M.;
RT "Myopathy caused by HRAS germline mutations: implications for
RT disturbed myogenic differentiation in the presence of constitutive
RT HRas activation.";
RL J. Med. Genet. 44:459-462(2007).
RN [50]
RP VARIANTS FCSS ILE-58 AND VAL-146.
RX PubMed=18247425; DOI=10.1002/ajmg.a.32227;
RA Gripp K.W., Innes A.M., Axelrad M.E., Gillan T.L., Parboosingh J.S.,
RA Davies C., Leonard N.J., Lapointe M., Doyle D., Catalano S.,
RA Nicholson L., Stabley D.L., Sol-Church K.;
RT "Costello syndrome associated with novel germline HRAS mutations: an
RT attenuated phenotype?";
RL Am. J. Med. Genet. A 146:683-690(2008).
RN [51]
RP VARIANTS FCSS ASP-12 AND CYS-12.
RX PubMed=18039947; DOI=10.1136/jmg.2007.054411;
RA Lo I.F., Brewer C., Shannon N., Shorto J., Tang B., Black G.,
RA Soo M.T., Ng D.K., Lam S.T., Kerr B.;
RT "Severe neonatal manifestations of Costello syndrome.";
RL J. Med. Genet. 45:167-171(2008).
RN [52]
RP VARIANT FCSS GLU-37 INS.
RX PubMed=19995790; DOI=10.1093/hmg/ddp548;
RA Gremer L., De Luca A., Merbitz-Zahradnik T., Dallapiccola B.,
RA Morlot S., Tartaglia M., Kutsche K., Ahmadian M.R., Rosenberger G.;
RT "Duplication of Glu37 in the switch I region of HRAS impairs
RT effector/GAP binding and underlies Costello syndrome by promoting
RT enhanced growth factor-dependent MAPK and AKT activation.";
RL Hum. Mol. Genet. 19:790-802(2010).
RN [53]
RP VARIANT SFM ARG-13, AND CHARACTERIZATION OF VARIANT SFM ARG-13.
RX PubMed=22683711; DOI=10.1038/ng.2316;
RA Groesser L., Herschberger E., Ruetten A., Ruivenkamp C., Lopriore E.,
RA Zutt M., Langmann T., Singer S., Klingseisen L.,
RA Schneider-Brachert W., Toll A., Real F.X., Landthaler M., Hafner C.;
RT "Postzygotic HRAS and KRAS mutations cause nevus sebaceous and
RT Schimmelpenning syndrome.";
RL Nat. Genet. 44:783-787(2012).
CC -!- FUNCTION: Ras proteins bind GDP/GTP and possess intrinsic GTPase
CC activity.
CC -!- ENZYME REGULATION: Alternates between an inactive form bound to
CC GDP and an active form bound to GTP. Activated by a guanine
CC nucleotide-exchange factor (GEF) and inactivated by a GTPase-
CC activating protein (GAP).
CC -!- SUBUNIT: In its GTP-bound form interacts with PLCE1. Interacts
CC with TBC1D10C. Interacts with RGL3. Interacts with HSPD1. Found in
CC a complex with at least BRAF, HRAS1, MAP2K1, MAPK3 and RGS14.
CC Interacts (active GTP-bound form) with RGS14 (via RBD 1 domain)
CC (By similarity). Forms a signaling complex with RASGRP1 and DGKZ.
CC Interacts with RASSF5. Interacts with PDE6D. Interacts with IKZF3.
CC Interacts with GNB2L1. Interacts with PIK3CG; the interaction is
CC required for membrane recruitment and beta-gamma G protein dimer-
CC dependent activation of the PI3K gamma complex PIK3CG:PIK3R6 (By
CC similarity). Interacts with RAPGEF2.
CC -!- INTERACTION:
CC Q7Z569:BRAP; NbExp=3; IntAct=EBI-350145, EBI-349900;
CC P42337:Pik3ca (xeno); NbExp=2; IntAct=EBI-350145, EBI-641748;
CC O00329:PIK3CD; NbExp=2; IntAct=EBI-350145, EBI-718309;
CC O00329-2:PIK3CD; NbExp=2; IntAct=EBI-350145, EBI-6470902;
CC Q9Z0S9:Rabac1 (xeno); NbExp=4; IntAct=EBI-350145, EBI-476965;
CC P04049:RAF1; NbExp=14; IntAct=EBI-350145, EBI-365996;
CC Q9EQZ6:Rapgef4 (xeno); NbExp=3; IntAct=EBI-350145, EBI-772212;
CC Q9NS23-2:RASSF1; NbExp=2; IntAct=EBI-350145, EBI-438698;
CC Q8WWW0:RASSF5; NbExp=2; IntAct=EBI-350145, EBI-367390;
CC Q5EBH1:Rassf5 (xeno); NbExp=11; IntAct=EBI-350145, EBI-960530;
CC Q5EBH1-2:Rassf5 (xeno); NbExp=3; IntAct=EBI-350145, EBI-960547;
CC Q13671:RIN1; NbExp=5; IntAct=EBI-350145, EBI-366017;
CC Q07889:SOS1; NbExp=8; IntAct=EBI-350145, EBI-297487;
CC -!- SUBCELLULAR LOCATION: Cell membrane. Cell membrane; Lipid-anchor;
CC Cytoplasmic side. Golgi apparatus. Golgi apparatus membrane;
CC Lipid-anchor. Note=The active GTP-bound form is localized most
CC strongly to membranes than the inactive GDP-bound form (By
CC similarity). Shuttles between the plasma membrane and the Golgi
CC apparatus.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Nucleus. Cytoplasm. Cytoplasm,
CC perinuclear region. Note=Colocalizes with GNB2L1 to the
CC perinuclear region.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=H-Ras4A, p21;
CC IsoId=P01112-1; Sequence=Displayed;
CC Name=2; Synonyms=H-RasIDX, p19;
CC IsoId=P01112-2; Sequence=VSP_041597;
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- PTM: Palmitoylated by the ZDHHC9-GOLGA7 complex. A continuous
CC cycle of de- and re-palmitoylation regulates rapid exchange
CC between plasma membrane and Golgi.
CC -!- PTM: S-nitrosylated; critical for redox regulation. Important for
CC stimulating guanine nucleotide exchange. No structural
CC perturbation on nitrosylation.
CC -!- PTM: The covalent modification of cysteine by 15-deoxy-Delta12,14-
CC prostaglandin-J2 is autocatalytic and reversible. It may occur as
CC an alternative to other cysteine modifications, such as S-
CC nitrosylation and S-palmitoylation.
CC -!- PTM: Acetylation at Lys-104 prevents interaction with guanine
CC nucleotide exchange factors (GEFs) (By similarity).
CC -!- MASS SPECTROMETRY: Mass=6223; Mass_error=2; Method=Electrospray;
CC Range=112-166; Source=PubMed:9020151;
CC -!- MASS SPECTROMETRY: Mass=6253; Mass_error=2; Method=Electrospray;
CC Range=112-166; Note=Includes one nitric oxide molecule;
CC Source=PubMed:9020151;
CC -!- DISEASE: Faciocutaneoskeletal syndrome (FCSS) [MIM:218040]: A rare
CC condition characterized by prenatally increased growth, postnatal
CC growth deficiency, mental retardation, distinctive facial
CC appearance, cardiovascular abnormalities (typically pulmonic
CC stenosis, hypertrophic cardiomyopathy and/or atrial tachycardia),
CC tumor predisposition, skin and musculoskeletal abnormalities.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Congenital myopathy with excess of muscle spindles
CC (CMEMS) [MIM:218040]: Variant of Costello syndrome. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Hurthle cell thyroid carcinoma (HCTC) [MIM:607464]: A
CC rare type of thyroid cancer accounting for only about 3-10% of all
CC differentiated thyroid cancers. These neoplasms are considered a
CC variant of follicular carcinoma of the thyroid and are referred to
CC as follicular carcinoma, oxyphilic type. Note=Disease
CC susceptibility is associated with variations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Note=Mutations which change positions 12, 13 or 61
CC activate the potential of HRAS to transform cultured cells and are
CC implicated in a variety of human tumors.
CC -!- DISEASE: Bladder cancer (BLC) [MIM:109800]: A malignancy
CC originating in tissues of the urinary bladder. It often presents
CC with multiple tumors appearing at different times and at different
CC sites in the bladder. Most bladder cancers are transitional cell
CC carcinomas that begin in cells that normally make up the inner
CC lining of the bladder. Other types of bladder cancer include
CC squamous cell carcinoma (cancer that begins in thin, flat cells)
CC and adenocarcinoma (cancer that begins in cells that make and
CC release mucus and other fluids). Bladder cancer is a complex
CC disorder with both genetic and environmental influences.
CC Note=Disease susceptibility is associated with variations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Note=Defects in HRAS are the cause of oral squamous cell
CC carcinoma (OSCC).
CC -!- DISEASE: Schimmelpenning-Feuerstein-Mims syndrome (SFM)
CC [MIM:163200]: A disease characterized by sebaceous nevi, often on
CC the face, associated with variable ipsilateral abnormalities of
CC the central nervous system, ocular anomalies, and skeletal
CC defects. Many oral manifestations have been reported, not only
CC including hypoplastic and malformed teeth, and mucosal
CC papillomatosis, but also ankyloglossia, hemihyperplastic tongue,
CC intraoral nevus, giant cell granuloma, ameloblastoma, bone cysts,
CC follicular cysts, oligodontia, and odontodysplasia. Sebaceous nevi
CC follow the lines of Blaschko and these can continue as linear
CC intraoral lesions, as in mucosal papillomatosis. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Ras family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/HRASID108.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HRAS";
CC -----------------------------------------------------------------------
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DR EMBL; J00277; AAB02605.1; -; Genomic_DNA.
DR EMBL; AJ437024; CAD24594.1; -; mRNA.
DR EMBL; AF493916; AAM12630.1; -; mRNA.
DR EMBL; CR536579; CAG38816.1; -; mRNA.
DR EMBL; CR542271; CAG47067.1; -; mRNA.
DR EMBL; BT019421; AAV38228.1; -; mRNA.
DR EMBL; EF015887; ABI97389.1; -; Genomic_DNA.
DR EMBL; AB451336; BAG70150.1; -; mRNA.
DR EMBL; AB451485; BAG70299.1; -; mRNA.
DR EMBL; CH471158; EAX02337.1; -; Genomic_DNA.
DR EMBL; CH471158; EAX02338.1; -; Genomic_DNA.
DR EMBL; BC006499; AAH06499.1; -; mRNA.
DR EMBL; BC095471; AAH95471.1; -; mRNA.
DR EMBL; M17232; AAA35685.1; -; Genomic_DNA.
DR PIR; A93299; TVHUH.
DR RefSeq; NP_001123914.1; NM_001130442.1.
DR RefSeq; NP_005334.1; NM_005343.2.
DR RefSeq; NP_789765.1; NM_176795.3.
DR UniGene; Hs.37003; -.
DR PDB; 121P; X-ray; 1.54 A; A=1-166.
DR PDB; 1AA9; NMR; -; A=1-171.
DR PDB; 1AGP; X-ray; 2.30 A; A=1-166.
DR PDB; 1BKD; X-ray; 2.80 A; R=1-166.
DR PDB; 1CLU; X-ray; 1.70 A; A=1-166.
DR PDB; 1CRP; NMR; -; A=1-166.
DR PDB; 1CRQ; NMR; -; A=1-166.
DR PDB; 1CRR; NMR; -; A=1-166.
DR PDB; 1CTQ; X-ray; 1.26 A; A=1-166.
DR PDB; 1GNP; X-ray; 2.70 A; A=1-166.
DR PDB; 1GNQ; X-ray; 2.50 A; A=1-166.
DR PDB; 1GNR; X-ray; 1.85 A; A=1-166.
DR PDB; 1HE8; X-ray; 3.00 A; B=1-166.
DR PDB; 1IAQ; X-ray; 2.90 A; A/B/C=1-166.
DR PDB; 1IOZ; X-ray; 2.00 A; A=1-171.
DR PDB; 1JAH; X-ray; 1.80 A; A=1-166.
DR PDB; 1JAI; X-ray; 1.80 A; A=1-166.
DR PDB; 1K8R; X-ray; 3.00 A; A=1-166.
DR PDB; 1LF0; X-ray; 1.70 A; A=1-166.
DR PDB; 1LF5; X-ray; 1.70 A; A=1-166.
DR PDB; 1LFD; X-ray; 2.10 A; B/D=1-167.
DR PDB; 1NVU; X-ray; 2.20 A; Q/R=1-166.
DR PDB; 1NVV; X-ray; 2.18 A; Q/R=1-166.
DR PDB; 1NVW; X-ray; 2.70 A; Q/R=1-166.
DR PDB; 1NVX; X-ray; 3.20 A; Q/R=1-166.
DR PDB; 1P2S; X-ray; 2.45 A; A=1-166.
DR PDB; 1P2T; X-ray; 2.00 A; A=1-166.
DR PDB; 1P2U; X-ray; 2.00 A; A=1-166.
DR PDB; 1P2V; X-ray; 2.30 A; A=1-166.
DR PDB; 1PLJ; X-ray; 2.80 A; A=1-166.
DR PDB; 1PLK; X-ray; 2.80 A; A=1-166.
DR PDB; 1PLL; X-ray; 2.80 A; A=1-166.
DR PDB; 1Q21; X-ray; 2.20 A; A=1-171.
DR PDB; 1QRA; X-ray; 1.60 A; A=1-166.
DR PDB; 1RVD; X-ray; 1.90 A; A=1-166.
DR PDB; 1WQ1; X-ray; 2.50 A; R=1-166.
DR PDB; 1XCM; X-ray; 1.84 A; A=1-167.
DR PDB; 1XD2; X-ray; 2.70 A; A/B=1-166.
DR PDB; 1XJ0; X-ray; 1.70 A; A=1-166.
DR PDB; 1ZVQ; X-ray; 2.00 A; A=1-166.
DR PDB; 1ZW6; X-ray; 1.50 A; A=1-166.
DR PDB; 221P; X-ray; 2.30 A; A=1-166.
DR PDB; 2C5L; X-ray; 1.90 A; A/B=1-166.
DR PDB; 2CE2; X-ray; 1.00 A; X=1-166.
DR PDB; 2CL0; X-ray; 1.80 A; X=1-166.
DR PDB; 2CL6; X-ray; 1.24 A; X=1-166.
DR PDB; 2CL7; X-ray; 1.25 A; X=1-166.
DR PDB; 2CLC; X-ray; 1.30 A; X=1-166.
DR PDB; 2CLD; X-ray; 1.22 A; X=1-166.
DR PDB; 2EVW; X-ray; 1.05 A; X=1-166.
DR PDB; 2GDP; Model; -; A=1-171.
DR PDB; 2LCF; NMR; -; A=1-166.
DR PDB; 2LWI; NMR; -; A=1-166.
DR PDB; 2Q21; X-ray; 2.20 A; A=1-171.
DR PDB; 2QUZ; X-ray; 1.49 A; A=1-166.
DR PDB; 2RGA; X-ray; 1.90 A; A=1-166.
DR PDB; 2RGB; X-ray; 1.35 A; A=1-166.
DR PDB; 2RGC; X-ray; 1.60 A; A=1-166.
DR PDB; 2RGD; X-ray; 2.00 A; A=1-166.
DR PDB; 2RGE; X-ray; 1.40 A; A=1-166.
DR PDB; 2RGG; X-ray; 1.45 A; A=1-166.
DR PDB; 2UZI; X-ray; 2.00 A; R=1-166.
DR PDB; 2VH5; X-ray; 2.70 A; R=1-166.
DR PDB; 2X1V; X-ray; 1.70 A; A=1-166.
DR PDB; 3DDC; X-ray; 1.80 A; A=1-166.
DR PDB; 3I3S; X-ray; 1.36 A; R=1-166.
DR PDB; 3K8Y; X-ray; 1.30 A; A=1-166.
DR PDB; 3K9L; X-ray; 1.80 A; A/B/C=1-166.
DR PDB; 3K9N; X-ray; 2.00 A; A=1-166.
DR PDB; 3KKM; X-ray; 1.70 A; A=1-166.
DR PDB; 3KKN; X-ray; 2.09 A; A=1-166.
DR PDB; 3KUD; X-ray; 2.15 A; A=1-166.
DR PDB; 3L8Y; X-ray; 2.02 A; A=1-166.
DR PDB; 3L8Z; X-ray; 1.44 A; A=1-166.
DR PDB; 3LBH; X-ray; 1.85 A; A=1-166.
DR PDB; 3LBI; X-ray; 2.09 A; A=1-166.
DR PDB; 3LBN; X-ray; 1.86 A; A=1-166.
DR PDB; 3LO5; X-ray; 2.57 A; A/C/E=1-166.
DR PDB; 3OIU; X-ray; 1.32 A; A=1-166.
DR PDB; 3OIV; X-ray; 1.84 A; A=1-166.
DR PDB; 3OIW; X-ray; 1.30 A; A=1-166.
DR PDB; 3RRY; X-ray; 1.60 A; A=1-166.
DR PDB; 3RRZ; X-ray; 1.60 A; A=1-166.
DR PDB; 3RS0; X-ray; 1.40 A; A=1-166.
DR PDB; 3RS2; X-ray; 1.84 A; A=1-166.
DR PDB; 3RS3; X-ray; 1.52 A; A=1-166.
DR PDB; 3RS4; X-ray; 1.70 A; A=1-166.
DR PDB; 3RS5; X-ray; 1.68 A; A=1-166.
DR PDB; 3RS7; X-ray; 1.70 A; A=1-166.
DR PDB; 3RSL; X-ray; 1.70 A; A=1-166.
DR PDB; 3RSO; X-ray; 1.60 A; A=1-166.
DR PDB; 3TGP; X-ray; 1.31 A; A=1-166.
DR PDB; 421P; X-ray; 2.20 A; A=1-166.
DR PDB; 4DLR; X-ray; 1.32 A; A=1-166.
DR PDB; 4DLS; X-ray; 1.82 A; A=1-166.
DR PDB; 4DLT; X-ray; 1.70 A; A=1-166.
DR PDB; 4DLU; X-ray; 1.60 A; A=1-166.
DR PDB; 4DLV; X-ray; 1.57 A; A=1-166.
DR PDB; 4DLW; X-ray; 1.72 A; A=1-166.
DR PDB; 4DLX; X-ray; 1.73 A; A=1-166.
DR PDB; 4DLY; X-ray; 1.57 A; A=1-166.
DR PDB; 4DLZ; X-ray; 1.66 A; A=1-166.
DR PDB; 4DST; X-ray; 2.30 A; A=2-167.
DR PDB; 4DSU; X-ray; 1.70 A; A=2-167.
DR PDB; 4EFL; X-ray; 1.90 A; A=1-166.
DR PDB; 4EFM; X-ray; 1.90 A; A=1-166.
DR PDB; 4EFN; X-ray; 2.30 A; A=1-166.
DR PDB; 4G0N; X-ray; 2.45 A; A=1-166.
DR PDB; 4G3X; X-ray; 3.25 A; A=1-166.
DR PDB; 4K81; X-ray; 2.40 A; B/D/F/H=1-166.
DR PDB; 4Q21; X-ray; 2.00 A; A=1-189.
DR PDB; 521P; X-ray; 2.60 A; A=1-166.
DR PDB; 5P21; X-ray; 1.35 A; A=1-166.
DR PDB; 621P; X-ray; 2.40 A; A=1-166.
DR PDB; 6Q21; X-ray; 1.95 A; A/B/C/D=1-171.
DR PDB; 721P; X-ray; 2.00 A; A=1-166.
DR PDB; 821P; X-ray; 1.50 A; A=1-166.
DR PDBsum; 121P; -.
DR PDBsum; 1AA9; -.
DR PDBsum; 1AGP; -.
DR PDBsum; 1BKD; -.
DR PDBsum; 1CLU; -.
DR PDBsum; 1CRP; -.
DR PDBsum; 1CRQ; -.
DR PDBsum; 1CRR; -.
DR PDBsum; 1CTQ; -.
DR PDBsum; 1GNP; -.
DR PDBsum; 1GNQ; -.
DR PDBsum; 1GNR; -.
DR PDBsum; 1HE8; -.
DR PDBsum; 1IAQ; -.
DR PDBsum; 1IOZ; -.
DR PDBsum; 1JAH; -.
DR PDBsum; 1JAI; -.
DR PDBsum; 1K8R; -.
DR PDBsum; 1LF0; -.
DR PDBsum; 1LF5; -.
DR PDBsum; 1LFD; -.
DR PDBsum; 1NVU; -.
DR PDBsum; 1NVV; -.
DR PDBsum; 1NVW; -.
DR PDBsum; 1NVX; -.
DR PDBsum; 1P2S; -.
DR PDBsum; 1P2T; -.
DR PDBsum; 1P2U; -.
DR PDBsum; 1P2V; -.
DR PDBsum; 1PLJ; -.
DR PDBsum; 1PLK; -.
DR PDBsum; 1PLL; -.
DR PDBsum; 1Q21; -.
DR PDBsum; 1QRA; -.
DR PDBsum; 1RVD; -.
DR PDBsum; 1WQ1; -.
DR PDBsum; 1XCM; -.
DR PDBsum; 1XD2; -.
DR PDBsum; 1XJ0; -.
DR PDBsum; 1ZVQ; -.
DR PDBsum; 1ZW6; -.
DR PDBsum; 221P; -.
DR PDBsum; 2C5L; -.
DR PDBsum; 2CE2; -.
DR PDBsum; 2CL0; -.
DR PDBsum; 2CL6; -.
DR PDBsum; 2CL7; -.
DR PDBsum; 2CLC; -.
DR PDBsum; 2CLD; -.
DR PDBsum; 2EVW; -.
DR PDBsum; 2GDP; -.
DR PDBsum; 2LCF; -.
DR PDBsum; 2LWI; -.
DR PDBsum; 2Q21; -.
DR PDBsum; 2QUZ; -.
DR PDBsum; 2RGA; -.
DR PDBsum; 2RGB; -.
DR PDBsum; 2RGC; -.
DR PDBsum; 2RGD; -.
DR PDBsum; 2RGE; -.
DR PDBsum; 2RGG; -.
DR PDBsum; 2UZI; -.
DR PDBsum; 2VH5; -.
DR PDBsum; 2X1V; -.
DR PDBsum; 3DDC; -.
DR PDBsum; 3I3S; -.
DR PDBsum; 3K8Y; -.
DR PDBsum; 3K9L; -.
DR PDBsum; 3K9N; -.
DR PDBsum; 3KKM; -.
DR PDBsum; 3KKN; -.
DR PDBsum; 3KUD; -.
DR PDBsum; 3L8Y; -.
DR PDBsum; 3L8Z; -.
DR PDBsum; 3LBH; -.
DR PDBsum; 3LBI; -.
DR PDBsum; 3LBN; -.
DR PDBsum; 3LO5; -.
DR PDBsum; 3OIU; -.
DR PDBsum; 3OIV; -.
DR PDBsum; 3OIW; -.
DR PDBsum; 3RRY; -.
DR PDBsum; 3RRZ; -.
DR PDBsum; 3RS0; -.
DR PDBsum; 3RS2; -.
DR PDBsum; 3RS3; -.
DR PDBsum; 3RS4; -.
DR PDBsum; 3RS5; -.
DR PDBsum; 3RS7; -.
DR PDBsum; 3RSL; -.
DR PDBsum; 3RSO; -.
DR PDBsum; 3TGP; -.
DR PDBsum; 421P; -.
DR PDBsum; 4DLR; -.
DR PDBsum; 4DLS; -.
DR PDBsum; 4DLT; -.
DR PDBsum; 4DLU; -.
DR PDBsum; 4DLV; -.
DR PDBsum; 4DLW; -.
DR PDBsum; 4DLX; -.
DR PDBsum; 4DLY; -.
DR PDBsum; 4DLZ; -.
DR PDBsum; 4DST; -.
DR PDBsum; 4DSU; -.
DR PDBsum; 4EFL; -.
DR PDBsum; 4EFM; -.
DR PDBsum; 4EFN; -.
DR PDBsum; 4G0N; -.
DR PDBsum; 4G3X; -.
DR PDBsum; 4K81; -.
DR PDBsum; 4Q21; -.
DR PDBsum; 521P; -.
DR PDBsum; 5P21; -.
DR PDBsum; 621P; -.
DR PDBsum; 6Q21; -.
DR PDBsum; 721P; -.
DR PDBsum; 821P; -.
DR DisProt; DP00153; -.
DR ProteinModelPortal; P01112; -.
DR SMR; P01112; 1-166.
DR DIP; DIP-1050N; -.
DR IntAct; P01112; 26.
DR MINT; MINT-5002362; -.
DR STRING; 9606.ENSP00000309845; -.
DR BindingDB; P01112; -.
DR ChEMBL; CHEMBL2167; -.
DR DrugBank; DB00605; Sulindac.
DR PhosphoSite; P01112; -.
DR DMDM; 131869; -.
DR PaxDb; P01112; -.
DR PRIDE; P01112; -.
DR DNASU; 3265; -.
DR Ensembl; ENST00000311189; ENSP00000309845; ENSG00000174775.
DR Ensembl; ENST00000397594; ENSP00000380722; ENSG00000174775.
DR Ensembl; ENST00000397596; ENSP00000380723; ENSG00000174775.
DR Ensembl; ENST00000417302; ENSP00000388246; ENSG00000174775.
DR Ensembl; ENST00000451590; ENSP00000407586; ENSG00000174775.
DR Ensembl; ENST00000493230; ENSP00000434023; ENSG00000174775.
DR GeneID; 3265; -.
DR KEGG; hsa:3265; -.
DR UCSC; uc001lpv.3; human.
DR CTD; 3265; -.
DR GeneCards; GC11M000522; -.
DR HGNC; HGNC:5173; HRAS.
DR HPA; CAB002015; -.
DR MIM; 109800; phenotype.
DR MIM; 163200; phenotype.
DR MIM; 190020; gene.
DR MIM; 218040; phenotype.
DR MIM; 607464; phenotype.
DR neXtProt; NX_P01112; -.
DR Orphanet; 3071; Costello syndrome.
DR Orphanet; 2612; Linear nevus sebaceus syndrome.
DR PharmGKB; PA29444; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233973; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; P01112; -.
DR KO; K02833; -.
DR OMA; RSSYDEI; -.
DR OrthoDB; EOG7QVM41; -.
DR PhylomeDB; P01112; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_13685; Neuronal System.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P01112; -.
DR EvolutionaryTrace; P01112; -.
DR GeneWiki; HRAS; -.
DR GenomeRNAi; 3265; -.
DR NextBio; 12961; -.
DR PRO; PR:P01112; -.
DR ArrayExpress; P01112; -.
DR Bgee; P01112; -.
DR CleanEx; HS_HRAS; -.
DR Genevestigator; P01112; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB.
DR GO; GO:0003924; F:GTPase activity; IEA:Ensembl.
DR GO; GO:0030036; P:actin cytoskeleton organization; IEA:Ensembl.
DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0007050; P:cell cycle arrest; IDA:BHF-UCL.
DR GO; GO:0008283; P:cell proliferation; IEA:Ensembl.
DR GO; GO:0090398; P:cellular senescence; IDA:BHF-UCL.
DR GO; GO:0006897; P:endocytosis; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
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:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IEA:Ensembl.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0000165; P:MAPK cascade; TAS:Reactome.
DR GO; GO:0007093; P:mitotic cell cycle checkpoint; IDA:BHF-UCL.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IDA:BHF-UCL.
DR GO; GO:0010629; P:negative regulation of gene expression; IDA:BHF-UCL.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0034259; P:negative regulation of Rho GTPase activity; IDA:BHF-UCL.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0009887; P:organ morphogenesis; TAS:ProtInc.
DR GO; GO:2000251; P:positive regulation of actin cytoskeleton reorganization; IDA:BHF-UCL.
DR GO; GO:0030335; P:positive regulation of cell migration; IDA:BHF-UCL.
DR GO; GO:0045740; P:positive regulation of DNA replication; IDA:BHF-UCL.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IMP:BHF-UCL.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:BHF-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:BHF-UCL.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:BHF-UCL.
DR GO; GO:2000630; P:positive regulation of miRNA metabolic process; IDA:BHF-UCL.
DR GO; GO:0032855; P:positive regulation of Rac GTPase activity; IDA:BHF-UCL.
DR GO; GO:0035022; P:positive regulation of Rac protein signal transduction; IEA:Ensembl.
DR GO; GO:1900029; P:positive regulation of ruffle assembly; IDA:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL.
DR GO; GO:0090303; P:positive regulation of wound healing; IDA:BHF-UCL.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0007265; P:Ras protein signal transduction; IDA:BHF-UCL.
DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IEA:Ensembl.
DR GO; GO:0032228; P:regulation of synaptic transmission, GABAergic; IEA:Ensembl.
DR GO; GO:0035176; P:social behavior; IEA:Ensembl.
DR GO; GO:0051146; P:striated muscle cell differentiation; IEA:Ensembl.
DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome.
DR GO; GO:0008542; P:visual learning; IEA:Ensembl.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR020849; Small_GTPase_Ras.
DR PANTHER; PTHR24070; PTHR24070; 1.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00449; RASTRNSFRMNG.
DR SMART; SM00173; RAS; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51421; RAS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell membrane;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Disease mutation; Golgi apparatus; GTP-binding; Lipoprotein; Membrane;
KW Methylation; Nucleotide-binding; Nucleus; Palmitate; Prenylation;
KW Proto-oncogene; Reference proteome; S-nitrosylation.
FT CHAIN 1 186 GTPase HRas.
FT /FTId=PRO_0000042996.
FT INIT_MET 1 1 Removed; alternate.
FT CHAIN 2 186 GTPase HRas, N-terminally processed.
FT /FTId=PRO_0000326476.
FT PROPEP 187 189 Removed in mature form.
FT /FTId=PRO_0000042997.
FT NP_BIND 10 17 GTP.
FT NP_BIND 57 61 GTP.
FT NP_BIND 116 119 GTP.
FT REGION 166 185 Hypervariable region.
FT MOTIF 32 40 Effector region.
FT MOD_RES 1 1 N-acetylmethionine; in GTPase HRas;
FT alternate.
FT MOD_RES 2 2 N-acetylthreonine; in GTPase HRas, N-
FT terminally processed.
FT MOD_RES 118 118 S-nitrosocysteine.
FT MOD_RES 186 186 Cysteine methyl ester.
FT LIPID 181 181 S-palmitoyl cysteine.
FT LIPID 184 184 S-(15-deoxy-Delta12,14-prostaglandin J2-
FT 9-yl)cysteine; alternate.
FT LIPID 184 184 S-palmitoyl cysteine; alternate.
FT LIPID 186 186 S-farnesyl cysteine.
FT VAR_SEQ 152 189 VEDAFYTLVREIRQHKLRKLNPPDESGPGCMSCKCVLS ->
FT SRSGSSSSSGTLWDPPGPM (in isoform 2).
FT /FTId=VSP_041597.
FT VARIANT 12 12 G -> A (in FCSS).
FT /FTId=VAR_026106.
FT VARIANT 12 12 G -> C (in FCSS).
FT /FTId=VAR_045975.
FT VARIANT 12 12 G -> D (in FCSS; severe mutation).
FT /FTId=VAR_068816.
FT VARIANT 12 12 G -> E (in FCSS).
FT /FTId=VAR_045976.
FT VARIANT 12 12 G -> S (in FCSS, OSCC and CMEMS).
FT /FTId=VAR_006837.
FT VARIANT 12 12 G -> V (in FCSS, bladder carcinoma and
FT CMEMS; constitutively activated;
FT interacts and recruits PLCE1 to plasma
FT membrane; loss of interaction with and
FT recruitment to plasma membrane of PLCE1
FT when associated with F-32; loss of
FT interaction with PLCE1 when associated
FT with G-26, F-32 and S-35; no effect on
FT interaction with PLCE1 when associated
FT with A-29, G-34, G-37, N-38 and C-39; no
FT effect on subcellular location of isoform
FT 2).
FT /FTId=VAR_006836.
FT VARIANT 13 13 G -> C (in FCSS).
FT /FTId=VAR_026107.
FT VARIANT 13 13 G -> D (in FCSS).
FT /FTId=VAR_026108.
FT VARIANT 13 13 G -> R (in SFM; somatic mutation; shows
FT constitutive activation of the MAPK and
FT PI3K-AKT signaling pathways).
FT /FTId=VAR_068817.
FT VARIANT 22 22 Q -> K (in CMEMS).
FT /FTId=VAR_045977.
FT VARIANT 37 37 E -> EE (in FCSS).
FT /FTId=VAR_068818.
FT VARIANT 58 58 T -> I (in FCSS).
FT /FTId=VAR_045978.
FT VARIANT 61 61 Q -> K (in follicular thyroid carcinoma
FT samples; somatic mutation; increases
FT transformation of cultured cell lines;
FT dbSNP:rs28933406).
FT /FTId=VAR_045979.
FT VARIANT 61 61 Q -> L (in melanoma; strongly reduced GTP
FT hydrolysis in the presence of RAF1;
FT increases transformation of cultured cell
FT lines).
FT /FTId=VAR_006838.
FT VARIANT 63 63 E -> K (in CMEMS).
FT /FTId=VAR_045980.
FT VARIANT 117 117 K -> R (in FCSS).
FT /FTId=VAR_045981.
FT VARIANT 146 146 A -> T (in FCSS).
FT /FTId=VAR_045982.
FT VARIANT 146 146 A -> V (in FCSS).
FT /FTId=VAR_045983.
FT MUTAGEN 17 17 S->N: Dominant negative. Prevents PLCE1
FT EGF-induced recruitment to plasma
FT membrane. No effect on subcellular
FT location of isoform 2.
FT MUTAGEN 26 26 N->G: Loss of interaction with PLCE1;
FT when associated with V-12.
FT MUTAGEN 29 29 V->A: No effect on interaction with
FT PLCE1; when associated with V-12.
FT MUTAGEN 32 32 Y->F: Loss of interaction and recruitment
FT to plasma membrane of PLCE1; when
FT associated with V-12.
FT MUTAGEN 34 34 P->G: No effect on interaction with
FT PLCE1; when associated with V-12.
FT MUTAGEN 35 35 T->S: Loss of interaction with PLCE1;
FT when associated with V-12.
FT MUTAGEN 37 37 E->G: No effect on interaction with
FT PLCE1; when associated with V-12.
FT MUTAGEN 38 38 D->N: No effect on interaction with
FT PLCE1; when associated with V-12.
FT MUTAGEN 39 39 S->C: No effect on interaction with
FT PLCE1; when associated with V-12.
FT MUTAGEN 59 59 A->T: Loss of GTPase activity and
FT creation of an autophosphorylation site.
FT MUTAGEN 61 61 Q->I: Moderately increased transformation
FT of cultured cell lines.
FT MUTAGEN 61 61 Q->V: Strongly increased transformation
FT of cultured cell lines.
FT MUTAGEN 83 83 A->T: GTP-binding activity reduced by
FT factor of 30.
FT MUTAGEN 118 118 C->S: Abolishes S-nitrosylation. No
FT stimulation of guanine nucleotide
FT exchange.
FT MUTAGEN 119 119 D->N: Loss of GTP-binding activity.
FT MUTAGEN 144 144 T->I: GTP-binding activity reduced by
FT factor of 25.
FT MUTAGEN 164 165 RQ->AV: Loss of GTP-binding activity.
FT MUTAGEN 181 181 C->S: Exclusively localized in Golgi.
FT Non-specifically localized on all
FT endomembranes; when associated with S-
FT 184.
FT MUTAGEN 184 184 C->S: Loss of S-(15-deoxy-Delta12,14-
FT prostaglandin J2-9-yl)cysteine
FT stimulation of Ras-GTPase activity.
FT Mainly localized in Golgi. Non-
FT specifically localized on all
FT endomembranes; when associated with S-
FT 181.
FT STRAND 3 11
FT STRAND 12 14
FT HELIX 16 25
FT STRAND 27 31
FT STRAND 34 37
FT STRAND 38 46
FT STRAND 49 57
FT STRAND 60 63
FT HELIX 66 74
FT STRAND 76 83
FT TURN 84 86
FT HELIX 87 104
FT STRAND 105 107
FT STRAND 111 116
FT STRAND 120 122
FT HELIX 127 136
FT STRAND 141 144
FT TURN 146 148
FT HELIX 152 164
SQ SEQUENCE 189 AA; 21298 MW; EE6DC2D933E2856A CRC64;
MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG
QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHQYREQI KRVKDSDDVP MVLVGNKCDL
AARTVESRQA QDLARSYGIP YIETSAKTRQ GVEDAFYTLV REIRQHKLRK LNPPDESGPG
CMSCKCVLS
//

MIM 109800
*RECORD*
*FIELD* NO
109800
*FIELD* TI
#109800 BLADDER CANCER
*FIELD* TX
A number sign (#) is used with this entry because bladder cancer is a
read morecomplex disorder with both genetic and environmental influences. Somatic
mutations in several genes, e.g., HRAS (190020), KRAS2 (190070), RB1
(614041), and FGFR3 (134934), have been implicated in bladder
carcinogenesis. See Bishop (1982) for a discussion of oncogenes.

CLINICAL FEATURES

Patients with cancer of the urinary bladder often present with multiple
tumors appearing at different times and at different sites in the
bladder. This observation had been attributed to a 'field defect' in the
bladder that allowed the independent transformation of epithelial cells
at a number of sites. Sidransky et al. (1992) tested this hypothesis
with molecular genetic techniques and concluded that in fact multiple
bladder tumors are of clonal origin. A number of bladder tumors can
arise from the uncontrolled spread of a single transformed cell. These
tumors can then grow independently with variable subsequent genetic
alterations.

Dyrskjot et al. (2003) reported the identification of clinically
relevant subclasses of bladder carcinoma using expression microarray
analysis of 40 well-characterized bladder tumors. Gene expression
profiles characterizing each stage and subtype identified their biologic
properties, producing potential targets for therapy.

INHERITANCE

Fraumeni and Thomas (1967) observed affected father and 3 sons. McKusick
(1972) encountered 2 instances of affected father and son at the Johns
Hopkins Hospital. McCullough et al. (1975) found transitional cell
carcinoma (TCC) in 6 persons in 3 sibships of 2 generations of a
kindred.

In a review of case reports and epidemiologic studies in the literature,
Kiemeney and Schoenberg (1996) concluded that first-degree relatives
have an increased risk for TCC by a factor of 2. Familial clustering of
smoking did not appear to be the cause of this increased risk.

In Iceland, Kiemeney et al. (1997) studied the first- to third-degree
relatives of 190 patients with bladder, ureter, or renal pelvis TCC
diagnosed between 1983 and 1992. In 41 of the 190 pedigrees, at least 1
relative had TCC of the urinary tract. Of the probands, 38 had only 1
and 3 had 2 affected relatives. The prevalence of family history of TCC
was 3% in first-degree and 10% in first- or second-degree relatives. The
risk of TCC among all relatives was slightly elevated, the
observed-to-expected ratio being greater among second- and third-degree
relatives than among first-degree relatives. Kiemeney et al. (1997)
concluded that the greater risk among distant relatives argues against
the existence of a hereditary subtype of bladder TCC, at least in the
founder population of Iceland.

MAPPING

Goldfarb et al. (1982) studied the DNA from T24, a cell line derived
from a human bladder carcinoma, which can induce the morphologic
transformation of nonmalignant cells. The gene responsible for this
transformation was cloned by techniques of gene rescue: it was shown to
be human in origin and less than 5 kb long. By Southern blot analysis of
human-rodent hybrid cell DNA, de Martinville et al. (1983) found that
the cellular homolog of the transforming DNA sequence isolated from the
bladder carcinoma line EJ is located on the short arm of chromosome 11,
which contains sequences homologous to the HRAS (190020) oncogene. No
evidence of gene amplification was found. These workers also found
karyologically 'a complex rearrangement of the short arm in two of the
four copies of chromosome 11 present in this heteroploid cell line'
(EJ). Shih et al. (1981) found that DNA from mouse and rabbit bladder
cancers as well as from the human bladder cancer cell line EJ induced
foci of transformed cells when applied to monolayer cultures of NIH3T3
cells.

Deletions involving chromosome 9 represent the most frequent genetic
change identified in bladder tumors. Several independent studies had
reported overall deletion frequencies of 50 to 70% in large series of
tumors (see review by Sandberg, 2002). It was of particular interest
that these deletions were present at similar frequency in bladder tumors
of all grades and stages (Tsai et al., 1990). This finding of chromosome
9 deletions as the sole genetic change in many low-grade, early-stage
tumors suggests that it may represent an early or initiating genetic
event. Keen and Knowles (1994) used a panel of 22 highly informative
microsatellite markers, evenly distributed along chromosome 9, to
analyze LOH in 95 cases of primary TCC of the bladder. In 49 tumors
(53%), LOH was demonstrated at one or more loci. Of these 49, 30 had LOH
at all informative loci, indicating probable monosomy 9. Subchromosomal
deletions were found in 19 tumors (22%), 5 of 9p only, 9 of 9q only, and
5 of both 9p and 9q with a clear region of retention of heterozygosity
between. The patterns of LOH in these tumors indicated a common region
of deletion on 9p between D9S126 (9p21) and the interferon-alpha cluster
(IFNA; 147660) located also at 9p21. A single tumor showed a second site
of deletion on 9p telomeric to IFNA, indicating the possible existence
of 2 target genes on 9p. All deletions of 9q were large, with a common
region of deletion between D9S15 (9q13-q21.1) and D9S60 (9q33-q34.1).
The results provided evidence for the simultaneous involvement of
distinct suppressor loci on 9p and 9q in bladder carcinoma.

In a study of loss of heterozygosity (LOH), Shipman et al. (1993) found
no evidence of deletion at 17p13, the region known to contain the p53
tumor suppressor gene (TP53; 191170).

In a genomewide SNP association study involving 1,803 patients with
urinary bladder cancer and 34,336 controls from Iceland and the
Netherlands, and follow-up studies in 7 additional case-control groups
(2,165 cases and 3,800 controls), Kiemeney et al. (2008) found a strong
association with allele T of dbSNP rs9642880 on chromosome 8q24, 30 kb
upstream of the MYC gene (190080) (odds ratio = 1.22; p = 9.34 x
10(-12)). Kiemeney et al. (2008) estimated that approximately 20% of
individuals of European ancestry are homozygous for the T allele, and
their estimated risk of developing UBC is 1.49 times that of
noncarriers. No association was observed between bladder cancer and
other 8q24 variants previously associated with prostate, colorectal, and
breast cancers. A weaker signal was observed with dbSNP rs710521 located
near TP63 (603273) on chromosome 3q28 (odds ratio = 1.19; p = 1.15 x
10(-7)).

In a follow-up study of bladder cancer (Kiemeney et al., 2008) using
several European case-control sample sets comprising 4,739 patients and
45,549 controls, Kiemeney et al. (2010) found a significant association
between the T allele of dbSNP rs798766 in intron 5 of the TACC3 gene
(605303) on chromosome 4p16.3 and bladder cancer (odds ratio of 1.24, p
= 9.9 x 10(-12)). TACC3 is located 70 kb from FGFR3 (134934). The SNP
dbSNP rs798766 showed a stronger association with low-grade and
low-stage UBC than with more aggressive forms of the disease, and was
associated with higher risk of recurrence in low-grade stage Ta tumors.
Moreover, the frequency of the T allele was higher in stage Ta
(noninvasive) tumors that had an activating mutation in the FGFR3 gene
than in Ta tumors with wildtype FGFR3. Further cellular studies
suggested that the T allele of dbSNP rs798766 may influence expression
of FGFR3. The results suggested a link between germline variants,
somatic mutations of FGFR3, and risk of urinary bladder cancer.

MOLECULAR GENETICS

Analysis of LOH at 11p13, a region containing the Wilms tumor suppressor
gene (WT1; 607102), showed deletion at the CAT locus (115500) in 13 of
18 bladder cancers (72%), at the WT1 locus in 7 of 14 (50%), and at the
FSHB locus (136530) in 6 of 16 (38%).

See 190020.0001 for a somatic mutation identified in the HRAS oncogene
in a bladder carcinoma.

See 190070.0002 for a somatic mutation identified in the KRAS oncogene
in a bladder carcinoma.

See 614041.0009 for a somatic mutation identified in the RB1 gene in a
bladder carcinoma.

Risch et al. (1995) demonstrated that the slow N-acetylation genotype
(NAT2; 612182) is a susceptibility factor in occupational and
smoking-related bladder cancer. Employing PCR-based genotyping, they
investigated NAT2 type among 189 Caucasian bladder cancer patients
attending a clinic in Birmingham, U.K. The results were compared to
those from an age-matched nonmalignant Caucasian control population from
the same region. Risch et al. (1995) found a significant excess of
genotypic slow acetylators in patients exposed to arylamines as a result
of their occupation or cigarette use. A higher proportion of slow
acetylators was also found in most bladder cancer patients without
identified exposure to arylamines when compared to the nonmalignant
controls.

Hruban et al. (1994) did a retrospective molecular genetic analysis of
the bladder carcinoma that was the cause of death in the case of Hubert
H. Humphrey (1911-1978), U.S. senator and vice president. In 1967,
hematuria led to a diagnosis of chronic proliferative cystitis. Although
urine cytology at that time was thought by one prominent cytopathologist
to be diagnostic of carcinoma, a diagnosis of infiltrating carcinoma of
the bladder was not made until August 1976. Hruban et al. (1994)
analyzed both the invasive bladder carcinoma resected in 1976 and the
filters prepared from urine in 1967. Both showed a transversion from
adenine to thymine in codon 227, creating a cryptic splice site in exon
7 of the p53 gene (191170). The mutation resulted in the loss of several
amino acids and in the production of a shortened, mutant p53 protein.
This mutation was not present in nonneoplastic tissue of the resected
bladder.

Cappellen et al. (1999) found expression of a constitutively activated
FGFR3 in a large proportion of 2 common epithelial cancers, bladder
cancer and cervical cancer (603956). The most frequent FGFR3 somatic
mutation in epithelial tumors was ser249 to cys (134934.0013), affecting
5 of 9 bladder cancers and 3 of 3 cervical cancers.

In studies for bladder cancer predisposition, Wu et al. (2006) applied a
multigenic approach using a comprehensive panel of 44 selected
polymorphisms in 2 pathways, DNA repair and cell cycle control, and, to
evaluate higher order gene-gene interactions, classification and
regression tree (CART) analysis. This hospital-based case-control study
involved 696 white patients newly diagnosed with bladder cancer and 629
unaffected white controls. Individually, only the asp312-to-asn
polymorphism of the XPD gene (126340), the lys820-to-arg polymorphism of
the RAG1 gene (179615), and an intronic SNP of the p53 gene (191170)
exhibited statistically significant main effects. However, Wu et al.
(2006) found a significant gene dosage effect for increasing numbers of
potential high risk alleles in DNA repair and cell cycle pathways
separately and combined. In addition, they found that smoking had a
significant multiplicative interaction with SNPs in the combined DNA
repair and cell cycle control pathways (P less than 0.01). All genetic
effects were evident only in 'ever smokers' (persons who had smoked more
than 100 cigarettes) and not in 'never smokers.' Moreover, subgroups
identified with higher cancer risk also exhibited higher levels of
induced genetic damage than did subgroups with lower risk. There was a
significant trend of higher numbers of bleomycin- and benzo[a]pyrine
diol-epoxide (BPDE)-induced chromatid breaks (by mutagen sensitivity
assay) and DNA damage (by comet assay) for individuals in higher risk
subgroups among cases of bladder cancer in smokers. Thus, higher order
gene-gene and gene-smoking interactions included SNPs that modulated
repair and resulted in diminished DNA repair capacity. This study
confirmed the importance of taking a multigene pathway-based approach to
risk assessment.

Fliss et al. (2000) identified a somatic 21-bp deletion in the
mitochondrial MTCYB gene in tumor tissue from a patient with bladder
cancer. Dasgupta et al. (2008) found that overexpression of the deletion
identified by Fliss et al. (2000) in murine bladder cancer cells
resulted in increased tumor growth and an invasive phenotype in vitro
and after injection into mice. Increased tumor growth was associated
with shifts toward glycolysis and production of reactive oxygen species
(ROS). Rapid cell cycle progression was associated with upregulation of
the NFKB (164011) signaling pathway, and inhibition of ROS or NFKB
diminished tumor growth in vitro. Transfection of the 21-bp deletion
into human uroepithelial cells resulted in similar effects. The findings
suggested that mitochondrial mutations may contribute to tumor growth.

Van der Post et al. (2010) used a questionnaire-based survey to
ascertain the risk of urogenital cancer in 95 families with HNPCC (see,
e.g., 120435). Bladder cancer was diagnosed in 21 patients (90% men)
from 19 families; 15 had mutations in the MSH2 gene (609309). Men
carrying an MSH2 mutation and their first degree relatives had a
cumulative risk by age 70 of 12.3% for bladder cancer and 5.9% for upper
urinary tract cancer. Van der Post et al. (2010) concluded that patients
with Lynch syndrome, particularly those carrying MSH2 mutations, have an
increased risk of urinary tract cancer, which may warrant surveillance.

Gui et al. (2011) sequenced the exomes of 9 individuals with TCC and
screened all somatically mutated genes in a covalent set of 88
additional individuals with TCC with different tumor stages and grades.
Gui et al. (2011) discovered a variety of genes previously unknown to be
mutated in TCC. Notably, they identified genetic aberrations of the
chromatin remodeling genes UTX (300128), MLL (159555), MLL3 (606833),
CREBBP (600140), EP300 (602700), NCOR1 (600849), ARID1A (603024), and
CHD6 in 59% of 97 subjects with TCC. Of these genes, UTX was altered
substantially more frequently in tumors of low stages and grades,
highlighting its potential role in the classification and diagnosis of
bladder cancer.

Solomon et al. (2013) reported the discovery of truncating mutations of
STAG2 (300826), which regulates sister chromatid cohesion and
segregation, in 36% of papillary noninvasive urothelial carcinomas and
16% of invasive urothelial carcinomas of the bladder. Solomon et al.
(2013) stated that their studies suggested that STAG2 has a role in
controlling chromosome number but not the proliferation of bladder
cancer cells.

Guo et al. (2013) reported genomic analysis of transitional cell
carcinoma (TCC) by both whole-genome and whole-exome sequencing in 99
individuals. Beyond confirming recurrent mutations in genes previously
identified as being mutated in TCC, Guo et al. (2013) identified
additional altered genes and pathways that were implicated in TCC. Guo
et al. (2013) discovered frequent alterations in STAG2 (300826) and
ESPL1 (604143), both involved in the sister chromatid cohesion and
segregation process. Overall, 32 of the 99 tumors (32%) harbored genetic
alterations in the sister chromatid cohesion and segregation process.

Balbas-Martinez et al. (2013) found that STAG2 was significantly and
commonly mutated or lost in urothelial bladder cancer, mainly in tumors
of low stage or grade, and that its loss was associated with improved
outcome. Loss of expression was often observed in chromosomally stable
tumors, and STAG2 knockdown in bladder cancer cells did not increase
aneuploidy. STAG2 reintroduction in nonexpressing cells led to reduced
colony formation. Balbas-Martinez et al. (2013) found that STAG2 is a
novel urothelial bladder cancer tumor suppressor acting through
mechanisms that are different from its role in preventing aneuploidy.

CLINICAL MANAGEMENT

Iyer et al. (2012) studied the tumor genome of a patient with metastatic
bladder cancer who achieved a durable (greater than 2 years) and ongoing
complete response to everolimus, a drug targeting the mTORC1 complex
(see 601231). Whole genome sequencing of DNA derived from the primary
tumor and blood identified a 2-bp deletion in the TSC1 (605284) gene
resulting in a frameshift truncation, and a nonsense mutation in the NF2
(607379) gene. Iyer et al. (2012) sequenced both genes in a second
cohort of 96 high-grade bladder cancers and identified 5 additional
somatic TSC1 mutations, whereas no additional NF2 mutations were
detected. Subsequently, Iyer et al. (2012) explored whether TSC1
mutation is a biomarker of clinical benefit from everolimus therapy in
bladder cancer, and studied 13 additional bladder cancer patients
treated with everolimus. Three additional tumors harbored nonsense
mutations in TSC1, including 2 patients who had minor responses to
everolimus (17% and 24% tumor regression, respectively). Tumors from 8
of the 9 patients who showed disease progression were TSC1 wildtype.
Patients with TSC1-mutant tumors remained on everolimus longer than
those with wildtype tumors (7.7 vs 2.0 months, p = 0.004) with a
significant improvement in time to recurrence (4.1 vs 1.8 months; hazard
ratio = 18.5, 95% confidence interval 2.1 to 162, p = 0.001). Iyer et
al. (2012) concluded that mTORC1-directed therapies may be most
effective in cancer patients whose tumors harbor TSC1 somatic mutations.

*FIELD* SA
Krontiris and Cooper (1981); Leklem and Brown (1976); Lynch et al.
(1979); Mahboubi et al. (1981)
*FIELD* RF
1. Balbas-Martinez, C.; Sagrera, A.; Carrillo-de-Santa-Pau, E.; Earl,
J.; Marquez, M.; Vazquez, M.; Lapi, E.; Castro-Giner, F.; Beltran,
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inactivation of STAG2 in bladder cancer is not associated with aneuploidy. Nature
Genet. 45: 1464-1469, 2013.

2. Bishop, J. M.: Oncogenes. Sci. Am. 246(3): 80-92, 1982.

3. Cappellen, D.; De Oliveira, C.; Ricol, D.; Gil Diez de Medina,
S.; Bourdin, J.; Sastre-Garau, X.; Chopin, D.; Thiery, J. P.; Radvanyi,
F.: Frequent activating mutations of FGFR3 in human bladder and cervix
carcinomas. (Letter) Nature Genet. 23: 18-20, 1999.

4. Dasgupta, S.; Hoque, M. O.; Upadhyay, S.; Sidransky, D.: Mitochondrial
cytochrome B gene mutation promotes tumor growth in bladder cancer. Cancer
Res. 68: 700-706, 2008.

5. de Martinville, B.; Giacalone, J.; Shih, C.; Weinberg, R. A.; Francke,
U.: Oncogene from human EJ bladder carcinoma is located on the short
arm of chromosome 11. Science 219: 498-501, 1983.

6. Dyrskjot, L.; Thykjaer, T.; Kruhoffer, M.; Jensen, J. L.; Marcussen,
N.; Hamilton-Dutoit, S.; Wolf, H.; Orntoft, T. F.: Identifying distinct
classes of bladder carcinoma using microarrays. Nature Genet. 33:
90-96, 2003.

7. Fliss, M. S.; Usadel, H.; Caballero, O. L.; Wu, L.; Buta, M. R.;
Eleff, S. M.; Jen, J.; Sidransky, D.: Facile detection of mitochondrial
DNA mutations in tumors and bodily fluids. Science 287: 2017-2019,
2000.

8. Fraumeni, J. F., Jr.; Thomas, L. B.: Malignant bladder tumors
in a family. JAMA 201: 507-509, 1967.

9. Goldfarb, M.; Shimizu, K.; Perucho, M.; Wigler, M.: Isolation
and preliminary characterization of a human transforming gene from
T24 bladder carcinoma cells. Nature 296: 404-409, 1982.

10. Gui, Y.; Guo, G.; Huang, Y.; Hu, X.; Tang, A.; Gao, S.; Wu, R.;
Chen, C.; Li, X.; Zhou, L.; He, M.; Li, Z.; and 41 others: Frequent
mutations of chromatin remodeling genes in transitional cell carcinoma
of the bladder. Nature Genet. 43: 875-878, 2011.

11. Guo, G.; Sun, X.; Chen, C.; Wu, S.; Huang, P.; Li, Z.; Dean, M.;
Huang, Y.; Jia, W.; Zhou, Q.; Tang, A.; Yang, Z.; and 44 others
: Whole-genome and whole-exome sequencing of bladder cancer identifies
frequent alterations in genes involved in sister chromatid cohesion
and segregation. Nature Genet. 45: 1459-1463, 2013.

12. Hruban, R. H.; van der Riet, P.; Erozan, Y. S.; Sidransky, D.
: Molecular biology and the early detection of carcinoma of the bladder:
the case of Hubert H. Humphrey. New Eng. J. Med. 330: 1276-1278,
1994.

13. Iyer, G. Hanrahan, A. J.; Milowsky, M. I.; Al-Ahmadie, H.; Scott,
S. N.; Janakiraman, M.; Pirun, M.; Sander, C.; Socci, N. D.; Ostrovnaya,
I.; Viale, A.; Heguy, A.; Peng, L.; Chan, T. A.; Bochner, B.; Bajorin,
D. F.; Berger, M. F.; Taylor, B. S.; Solit, D. B.: Genome sequencing
identifies a basis for everolimus sensitivity. Science 338: 221
only, 2012.

14. Keen, A. J.; Knowles, M. A.: Definition of two regions of deletion
on chromosome 9 in carcinoma of the bladder. Oncogene 9: 2083-2088,
1994.

15. Kiemeney, L. A.; Moret, N. C.; Witjes, J. A.; Schoenberg, M. P.;
Tulinius, H.: Familial transitional cell carcinoma among the population
of Iceland. J. Urol. 157: 1649-1651, 1997.

16. Kiemeney, L. A.; Sulem, P.; Besenbacher, S.; Vermeulen, S. H.;
Sigurdsson, A.; Thorleifsson, G.; Gudbjartsson, D. F.; Stacey, S.
N.; Gudmundsson, J.; Zanon, C.; Kostic, J.; Masson, G.; and 61 others
: A sequence variant at 4p16.3 confers susceptibility to urinary bladder
cancer. Nature Genet. 42: 415-419, 2010.

17. Kiemeney, L. A.; Thorlacius, S.; Sulem, P.; Geller, F.; Aben,
K. K. H.; Stacey, S. N.; Gudmundsson, J.; Jakobsdottir, M.; Bergthorsson,
J. T.; Sigurdsson, A.; Blondal, T.; Witjes, J. A.; and 52 others
: Sequence variant on 8q24 confers susceptibility to urinary bladder
cancer. Nature Genet. 40: 1307-1311, 2008.

18. Kiemeney, L. A. L. M.; Schoenberg, M.: Familial transitional
cell carcinoma. J. Urol. 156: 867-872, 1996.

19. Krontiris, T. G.; Cooper, G. M.: Transforming activity of human
tumor DNAs. Proc. Nat. Acad. Sci. 78: 1181-1184, 1981.

20. Leklem, J. E.; Brown, R. R.: Abnormal tryptophan metabolism in
a family with a history of bladder cancer. J. Nat. Cancer Inst. 56:
1101-1104, 1976.

21. Lynch, H. T.; Walzak, M. P.; Fried, R.; Domina, A. H.; Lynch,
J. F.: Familial factors in bladder carcinoma. J. Urol. 122: 458-461,
1979.

22. Mahboubi, A. O.; Ahlvin, R. C.; Mahboubi, E. O.: Familial aggregation
of urothelial carcinoma. J. Urol. 126: 691-692, 1981.

23. McCullough, D. L.; Lamm, D. L.; McLaughlin, A. P., III; Gittes,
R. F.: Familial transitional cell carcinoma of the bladder. J. Urol. 113:
629-635, 1975.

24. McKusick, V. A.: Personal Communication. Baltimore, Md. 1972.

25. Risch, A.; Wallace, D. M. A.; Bathers, S.; Sim, E.: Slow N-acetylation
genotype is a susceptibility factor in occupational and smoking related
bladder cancer. Hum. Molec. Genet. 4: 231-236, 1995.

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genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 290:
261-264, 1981.

28. Shipman, R.; Schraml, P.; Colombi, M.; Raefle, G.; Ludwig, C.
U.: Loss of heterozygosity on chromosome 11p13 in primary bladder
carcinoma. Hum. Genet. 91: 455-458, 1993.

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A. C.; Vogelstein, B.: Clonal origin of bladder cancer. New Eng.
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30. Solomon, D. A.; Kim, J.-S.; Bondaruk, J.; Shariat, S. F.; Wang,
Z.-F.; Elkahloun, A. G.; Ozawa, T.; Gerard, J.; Zhuang, D.; Zhang,
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in human bladder cancer. Cancer Res. 50: 44-47, 1990.

32. van der Post, R. S.; Kiemeney, L. A.; Ligtenberg, M. J. L.; Witjes,
J. A.; Hulsbergen-van de Kaa, C. A.; Bodmer, D.; Schaap, L.; Kets,
C. M.; van Krieken, J. H. J. M.; Hoogerbrugge, N.: Risk of urothelial
bladder cancer in Lynch syndrome is increased, in particular among
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33. Wu, X.; Gu, J.; Grossman, H. B.; Amos, C. I.; Etzel, C.; Huang,
M.; Zhang, Q.; Millikan, R. E.; Lerner, S.; Dinney, C. P.; Spitz,
M. R.: Bladder cancer predisposition: a multigenic approach to DNA-repair
and cell-cycle-control genes. Am. J. Hum. Genet. 78: 464-479, 2006.

*FIELD* CS

GU:
Transitional cell bladder carcinoma

Inheritance:
Autosomal dominant (11p)

*FIELD* CN
Ada Hamosh - updated: 01/09/2014
Ada Hamosh - updated: 11/5/2012
Ada Hamosh - updated: 10/7/2011
Cassandra L. Kniffin - updated: 12/3/2010
Cassandra L. Kniffin - updated: 5/10/2010
Cassandra L. Kniffin - updated: 11/19/2008
Cassandra L. Kniffin - updated: 10/23/2008
Victor A. McKusick - updated: 2/20/2006
Victor A. McKusick - updated: 12/31/2002
Victor A. McKusick - updated: 12/10/2002
Victor A. McKusick - updated: 1/12/2000
Victor A. McKusick - updated: 6/21/1997

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

*FIELD* ED
alopez: 01/09/2014
alopez: 11/5/2012
alopez: 10/13/2011
terry: 10/7/2011
carol: 6/17/2011
wwang: 1/4/2011
ckniffin: 12/3/2010
alopez: 5/12/2010
ckniffin: 5/10/2010
terry: 6/3/2009
alopez: 11/21/2008
ckniffin: 11/19/2008
wwang: 10/24/2008
ckniffin: 10/23/2008
carol: 8/28/2008
ckniffin: 3/1/2007
alopez: 2/22/2006
terry: 2/20/2006
alopez: 1/8/2003
carol: 1/3/2003
terry: 12/31/2002
alopez: 12/10/2002
terry: 12/10/2002
ckniffin: 8/26/2002
mgross: 1/31/2000
terry: 1/12/2000
terry: 6/24/1997
terry: 6/21/1997
terry: 10/22/1996
mark: 3/31/1995
carol: 9/12/1994
davew: 6/8/1994
mimadm: 4/9/1994
carol: 8/18/1993
carol: 5/11/1992

MIM 163200
*RECORD*
*FIELD* NO
163200
*FIELD* TI
#163200 SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME; SFM
;;SFM SYNDROME;;
LINEAR SEBACEOUS NEVUS SYNDROME;;
read moreSEBACEOUS NEVUS SYNDROME, LINEAR;;
JADASSOHN NEVUS PHAKOMATOSIS; JNP;;
NEVUS SEBACEUS OF JADASSOHN;;
ORGANOID NEVUS PHAKOMATOSIS;;
EPIDERMAL NEVUS SYNDROME, FORMERLY
*FIELD* TX
A number sign (#) is used with this entry because
Schimmelpenning-Feuerstein-Mims (SFM) syndrome can be caused by
postzygotic somatic mutation in either the HRAS (190020) gene on
chromosome 11p or the KRAS (190070) gene on chromosome 12p.

Isolated nevus sebaceous (see 162900) can be caused by somatic mutation
in several genes, including HRAS and KRAS.

DESCRIPTION

Schimmelpenning-Feuerstein-Mims syndrome, also known as linear sebaceous
nevus syndrome, is characterized by sebaceous nevi, often on the face,
associated with variable ipsilateral abnormalities of the central
nervous system, ocular anomalies, and skeletal defects (summary by
Happle, 1991 and Ernst et al., 2007). The linear sebaceous nevi follow
the lines of Blaschko (Hornstein and Knickenberg, 1974; Bouwes Bavinck
and van de Kamp, 1985). All cases are sporadic. The syndrome is believed
to be caused by an autosomal dominant lethal mutation that survives by
somatic mosaicism (Gorlin et al., 2001).

CLINICAL FEATURES

Feuerstein and Mims (1962) described 2 unrelated patients with linear
nevus sebaceous of the midline of the face associated with epilepsy,
focal EEG abnormalities, and mental retardation. Mehregan and Pinkus
(1965) outlined the natural history of organoid nevi. The first stage is
characterized by alopecia with absent or primitive hair follicles and
numerous small hypoplastic sebaceous glands. At puberty, the lesions
become verrucous with hyperplastic sebaceous glands. Benign or malignant
tumors develop in later stages.

Zaremba (1978) reviewed 37 reported cases of this disorder, described
under different terms and eponyms. He also reviewed an original 19th
century publication of Jadassohn and concluded that it was so good and
extensive that his name deserved being attached to the disorder. He
proposed that the condition be termed 'Jadassohn naevus phakomatosis'
(JNP). Zaremba et al. (1978) reported 2 cases from their own experience.
One of the patients required neurosurgical intervention, and histologic
changes in the brain were reported.

Baker et al. (1987) reported 4 patients with epidermal nevus syndrome
and neurologic manifestations, including mental retardation, seizures,
ophthalmologic anomalies, intracranial aneurysm, and porencephalic cyst.
A review of 60 reported cases suggested that central nervous system
complications were more likely associated with epidermal nevi on the
head and that the anomalies were most often ipsilateral to the skin
lesion.

Monk and Vollum (1982) reported mother and daughter with nevus sebaceous
of Jadassohn of the scalp. They suggested that this was the first
familial occurrence reported. A similar condition, inflammatory linear
verrucous epidermal nevus, was described by Hamm and Happle (1986) in
mother and daughter. In a black man, his daughter and a granddaughter,
Sahl (1990) described nevus sebaceus of the scalp. A basal cell
carcinoma had arisen in the nevus in the grandfather. Benedetto et al.
(1990) described the disorder in a boy and his maternal half brother.

Dodge and Dobyns (1995) described a girl, born of unrelated parents,
with sebaceous nevus syndrome, hemihypertrophy, coloboma of the left
iris, talipes equinovarus, genu recurvatum, syndactyly 3-4 on the left
foot, left hemimegalencephaly, and pachygyria. In addition, Dandy-Walker
malformation and agenesis of the corpus callosum were found on cranial
MRI. Consistent with the proposal by Happle (1991), Dodge and Dobyns
(1995) suggested that sebaceous nevus syndrome may be caused by mosaic
mutation of a gene that would be lethal if expressed in all cells.

Heike et al. (2005) described a 19-year-old man with epidermal nevus
syndrome who had right-sided linear skin lesions, generalized weakness,
diffuse osteopenia associated with hypophosphatemic rickets, and
distinctive focal bone lesions ipsilateral to the skin findings. The
patient did not have the typical radiographic or histopathologic
findings of fibrous dysplasia, although his circulating FGF23 (605380)
level was elevated; screening of the GNAS gene (139320) revealed no
mutation. Heike et al. (2005) reviewed 33 reported cases of ENS and
systemic skeletal disease and found 8 (24%) involving distinctly
asymmetric bone disease with more severe changes ipsilateral to the skin
lesions. Heike et al. (2005) suggested that the focal skeletal disease,
although different from fibrous dysplasia, may be a source of FGF23 in
ENS.

Hoffman et al. (2005) reported a 17.5-year-old man of Korean ancestry
who had onset of linear nevus sebaceous syndrome before age 1 year. At 7
years of age, he developed hypophosphatemic rickets and exhibited a
learning disability and an attention deficit disorder. Laboratory
studies showed elevated plasma FGF23, a phosphaturic peptide. Treatment
with the somatostatin (SST; 182450) agonist octreotide and excision of
the nevus resulted in normalization of plasma FGF23 and clinical
improvement. In addition, the patient had increased serum IgE levels,
which decreased somewhat after octreotide and surgery. Hoffman et al.
(2005) suggested that the hypophosphatemic rickets observed in linear
nevus sebaceous syndrome is a type of tumor-induced osteomalacia
resulting from a tumor-produced phosphaturic substance, and suggested
that FGF23 and perhaps IgE are the mediators.

Ernst et al. (2007) reported a 5-year-old girl with Schimmelpenning
syndrome. She had an extensive, darkly pigmented, verrucous skin patch
involving a large portion of the left side of her face and a smaller
similar lesion on the right side. She also had a linear verrucoid lesion
of the facial midline extending from the hairline to the chin.
Neurologic involvement included blindness, seizures, and developmental
delay. She presented with large mass in the left maxilla that was
surgically removed and shown to be a central giant cell granuloma. About
1 year later, she developed a swelling on the right side of her face.
Pathology showed foci of central giant cell granulomas and complex
fibroosseous lesions in the maxilla, and an adenomatoid odontogenic
tumor in the mandible. Hard tissue specimens from the mouth showed
irregular accumulations of enamel, dentin, cementum, and pulp tissue,
consistent with odontomas and foci of globular mineralized dentin. She
also had multiple pigmented malformed teeth. Cytogenetic analysis of
tissue from the second operation showed a complex karyotype with 62 to
68 chromosomes per cell; every chromosome pair had numerical or
structural alterations. Eleven months later, another central giant cell
granuloma was excised from the left maxilla.

Zutt et al. (2003) reported a 52-year-old woman with
Schimmelpenning-Feuerstein-Mims syndrome and hypophosphatemic rickets.
At birth she was noted to have a large, right-sided nevus sebaceous
following the lines of Blaschko and extending to her head, neck, arm,
and trunk. The scalp was also involved, resulting in alopecia. The
patient developed recurrent syringocystadenoma papilliferum and basal
cell carcinoma within the nevus. Other features included generalized
growth retardation, bone deformation due to rickets, exotropia and
ophthalmoplegia of the left eye, corneal clouding, xanthelasmata on the
eyelids, and precocious puberty. Intelligence was normal. She was
treated with multiple dermabrasions over the years. Phosphaturia
disappeared after a long period of time, and Zutt et al. (2003)
postulated that a phosphaturic factor may have been produced by the
nevus. There was no family history of a similar disorder.

INHERITANCE

Schimmelpenning-Feuerstein-Mims syndrome is believed to be caused by an
autosomal dominant lethal mutation that survives by somatic mosaicism.
All reported cases have occurred sporadically (Gorlin et al., 2001).

Schworm et al. (1996) reported a pair of 5-year-old Turkish monozygotic
twin girls discordant for SFM syndrome. The affected girl was noted at
birth to have a right-sided skin nevus on the temple, and bilateral but
asymmetric keratoconjunctival dermoids, more severe on the right. Skull
radiographs were normal. At age 5 years, she had skin lesions limited to
the scalp with associated frontoparietal alopecia. The right eye was
more severely involved, with decreased visual acuity and esotropia.
Mental development was age-appropriate. The other twin showed no signs
of the disorder. The report supported the concept of a postzygotic
somatic mutation in the etiology of the syndrome.

Rijntjes-Jacobs et al. (2010) reported a second case of monozygotic
twins discordant for SFM syndrome. The male monochorionic-diamniotic
twins were born of a Dutch mother. The affected infant was noted to have
several yellowish plaque skin lesions along the lines of Blaschko on the
face, and severe eye abnormalities, including cryptophthalmus, coloboma,
microcornea, and epibulbar lipodermoids. There was also a cleft palate
and patent ductus arteriosus, and brain imaging suggested cerebral
atrophy and calcifications. The child died on day 16 of life. The other
twin was normal. The findings provided evidence for a postzygotic
mutation as a pathogenetic mechanism.

PATHOGENESIS

Happle (1986) suggested that this condition may be explained by a
dominant lethal gene arising as a somatic mutation in the early embryo
or a gametic half-chromatid mutation and surviving by mosaicism. The
experimental model in mice is the rescue of a lethal genotype by
chimerism with a normal embryo (Bennett, 1978). Happle (1986) suggested
a similar mechanism for the Proteus syndrome (176920) and the
McCune-Albright syndrome (174800).

Kousseff (1992) posited that JNP is, like other phakomatoses, a
paracrine growth regulation disorder or paracrinopathy, i.e.,
dysregulation of paracrine growth and of transforming growth factors at
cellular and extracellular matrix levels, leading to localized over- and
undergrowth anomalies. For the deficiencies, he adopted the term used by
Gomez (1988), i.e., hamartias, parallel to the term hamartomas. He
reviewed 13 cases, including one of extraordinarily severe and
widespread distribution.

MOLECULAR GENETICS

Groesser et al. (2012) analyzed tissue from 2 unrelated patients with
Schimmelpenning-Feuerstein-Mims syndrome for RAS hotspot mutations. One
patient (Zutt et al., 2003) carried a mutation in the HRAS gene (G13R;
190020.0017) and the other patient (Rijntjes-Jacobs et al., 2010)
carried a mutation in the KRAS gene (G12D; 190070.0005). In both
patients, the mutations were present in lesional tissue, including nevus
sebaceous, but not in nonlesional skin or blood leukocytes, consistent
with a somatic mosaic state. Functional analysis of mutant cells
carrying the HRAS G13R mutation showed constitutive activation of the
MAPK (see 176948) and PI3K (see 171834)/AKT (164730) signaling pathways.
Somatic mutations in the HRAS and/or KRAS genes were also found in 97%
of 65 isolated sebaceous nevi tissues. The authors postulated that the
mosaic mutation likely extends to extracutaneous tissues in SFM compared
to isolated sebaceous nevi, which could explain the phenotypic
pleiotropy.

*FIELD* SA
Aschinberg et al. (1977); Lantis et al. (1968)
*FIELD* RF
1. Aschinberg, L. C.; Solomon, L. M.; Zeis, P. M.; Justice, P.; Rosenthal,
I. M.: Vitamin D-resistant rickets associated with epidermal nevus
syndrome: demonstration of a phosphaturic substance in the dermal
lesions. J. Pediat. 91: 56-60, 1977.

2. Baker, R. S.; Ross, P. A.; Baumann, R. J.: Neurologic complications
of the epidermal nevus syndrome. Arch. Neurol. 44: 227-232, 1987.

3. Benedetto, L.; Sood, U.; Blumenthal, N.; Madjar, D.; Sturman, S.;
Hashimoto, K.: Familial nevus sebaceus. J. Am. Acad. Derm. 23:
130-132, 1990.

4. Bennett, D.: Rescue of a lethal T/t locus genotype by chimerism
with normal embryos. Nature 272: 539 only, 1978.

5. Bouwes Bavinck, J. N.; van de Kamp, J. J. P.: Organoid naevus
phakomatosis: Schimmelpenning-Feuerstein-Mims syndrome. Brit. J.
Derm. 113: 491-492, 1985.

6. Dodge, N. N.; Dobyns, W. B.: Agenesis of the corpus callosum and
Dandy-Walker malformation associated with hemimegalencephaly in the
sebaceous nevus syndrome. Am. J. Med. Genet. 56: 147-150, 1995.

7. Ernst, L. M.; Quinn, P. D.; Alawi, F.: Novel oral findings in
Schimmelpenning syndrome. Am. J. Med. Genet. 143A: 881-883, 2007.

8. Feuerstein, R. C.; Mims, L. C.: Linear nevus sebaceus with convulsions
and mental retardation. Am. J. Dis. Child. 104: 675-679, 1962.

9. Gomez, M. R.: Varieties of expression of tuberous sclerosis. Neurofibromatosis 1:
330-338, 1988.

10. Gorlin, R. J.; Cohen, M. M., Jr.; Hennekam, R. C. M.: Syndromes
of the Head and Neck. New York: Oxford Univ. Press (pub.) (4th
ed.): 2001. Pp. 484-488.

11. Groesser, L.; Herschberger, E.; Ruetten, A.; Ruivenkamp, C.; Lopriore,
E.; Zutt, M.; Langmann, T.; Singer, S.; Klingseisen, L.; Schneider-Brachert,
W.; Toll, A.; Real, F. X.; Landthaler, M.; Hafner, C.: Postzygotic
HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning
syndrome. Nature Genet. 44: 783-787, 2012.

12. Hamm, H.; Happle, R.: Inflammatory linear verrucous epidermal
nevus (ILVEN) in a mother and her daughter. Am. J. Med. Genet. 24:
685-690, 1986.

13. Happle, R.: How many epidermal nevus syndromes exist? A clinicogenetic
classification. J. Am. Acad. Derm. 25: 550-556, 1991.

14. Happle, R.: Cutaneous manifestation of lethal genes. Hum. Genet. 72:
280 only, 1986.

15. Heike, C. L.; Cunningham, M. L.; Steiner, R. D.; Wenkert, D.;
Hornung, R. L.; Gruss, J. S.; Gannon, F. H.; McAlister, W. H.; Mumm,
S.; Whyte, M. P.: Skeletal changes in epidermal nevus syndrome: does
focal bone disease harbor clues concerning pathogenesis? Am. J. Med.
Genet. 139A: 67-77, 2005.

16. Hoffman, W. H.; Jueppner, H. W.; DeYoung, B. R.; O'Dorisio, M.
S.; Given, K. S.: Elevated fibroblast growth factor-23 in hypophosphatemic
linear nevus sebaceous syndrome. Am. J. Med. Genet. 134A: 233-236,
2005.

17. Hornstein, O. P.; Knickenberg, M.: Zur Kenntnis des Schimmelpenning-Feuerstein-Mims-Syndroms
(Organoide Naevus-Phakomatose). Arch. Derm. Forsch. 250: 33-50,
1974.

18. Kousseff, B. G.: Hypothesis: Jadassohn nevus phakomatosis: a
paracrinopathy with variable phenotype. Am. J. Med. Genet. 43: 651-661,
1992.

19. Lantis, S.; Leyden, J.; Thew, M.; Heaton, C.: Nevus sebaceus
of Jadassohn. Arch. Derm. 98: 117-123, 1968.

20. Mehregan, A. H.; Pinkus, H.: Life history of organoid nevi. Arch.
Derm. 91: 574-588, 1965.

21. Monk, B. E.; Vollum, D. I.: Familial naevus sebaceus. J. Roy.
Soc. Med. 75: 660-661, 1982.

22. Rijntjes-Jacobs, E. G. J.; Lopriore, E.; Steggerda, S. J.; Kant,
S. G.: Walther, F. J.: Discordance for Schimmelpenning-Feuerstein-Mims
syndrome in monochorionic twins supports the concept of a postzygotic
mutation. Am. J. Med. Genet. 152A: 2816-2819, 2010.

23. Sahl, W. J., Jr.: Familial nevus sebaceus of Jadassohn: occurrence
in three generations. J. Am. Acad. Derm. 22: 853-854, 1990.

24. Schworm, H. D.; Jedele, K. B.; Holinski, E.; Hortnagel, K.; Rudolph,
G.; Boergen, K.-P.; Kampik, A.; Meitinger, T.: Discordant monozygotic
twins with the Schimmelpenning-Feuerstein-Mims syndrome. Clin. Genet. 50:
393-397, 1996.

25. Zaremba, J.: Jadassohn's naevus phakomatosis: 2. A study based
on a review of thirty-seven cases. J. Ment. Defic. Res. 22: 103-123,
1978.

26. Zaremba, J.; Wislawski, J.; Bidzinski, J.; Kansy, J.; Sidor, B.
: Jadassohn's naevus phakomatosis: 1. A report of two cases. J. Ment.
Defic. Res. 22: 91-102, 1978.

27. Zutt, M.; Strutz, F.; Happle, R.; Habenicht, E. M.; Emmert, S.;
Haenssle, H. A.; Kretschmer, L.; Neumann, C.: Schimmelpenning-Feuerstein-Mims
syndrome with hypophosphatemic rickets. Dermatology 207: 72-76,
2003.

*FIELD* CS
INHERITANCE:
Somatic mosaicism

GROWTH:
[Height];
Short stature;
[Other];
Growth retardation;
Asymmetric overgrowth

HEAD AND NECK:
[Head];
Cranial asymmetry;
[Eyes];
Lid lipodermoid;
Coloboma of eyelids, iris, and choroid;
Ophthalmoplegia (in some);
Corneal clouding (in some);
[Teeth];
Pigmented, malformed teeth

CARDIOVASCULAR:
[Vascular];
Coarctation of aorta

GENITOURINARY:
[Kidneys];
Horseshoe kidney

SKELETAL:
Osteopenia;
Recurrent fractures;
Bone deformities;
[Spine];
Kyphoscoliosis;
[Hands];
Finger abnormalities;
[Feet];
Toe abnormalities

SKIN, NAILS, HAIR:
[Skin];
Linear nevus sebaceous, often in midfacial area;
Lesions follow the lines of Blaschko;
Ichthyosis hystrix;
Nevus unius lateris;
Hemangioma;
Hypopigmentation;
[Hair];
Alopecia within lesion

NEUROLOGIC:
[Central nervous system];
Neurologic abnormalities in about 7%;
Mental retardation;
Seizures;
Hemimegalencephaly

ENDOCRINE FEATURES:
Hypophosphatemic vitamin D-resistant rickets (in some);
Precocious puberty (less common)

NEOPLASIA:
Basal cell carcinoma;
Syringocystadenoma papilliferum;
Central giant cell granuloma;
Trichoblastoma

LABORATORY ABNORMALITIES:
Phosphaturia (in some);
Phosphaturia may disappear after a long period of time

MISCELLANEOUS:
Onset of skin lesions at birth;
Extracutaneous manifestations are variable;
Secondary tumors develop within the skin lesions

MOLECULAR BASIS:
Caused by mutation in the V-Ki-Ras2 kirsten rat sarcoma viral oncogene
homolog gene (KRAS, 190070.0005);
Caused by mutation in the V-Ha-Ras harvey rat sarcoma viral oncogene
homolog gene (HRAS, 190020.0017)

*FIELD* CN
Cassandra L. Kniffin - updated: 7/25/2012
Cassandra L. Kniffin - updated: 5/22/2007
Kelly A. Przylepa - revised: 12/3/1999

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

*FIELD* ED
joanna: 07/26/2012
ckniffin: 7/25/2012
joanna: 3/19/2008
ckniffin: 5/22/2007
joanna: 1/18/2000
joanna: 12/3/1999

*FIELD* CN
Cassandra L. Kniffin - updated: 7/25/2012
Cassandra L. Kniffin - updated: 3/22/2012
Cassandra L. Kniffin - updated: 5/22/2007
Cassandra L. Kniffin - updated: 10/2/2006
Marla J. F. O'Neill - updated: 1/12/2006
Victor A. McKusick - updated: 12/9/2003
Victor A. McKusick - updated: 6/17/1999

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

*FIELD* ED
carol: 07/25/2012
ckniffin: 7/25/2012
alopez: 3/30/2012
terry: 3/28/2012
ckniffin: 3/22/2012
wwang: 7/22/2011
carol: 5/4/2011
ckniffin: 10/13/2008
wwang: 6/11/2007
ckniffin: 5/22/2007
wwang: 10/12/2006
wwang: 10/9/2006
ckniffin: 10/2/2006
wwang: 1/18/2006
terry: 1/12/2006
terry: 6/2/2004
tkritzer: 12/17/2003
terry: 12/9/2003
carol: 7/18/2001
jlewis: 7/8/1999
terry: 6/17/1999
carol: 7/21/1996
mimadm: 12/2/1994
carol: 7/16/1992
carol: 7/2/1992
carol: 4/1/1992
supermim: 3/16/1992
carol: 10/5/1990

MIM 190020
*RECORD*
*FIELD* NO
190020
*FIELD* TI
*190020 V-HA-RAS HARVEY RAT SARCOMA VIRAL ONCOGENE HOMOLOG; HRAS
;;HRAS1;;
HARVEY MURINE SARCOMA VIRUS ONCOGENE; RASH1;;
read morep21(RAS);;
p21;;
TRANSFORMATION GENE: ONCOGENE HAMSV
*FIELD* TX

CLONING

The 3 RAS oncogenes, HRAS, KRAS (190070), and NRAS (164790), encode
21-kD proteins called p21s.

Wong-Staal et al. (1981) identified human DNA sequences homologous to
cloned DNA fragments containing the oncogenic nucleic acid sequences of
a type C mammalian retrovirus, the Harvey strain of murine sarcoma virus
(HaMSV) derived from the rat. Non-onc intervening sequences were present
in the human counterpart, which is rather highly conserved in mammalian
evolution and probably plays a role in normal cell growth or
differentiation. Allelic variation in the human onc HaMSV gene was
identified. The transforming genes of retroviruses are derived from a
group of cellular genes that are highly conserved evolutionarily. The
relationship between viral transforming genes (collectively called
v-onc) and their normal cellular counterparts (collectively called
c-onc) is obviously of great scientific and medical interest. Chang et
al. (1982) studied the Harvey and Kirsten murine sarcoma viruses, 2
closely related rat-derived transforming retroviruses called v-Ha-ras
and v-Ki-ras, respectively. They concluded that the human genome
contains several copies of the c-ras gene family and that c-Ha-ras-1
(with intervening sequences) (HRAS1) has been more highly conserved than
has c-Ha-ras-2 (HRAS2; 300437).

MAPPING

By Southern blot analysis of human-rodent hybrid cell DNA, de
Martinville et al. (1983) found that the cellular homolog of the
transforming DNA sequence isolated from the bladder carcinoma line EJ is
located on the short arm of chromosome 11. The locus also contains
sequences homologous to the Harvey ras oncogene. No evidence of gene
amplification was found. These workers also found karyologically 'a
complex rearrangement of the short arm in two of the four copies of
chromosome 11 present in this heteroploid cell line' (EJ). Region 11p15
was the site of a breakpoint in a t(3;11) translocation found in tumor
cells from a patient with hereditary renal cell carcinoma (144700).

By in situ molecular hybridization studies of meiotic chromosomes
(pachytene bivalents), Jhanwar et al. (1983) found that KRAS and HRAS
probes mapped to chromomeres corresponding to bands 11p14.1, 12p12.1,
and 12q24.2 of somatic chromosomes. HRAS hybridized most avidly at
11p14.1. A weak hybridization at 3p21.3 was noted.

By somatic cell hybridization, Junien et al. (1984) found that HRAS1
maps to 11p15.5-p15.1. The HRAS1 and insulin (INS; 176730) genes appear
to be closely situated in the 11pter area; Gerhard et al. (1984) found a
maximum lod score of 4.1 at theta = 0.0 for the HRAS1 and INS linkage.
Two obligatory recombinants were found. These findings are consistent
with the observation that the HRAS gene is not deleted in cases of Wilms
tumor with deleted 11p13 (Junien et al., 1984). De Martinville and
Francke (1984) likewise mapped HRAS1 and INS, and beta-globin (HBB;
141900) as well, outside the 11p14.1-p11.2 segment.

Fisher et al. (1984) concluded that HRAS1 is distal to the INS and HBB
loci on 11p. Fearon et al. (1984) demonstrated that HRAS1 is 8 cM distal
to the HBB gene and 4 cM proximal to the INS gene. The HBB gene is about
7 cM distal to the parathyroid hormone gene (PTH; 168450). The length of
11p is estimated to be about 50 cM.

By high resolution in situ hybridization to meiotic pachytene
chromosomes, Chaganti et al. (1985) concluded that HRAS1 is located at
11p14.1, HBB at 11p11.22, PTH (not previously assigned regionally) at
11p11.21, and INS at 11p14.1.

Russell et al. (1996) constructed a contiguous physical map from the
HRAS1 gene to the 11p telomere. The contig spanned approximately 500 kb.
Three genes were placed on the contig in the following order: tel--RNH
(173320)--HRAS1--HRC (142705).

Bianchi et al. (1993) mapped the H-ras-1 gene to the beta-globin region
of mouse chromosome 7.

GENE FUNCTION

Goyette et al. (1983) found that the number of transcripts of the Harvey
ras gene increases during liver regeneration in rats. This appeared to
indicate regulated change in activity of an 'oncogene' in a physiologic
growth process.

Ishii et al. (1985) pointed out similarities between the promoter of
HRAS and that of EGF receptor (131550). This similarity is intriguing in
light of the finding of Hiwasa et al. (1988) that the preferential
degradation of EGF receptors by cathepsin L (116880) may be suppressed
by HRAS gene products (p21s).

Sears et al. (1999) showed that RAS enhances the accumulation of MYC
(190080) activity by stabilizing the MYC protein. Whereas MYC has a very
short half-life when produced in the absence of mitogenic signals, due
to degradation by the 26S proteasome, the half-life of MYC increases
markedly in growth-stimulated cells. This stabilization is dependent on
the RAS/RAF/MAPK (see 176948) pathway and is not augmented by proteasome
inhibition, suggesting that RAS inhibits the proteasome-dependent
degradation of MYC. Sears et al. (1999) proposed that one aspect of
MYC-RAS collaboration is an ability of RAS to enhance the accumulation
of transcriptionally active MYC protein.

Hahn et al. (1999) found that ectopic expression of TERT (187270) in
combination with 2 oncogenes, the simian virus 40 large-T oncoprotein
and an oncogenic allele of HRAS (HRASV12), resulted in direct
tumorigenic conversion of normal human epithelial and fibroblast cells.
These results demonstrated that disruption of the intracellular pathways
regulated by large-T, oncogenic RAS, and telomerase suffices to create a
human tumor cell.

Mochizuki et al. (2001) used fluorescent resonance energy transfer
(FRET)-based sensors to evaluate the spatiotemporal images of growth
factor-induced activation of RAS and RAP1 (179520). Epidermal growth
factor (131530) activated RAS at the peripheral plasma membrane and RAP1
at the intracellular perinuclear region of COS-1 cells. In PC12 cells,
nerve growth factor (see 162030)-induced activation of RAS was initiated
at the plasma membrane and transmitted to the whole cell body. After 3
hours, high RAS activity was observed at the extending neurites. By
using the FRAP (fluorescence recovery after photobleaching) technique,
Mochizuki et al. (2001) found that RAS at the neurites turned over
rapidly; therefore, the sustained RAS activity at neurites was due to
high GTP/GDP exchange rate and/or low GTPase activity, but not to the
retention of the active RAS. While previous biochemical analyses rarely
detected more than 40% activation of RAS upon growth factor stimulation,
Mochizuki et al. (2001) concluded that their data show that growth
factor stimulation strongly activates RAS/RAP1 in a very restricted area
within cells, and that a large population of RAS or RAP1 remains
inactive, causing an apparent low-level response in biochemical assays.

Zhu et al. (2002) examined the small GTPases RAS and RAP in the
postsynaptic signaling underlying synaptic plasticity. They showed that
RAS relays the NMDA receptor (see 138252) and
calcium/calmodulin-dependent protein kinase II (see 114078) signaling
that drives synaptic delivery of AMPA receptors (see 138248) during
long-term potentiation. In contrast, RAP was found to mediate the NMDA
receptor-dependent removal of synaptic AMPA receptors that occurs during
long-term depression. The authors determined that RAS and RAP exert
their effects on AMPA receptors that contain different subunit
composition. Thus, RAS and RAP, whose activities can be controlled by
postsynaptic enzymes, serve as independent regulators for potentiating
and depressing central synapses.

Oft et al. (2002) found that activation of Smad2 (601366) induced
migration of mouse squamous carcinoma cells, but that elevated levels of
H-ras were required for nuclear accumulation of Smad2. Elevated levels
of both were required for induction of spindle-cell transformation and
metastasis.

Weijzen et al. (2002) demonstrated that oncogenic Ras activates Notch
(190198) signaling and that wildtype Notch1 is necessary to maintain the
neoplastic phenotype in Ras-transformed human cells in vitro and in
vivo. Oncogenic Ras increases levels and activity of the intracellular
form of wildtype Notch1, and upregulates Notch1 ligand Delta1 (606582)
and also presenilin-1 (104311), a protein involved in Notch processing,
through a p38 (600289)-mediated pathway. Weijzen et al. (2002) concluded
that their observations placed Notch signaling among key downstream
effectors of oncogenic Ras.

Because therapeutics inhibiting RAS and NFKB (see 164011) pathways are
used to treat human cancer, experiments assessing the effects of
altering these regulators have been performed in mice. The medical
relevance of murine studies is limited, however, by differences between
mouse and human skin, and by the greater ease of transforming murine
cells. To study RAS and NFKB in a setting more relevant to human
tumorigenesis, Dajee et al. (2003) expressed the active HRAS
gly12-to-val mutation (190020.0001), NFKB p65 (164014), and a stable
NFKB repressor mutant of IKBA (164008) in human skin tissue. Primary
human keratinocytes were retrovirally transduced and used to regenerate
human skin on immune-deficient mice. Tissue expressing IKBA alone showed
mild hyperplasia, whereas expression of oncogenic RAS induced growth
arrest with graft failure. Although implicated in promoting features of
neoplasia in other settings, the coexpression of oncogenic RAS with NFKB
subunits failed to support proliferation. Coexpression of RAS and IKBA
produced large neoplasms with deep invasion through fat into underlying
muscle and fascia, similar to human squamous cell carcinomas (SCC), in 3
weeks. These tumors showed more than 10-fold increase in mitotic index,
preserved telomeres, and increased amounts of TERT (187270) protein.
Human keratinocytes lacking laminin-5 (LAMB3; 150310) and ITGB4 (147557)
failed to form tumors on coexpression with RAS and IKBA; however,
introduction of wildtype LAMB3 and ITGB4 restored tumor-forming
capacity, suggesting that these 2 proteins are required for SCC
tumorigenesis. Dajee et al. (2003) demonstrated that growth arrest
triggered by oncogenic RAS can be bypassed by IKBA-mediated blockade of
NFKB and that RAS opposed the increased susceptibility to apoptosis
caused by NFKB blockade. Thus, IKBA circumvents restraints on growth
promotion induced by oncogenic RAS and can act with RAS to induce
invasive human tissue neoplasia.

Johnson et al. (2005) found that the 3 human RAS genes, HRAS, KRAS, and
NRAS, contain multiple let-7 (605386) complementary sites in their
3-prime UTRs that allow let-7 miRNA to regulate their expression. Let-7
expression was lower in lung tumors than in normal lung tissue, whereas
expression of the RAS proteins was significantly higher in lung tumors,
suggesting a possible mechanism for let-7 in cancer.

Substitution of ser17 with asn (S17N) in any of the RAS proteins
produces dominant-inhibitory proteins with higher affinities for
exchange factors than normal RAS. These mutants cannot interact with
downstream effectors and therefore form unproductive complexes,
preventing activation of endogenous RAS. Using experiments in COS-7
cells, mouse fibroblasts, and canine kidney cells, Matallanas et al.
(2003) found that the Hras, Kras, and Nras S17N mutants exhibited
distinct inhibitory effects that appeared to be due largely to their
specific membrane localizations. The authors demonstrated that Hras is
present in caveolae, lipid rafts, and bulk disordered membranes, whereas
Kras and Nras are present primarily in disordered membranes and lipid
rafts, respectively. Thus, the Hras S17N mutant inhibited activation of
all 3 wildtype RAS isoforms, the Kras S17N mutant inhibited wildtype
Kras and the portion of Hras in disordered membranes, and the Nras S17N
mutant inhibited wildtype Nras and the portion of Hras in lipid rafts.

Rocks et al. (2005) showed that the specific subcellular distribution of
HRAS and NRAS guanosine triphosphate-binding proteins is generated by a
constitutive de/reacylation cycle that operates on palmitoylated
proteins, driving their rapid exchange between the plasma membrane and
the Golgi apparatus. Depalmitoylation redistributes farnesylated Ras in
all membranes, followed by repalmitoylation and trapping of Ras at the
Golgi, from where it is redirected to the plasma membrane via the
secretory pathway. This continuous cycle prevents Ras from nonspecific
residence on endomembranes, thereby maintaining the specific
intracellular compartmentalization. Rocks et al. (2005) found that the
de/reacylation cycle also initiates Ras activation at the Golgi by
transport of plasma membrane-localized Ras guanosine triphosphate.
Different de/repalmitoylation kinetics account for isoform-specific
activation responses to growth factors.

Ancrile et al. (2007) found that expression of an oncogenic form of HRAS
induced secretion of the cytokine IL6 (147620) in normal primary human
kidney cells, fibroblasts, myoblasts, and mammary epithelial cells.
Knockdown of IL6, genetic ablation of the Il6 gene in mice, or treatment
with IL6-neutralizing antibody retarded HRAS-driven tumorigenesis. IL6
appeared to act in a paracrine fashion to promote angiogenesis and tumor
growth.

Stites et al. (2007) developed and validated a mathematical model of Ras
signaling. The model-based predictions and associated experiments help
explain why only 1 of 2 classes of activating Ras point mutations with
in vitro transformation potential is commonly found in cancers.
Model-based analysis of these mutants uncovered a systems-level process
that contributes to total Ras activation in cells. This predicted
behavior was supported by experimental observations. Stites et al.
(2007) also used the model to identify a strategy in which a drug could
cause stronger inhibition on the cancerous Ras network than on the
wildtype network.

McMurray et al. (2008) showed that a large proportion of genes
controlled synergistically by loss-of-function p53 (TP53; 191170) and
Ras activation are critical to the malignant state of murine and human
colon cells. Notably, 14 of 24 'cooperation response genes' were found
to contribute to tumor formation in gene perturbation experiments. In
contrast, only 1 of 14 perturbations of the genes responding in a
nonsynergistic manner had a similar effect. McMurray et al. (2008)
concluded that synergistic control of gene expression by oncogenic
mutations thus emerges as an underlying key to malignancy, and provides
an attractive rationale for identifying intervention targets in gene
networks downstream of oncogenic gain- and loss-of-function mutations.

Lu et al. (2008) found that conditional activation of HRAS1(Q61L) in
embryonic stem cells in vitro induced the trophectoderm marker Cdx2
(600297) and enabled derivation of trophoblast stem cell lines that,
when injected into blastocysts, chimerized placental tissues. Erk2
(176948), the downstream effector of Ras-MAPK signaling, was
asymmetrically expressed in the apical membranes of the 8-cell-stage
embryo just before morula compaction. Inhibition of MAPK signaling in
cultured mouse embryos compromised Cdx2 expression, delayed blastocyst
development, and reduced trophectoderm outgrowth from embryo explants.
Lu et al. (2008) concluded that ectopic Ras activation can divert
embryonic stem cells toward extraembryonic trophoblastic fates and that
Ras-MAPK signaling has a role in promoting trophectoderm formation from
mouse embryos.

Gough et al. (2009) reported that malignant transformation by activated
Ras (190020.0001) is impaired without STAT3 (102582), in spite of the
inability of Ras to drive STAT3 tyrosine phosphorylation or nuclear
translocation. Moreover, STAT3 mutants that cannot be
tyrosine-phosphorylated, that are retained in the cytoplasm, or that
cannot bind DNA nonetheless supported Ras-mediated transformation.
Unexpectedly, STAT3 was detected within mitochondria, and exclusive
targeting of STAT3 to mitochondria without nuclear accumulation
facilitated Ras transformation. Mitochondrial STAT3 sustained altered
glycolytic and oxidative phosphorylation activities characteristic of
cancer cells. Thus, Gough et al. (2009) concluded that, in addition to
its nuclear transcriptional role, STAT3 regulates a metabolic function
in mitochondria, supporting Ras-dependent malignant transformation.

MOLECULAR GENETICS

- Somatic Mutations in Tumors

Der et al. (1982) found that mouse cells transformed by high molecular
weight DNAs of a human bladder and a human lung carcinoma cell line
contained new sequences homologous, respectively, to the transforming
genes of Harvey (ras-H) and Kirsten (ras-K) sarcoma viruses. The HRAS1
oncogene differs from its normal cellular counterpart by the absence of
a restriction endonuclease site. This sequence change could be used as
the basis of a rapid screening method for this oncogene. Muschel et al.
(1983) screened DNA from 34 persons and found that all were homozygous
for the normal allele. On the other hand, DNA from a patient's bladder
tumor, as well as DNA from his normal bladder and leukocytes, was
heterozygous at that restriction endonuclease site. The change was
pinpointed to 1 of 2 nucleotides, either of which would change the
twelfth amino acid (glycine) in the normal HRAS1 gene product. Thus, the
patient appeared to be carrying an HRAS1 mutation in his germline that
predisposed him to bladder cancer. The restriction enzyme used in the
screen was HpaII or its isoschizomer MspI. However, the authors
retracted their data that purported to show an HRAS1 mutation in both
tumor tissue and normal tissue; they concluded that the original
extractions of DNA from that patient were contaminated by a plasmid DNA
containing the HRAS1 oncogene. By restriction analysis, Feinberg et al.
(1983) tested 29 human cancers for this mutation and found it in none.
Included were 10 primary bladder cancers, 9 colon cancers, and 10 lung
cancers. The point mutation altering the twelfth amino acid of the HRAS1
gene product p21, found in a bladder cancer cell line, was the only one
known to result in a human transforming gene (see 190020.0001).

Capon et al. (1983) showed that the HRAS1 gene of the T24 human bladder
carcinoma line has at least 4 exons and that only a single point
mutation in the first exon distinguished the coding region of both
alleles of the normal gene from their activated counterpart. Both
versions of the gene encode a protein which is predicted to differ from
the corresponding viral gene product at 3 amino acid residues, one of
which was previously shown to represent the major site of
phosphorylation of the viral polypeptide. Pincus et al. (1983) concluded
that the bladder oncogene peptide (product of the mutant HRAS1 gene),
with valine rather than glycine at position 12 (190020.0001), has a
3-dimensional structure markedly different from the normal. Tong et al.
(1989) determined the structural change in the HRAS gene (called RASH by
them) resulting from replacement of glycine 12 by valine.

Sekiya et al. (1984) found a point mutation in the second exon of the
HRAS1 gene in a melanoma. Transversion from adenine to thymine resulted
in the substitution of leucine for glutamine as amino acid 61 in the
predicted p21 protein.

In 2 of 38 urinary tract tumors, Fujita et al. (1985) detected HRAS
oncogenes by transfection, cloned the oncogene in biologically active
form, and showed that it contained single base changes at codon 61
leading to substitutions of arginine and leucine, respectively, for
glutamine at this position. In 1 tumor, a 40-fold amplification of KRAS
was found. In the cell lines isolated from a single colon cancer,
Greenhalgh and Kinsella (1985) found a point mutation in codon 12 of
HRAS leading to an amino acid change in the gene product. The authors
cited experience with KRAS involvement in 3 colon cancers and NRAS
involvement in 1, while some 34 other colon cancers failed to
demonstrate HRAS activation at codon 12.

Goriely et al. (2009) screened 30 spermatocytic seminomas (see 273300)
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).

Yokota et al. (1986) concluded that alterations are found in oncogenes
MYC (190080), HRAS, or MYB (189990) in more than one-third of human
solid tumors. Amplification of MYC was found in advanced widespread
tumors and in aggressive primary tumors. Apparent allelic deletions of
HRAS and MYB could be correlated with progression and metastasis of
carcinomas and sarcomas.

Corell and Zoll (1988) used the restriction enzymes MspI, HpaII, BamHI,
and TaqI to analyze 426 alleles of the HRAS locus in DNA samples from 92
healthy individuals, 50 patients with breast cancer, 23 patients with
ovarian cancer, and 5 patients with lymphomas. The allelic distribution
was comparable among controls and tumor patients, indicating that a
genetic predisposition to malignancy is not conferred by unique alleles
at the HRAS locus. However, analysis of DNA isolated directly from
tumors revealed a discrepancy between the alleles in the white blood
cells and those in the tumor tissue. Six patients demonstrated alleles
in the tumor tissue which were not observed in DNA from the white blood
cells.

In a study of 118 lung cancer patients and 123 unaffected controls,
Ryberg et al. (1990) found striking differences in the distribution of
HRAS alleles. Six of 7 rare alleles were unique to the lung cancer group
and 1 rare allele for the control group; rare alleles were found in 10
of 236 chromosomes in lung cancer patients as compared to 1 of 246
chromosomes in the controls. The lung cancer group also had a
significantly lower frequency of 1 of the common alleles. The authors
emphasized the importance of control for ethnic factors and the
advantage in studying a relatively homogeneous population such as the
Norwegian one.

The HRAS1 gene is tightly linked to a minisatellite located
approximately 1 kb downstream from the gene's coding sequences and
composed of 30 to 100 units of a 28-bp consensus sequence. Thirty
alleles of 1,000 to 3,000 bp have been described. The 4 most common
alleles--A1, A2, A3, and A4--represent 94% of all alleles in whites and
have apparently served as progenitors for the remaining rare alleles.
Rare alleles appear in the genomes of patients with cancer about 3 times
as often as in controls without cancer (Krontiris et al., 1985); many
such alleles have been observed only in patients with cancer. Krontiris
et al. (1993) conducted a case-control study, typing 736 HRAS1 alleles
from patients with cancer and 652 from controls by Southern blotting of
leukocyte DNA. From analysis of the results and a meta-analysis of 22
other studies, they concluded that there was a significant association
of rare HRAS1 alleles with 4 types of cancer: carcinomas of the breast,
colorectum, and urinary bladder and acute leukemia. They considered it
unlikely that the explanation could be found in linkage disequilibrium
between these rare alleles and a pathogenetic lesion in the HRAS1 locus
or other neighboring loci. Alternatively, they pointed to observations
that new mutations of the HRAS1 minisatellite disrupt the controlled
expression of nearby genes, including HRAS1, by interacting directly
with transcriptional regulatory mechanisms. Furthermore, the
minisatellite is capable of activating and repressing transcription;
allele-specific effects have been observed.

Phelan et al. (1996) demonstrated a modifier effect of the HRAS1 locus
on the penetrance of the BRCA1 gene (113705) in causing ovarian cancer.
The polymorphism in question, a VNTR located 1 kb downstream of the
HRAS1 gene, had previously been found to show an association between
rare alleles and an increased risk of certain types of cancers,
including breast cancer. The risk for ovarian cancer was 2.11 times
greater for BRCA1 carriers harboring 1 or 2 rare HRAS1 alleles, compared
to carriers with only common alleles (P = 0.015). A magnitude of the
risk associated with a rare HRAS1 allele was not altered by adjusting
for the other known risk factors for hereditary ovarian cancer. This
study was said to have been the first to show the effect of a modifying
gene on the penetrance of an inherited cancer syndrome.

Groesser et al. (2012) analyzed tissue from 65 individuals with nevus
sebaceous (see 162900) for the presence of HRAS hotspot mutations. HRAS
mutations were present in 62 lesions (95%), with a G13R substitution
(190020.0017) accounting for 91%. Five sebaceous nevi carried 2 RAS
mutations; the other gene involved was KRAS. Nonlesional tissue from 18
patients showed a wildtype HRAS sequence. Eight individuals developed
secondary tumors within the nevus sebaceous, including 2
syringocystadenoma papilliferum, 3 trichoblastomas, and 3
trichilemmomas, and all secondary tumors carried the same mutation as
the nevi. Functional analysis of mutant cells carrying the G13R mutation
showed constitutive activation of the MAPK and PI3K (see 171834)/AKT
(164730) signaling pathways. Other somatic HRAS mutations identified
included G12S (190020.0003), G12D (190020.0013), and G12C (190020.0014).
One patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) was
found by Groesser et al. (2012) to carry the G13R mutation in the
somatic mosaic state. The authors postulated that the mosaic mutation
likely extends to extracutaneous tissues in that disorder, which could
explain the phenotypic pleiotropy.

Hafner et al. (2012) found somatic activating RAS mutations in 28 (39%)
of 72 keratinocytic epidermal nevi from 72 different individuals. HRAS
was the most commonly mutated gene, found in 29% of all nevi, with G13R
(190020.0017) being the most common mutation.

- Genotype/Phenotype Correlations among Somatic HRAS, KRAS,
and NRAS Mutations

In HRAS, KRAS, and NRAS, codons 12 and 61 are 'hotspots' for mutations
that activate their malignant transforming properties. Srivastava et al.
(1985) showed that mutation at these 3 loci result in changes in
electrophoretic mobility of the p21. Changes observed are, for the HRAS
gene, gly12 to val (bladder carcinoma), gly12 to asp (mammary
carcinosarcoma), gln61 to leu (lung carcinoma), and gln61 to arg (renal
pelvic carcinoma) and for the NRAS oncogene, gln61 to arg (lung
carcinoma). They proposed that the electrophoretic changes may be a
rapid method for identification of activated RAS genes, substituting for
the inherently insensitive and time-consuming transfection assay.

Vasko et al. (2003) performed a pooled analysis of 269 mutations in
HRAS, KRAS (190070), and NRAS (164790) garnered from 39 previous
studies. Mutations proved significantly less frequent when detected with
direct sequencing than without (12.3% vs 17%). The rates of mutation
involving NRAS exon 1 and KRAS exon 2 was less than 1%. Mutations of
codon 61 of NRAS were significantly more frequent in follicular tumors
(19%) than in papillary cancers (5%) and significantly more frequent in
malignant (25%) than in benign (14%) tumors. HRAS mutations in codons
12/13 were found in 2 to 3% of all types of tumors, but HRAS mutations
in codon 61 were observed in only 1.4% of tumors, and almost all of them
were malignant. KRAS mutations in exon 1 were found more often in
papillary than follicular cancers (2.7% vs 1.6%) and were sometimes
correlated with special epidemiologic circumstances. The second part of
this study involved analysis of 80 follicular tumors from patients
living in Marseille (France) and Kiev (Ukraine). HRAS mutations in
codons 12/13 were found in 12.5% of common adenomas and 1 follicular
carcinoma (2.9%). Mutations of codon 61 of NRAS occurred in 23.3% and
17.6% of atypical adenomas and follicular carcinomas, respectively. The
authors concluded that their results confirmed the predominance of
mutations of codon 61 of NRAS in thyroid follicular tumors and their
correlation with malignancy.

Nikiforova et al. (2003) analyzed a series of 88 conventional follicular
and Hurthle cell thyroid tumors for RAS (HRAS, NRAS, and KRAS) mutations
and PAX8 (167415)-PPARG (601487) rearrangements using molecular methods
and for galectin-3 (153619) and mesothelioma antibody HBME-1 expression
by immunohistochemistry. Forty-nine percent of conventional follicular
carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only
1 (3%) had both. Of follicular adenomas, 48% had RAS mutations, 4% had
PAX8-PPARG rearrangement, and 48% had neither. Follicular carcinomas
with RAS mutations most often displayed an
HBME-1-positive/galectin-3-negative immunophenotype and were either
minimally or overtly invasive. Hurthle cell tumors infrequently had
PAX8-PPARG rearrangement or RAS mutations.

- Costello Syndrome

Costello syndrome (218040), a multiple congenital anomaly and mental
retardation syndrome, overlaps phenotypically with Noonan syndrome
(163950), which is caused by mutation in the PTPN11 gene (176876) in
approximately 50% of cases. The PTPN11 gene encodes tyrosine phosphatase
SHP2; gain-of-function mutant SHP2 proteins identified in Noonan
syndrome have enhanced phosphatase activity, which results in activation
of a RAS-MAPK cascade in a cell-specific manner. Aoki et al. (2005)
hypothesized that genes mutated in Costello syndrome and in
PTPN11-negative Noonan syndrome encode molecules that function upstream
or downstream of SHP2 in signal pathways. Among these molecules, they
sequenced the entire coding region of 4 RAS genes in genomic DNA from 13
individuals with Costello syndrome and 28 individuals with
PTPN11-negative Noonan syndrome. In 12 of the 13 individuals with
Costello syndrome, they found one or another of 4 heterozygous mutations
in HRAS. These mutations had been identified somatically in various
tumors (Bos, 1989). Mutation analysis of genomic DNA from 2 different
tissues in 3 affected individuals and genomic DNA from parents in 4
families indicated that these 'oncogenic' and germline mutations
occurred de novo. No mutations in KRAS, NRAS (164790), HRAS, or ERAS
(300437) were observed in 28 individuals with Noonan syndrome or in 1
individual with Costello syndrome. Aoki et al. (2005) stated that to the
best of their knowledge, Costello syndrome was the first disorder
associated with germline mutations in the RAS family of GTPases. The
observations suggested that germline mutations in HRAS perturb human
development and increase susceptibility to tumors.

Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical
diagnosis of Costello syndrome and identified mutations in 37 (86%);
G12S (190020.0003) was the most common mutation, found in 30 of the 37
mutation-positive patients. The authors stated that, together with
previously published series (Aoki et al., 2005 and Gripp et al., 2006),
mutations in HRAS had been found in 82 (85%) of 96 patients with a
clinical diagnosis of Costello syndrome and that overall the frequency
of malignancy in the published mutation-positive cases was 11%.

Costello syndrome can be caused by heterozygous de novo missense
mutations affecting the codon for glycine-12 or glycine-13 of the HRAS
gene. Sol-Church et al. (2006) identified 39 Costello syndrome patients
harboring the gly12-to-ser mutation (190020.0003), the gly12-to-ala
substitution (190020.0004), and 1 patient with the gly13-to-cys
substitution (190020.0007). They conducted a search of the region
flanking the mutated sites in 42 probands and 59 parents, and used 4
polymorphic markers to trace the parental origin of the germline
mutations. One of the SNPs, dbSNP rs12628 (81T-C), was found in strong
linkage disequilibrium with a highly polymorphic hexanucleotide (GGGCCT)
repeat region. Of a total of 24 probands with polymorphic markers, 16
informative families were tested and a paternal origin of the germline
mutation was found in 14 Costello syndrome probands. This distribution
was consistent neither with an equal likelihood of mutations arising in
either parent (P = 0.0018), nor with exclusive paternal origin.

Zampino et al. (2007) identified the common G12S mutation in 8 of 9
unrelated patients with Costello syndrome; the ninth child had a
different mutation (190020.0008). All mutations were de novo, paternally
inherited, and associated with advanced paternal age. None of 36
patients with Noonan syndrome or 4 with cardiofaciocutaneous syndrome
(CFCS; 115150) had a mutation in the HRAS gene.

Lo et al. (2008) described 4 infants with an unusually severe Costello
syndrome phenotype and 3 different mutations in the HRAS gene: the
common G12S mutation (190020.0003) was seen in 1 case, 2 cases had a
G12D mutation (190020.0013), and 1 case had a G12C mutation
(190020.0014).

Gremer et al. (2010) reported 2 different 3-nucleotide duplications in
the first coding exon of the HRAS gene (exon 2) resulting in a
duplication of glutamate-37 (E37dup) associated with a phenotype
reminiscent of Costello syndrome. None of the parents carried the
mutations. The phenotype of the 2 affected individuals was remarkably
similar and characterized by severe mental retardation and pronounced
short stature in one (190020.0015) and relatively mild involvement of
the musculoskeletal system compared with the classical Costello syndrome
phenotype in the other (190020.0016). Ectopic expression of HRAS(E37dup)
in COS-7 cells resulted in enhanced growth factor-dependent stimulation
of the MEK-ERK (see MEK1, 176872) and phosphoinositide 3-kinase (PI3K;
601232)-AKT (164730) signaling pathways. Recombinant HRAS(E37dup) was
characterized by slightly increased GTP/GDP dissociation, lower
intrinsic GTPase activity, and complete resistance to neurofibromin-1
GTPase-activating protein (NF1; 613113) stimulation due to dramatically
reduced binding. Coprecipitation of GTP-bound HRAS(E37dup) by various
effector proteins, however, was inefficient because of drastically
diminished binding affinities. Thus, although HRAS(E37dup) was
predominantly present in the active, GTP-bound state, it promoted only a
weak hyperactivation of downstream signaling pathways. The authors
proposed that the mildly enhanced signal flux through the MAPK and
PI3K-AKT cascades promoted by these disease-causing germline HRAS
alleles may result from a balancing effect between a profound GAP
insensitivity and inefficient binding to effector proteins.

- Congenital Myopathy with Excess Muscle Spindles

Van der Burgt et al. (2007) identified mutations in the HRAS gene
(190020.0001; 190020.0003; 190020.0009; 190020.0010) in patients with
congenital myopathy with excess muscle spindles, a variant of Costello
syndrome.

ANIMAL MODEL

Schuhmacher et al. (2008) generated a mouse model of Costello syndrome
by introduction of an oncogenic gly12-to-val mutation (190020.0001) in
the mouse Hras gene. Mutant mice developed hyperplasia of the mammary
gland, but tumor development was rare. The mice showed some phenotypic
features similar to those in patients with Costello syndrome, including
facial dysmorphism and cardiomyopathy. Mutant mice also developed
systemic hypertension, extensive vascular remodeling, and fibrosis in
both the heart and the kidneys resulting from abnormal upregulation of
the renin-angiotensin II system, which responded to treatment with
captopril. Histologic studies with a tagged wildtype Hras gene showed
expression in most murine embryonic tissues and several adult tissues,
including the heart, aortic vascular smooth muscle cells, kidney,
mammary glands, skin epithelium, urinary bladder, colon, and brain.

Using an Hras knockin mouse model, To et al. (2008) demonstrated that
specificity for Kras (190070) mutations in lung and Hras mutations in
skin tumors is determined by local regulatory elements in the target Ras
genes. Although the Kras 4A isoform is dispensable for mouse
development, it is the most important isoform for lung carcinogenesis in
vivo and for the inhibitory effect of wildtype Kras on the mutant
allele. Kras 4A expression is detected in a subpopulation of normal lung
epithelial cells, but at very low levels in lung tumors, suggesting that
it may not be required for tumor progression. The 2 Kras isoforms
undergo different posttranslational modifications. To et al. (2008)
concluded that their findings may have implications for the design of
therapeutic strategies for inhibiting oncogenic Kras activity in human
cancers.

*FIELD* AV
.0001
BLADDER CANCER, SOMATIC
COSTELLO SYNDROME, INCLUDED;;
MYOPATHY, CONGENITAL, WITH EXCESS OF MUSCLE SPINDLES, INCLUDED;;
EPIDERMAL NEVUS, SOMATIC, INCLUDED
HRAS, GLY12VAL

Di Micco et al. (2006) showed that senescence triggered by the expansion
of an activated oncogene, HRAS V12, in normal human cells is a
consequence of the activation of a robust DNA-damage checkpoint
response. Experimental inactivation of this response abrogated
oncogene-induced senescence and promoted cell transformation. DNA damage
checkpoint response and oncogene-induced senescence were established
after a hyperreplicative phase occurring immediately after oncogene
expression. Senescent cells arrested with partly replicated DNA and with
DNA replication origins having fired multiple times. In vivo DNA
labeling and molecular DNA combing revealed that oncogene activation
leads to augmented numbers of active replicons and to alterations in DNA
replication fork progression. Di Micco et al. (2006) also showed that
oncogene expression does not trigger a DNA damage checkpoint response in
the absence of DNA replication. Last, Di Micco et al. (2006) showed that
oncogene activation was associated with DNA damage checkpoint response
activation in a mouse model in vivo. Di Micco et al. (2006) proposed
that oncogene-induced senescence results from the enforcement of a DNA
damage checkpoint response triggered by oncogene-induced DNA
hyperreplication.

Somatic Mutations

Taparowsky et al. (1982) found that the HRAS1 gene cloned from a human
bladder cancer cell line (T24) transformed NIH 3T3 cells, while the same
gene cloned from normal cellular DNA did not. Furthermore, they showed
that the change in the transforming gene was a single nucleotide
substitution that produced change of a single amino acid in the sequence
of the protein that the gene encodes. They suggested that antibodies
against Ras proteins might be diagnostic for certain forms of cancer.
The T24 gene had a change from GGC (glycine) to GTC (valine) as codon
12. Fearon et al. (1985) examined constitutional and tumor genotypes at
loci on the short arm of chromosome 11 in 12 patients with transitional
cell carcinomas of the bladder. In 5 they found loss of genes in the
tumor, resulting in homozygosity or hemizygosity of the remaining
allele. This frequency (42%) approached that seen in Wilms tumor (55%).

The G12V mutant of HRAS had the lowest GTPase activity among various
substitutions at codon 12 (Colby et al., 1986), and biologic assays by
focus formation in NIH3T3 cells or soft agar growth showed that this
substitution had the highest transformation potential among
substitutions tested at this codon (Seeburg et al., 1984, Fasano et al.,
1984). Aoki et al. (2005) noted that among codon 12 HRAS mutations found
somatically in human cancers, G12V is the predominant mutation.

Hafner et al. (2012) identified a somatic G12V mutation in 1 of 72
keratinocytic epidermal nevi (162900).

Costello Syndrome

In a Japanese patient with Costello syndrome (218040), Aoki et al.
(2005) found a germline 35GC-TT nucleotide substitution in the HRAS gene
that resulted in a gly12-to-val amino acid change (G12V). This
individual died of severe cardiomyopathy at 18 months of age.

Congenital Myopathy with Excess of Muscle Spindles

Van der Burgt et al. (2007) identified a heterozygous G12V mutation in
the HRAS gene in a patient with congenital myopathy with excess of
muscle spindles (see 218040), a variant of Costello syndrome. The
patient, originally reported by de Boode et al. (1996), died at age 3
weeks. He was a preterm infant with generalized hypotonia and
progressive hypertrophic obstructive cardiomyopathy.

.0002
THYROID CARCINOMA, FOLLICULAR, SOMATIC
SPERMATOCYTIC SEMINOMA, SOMATIC, INCLUDED
HRAS, GLN61LYS

Nikiforova et al. (2003) found that a CAG-to-AAG change at HRAS codon
61, resulting in a gln-to-lys amino acid change (Q61K), was present in 2
follicular carcinomas (see 188470), 2 follicular adenomas, and 1 Hurthle
cell adenoma, accounting for 12%, 18%, and 100% of each tumor type
examined, respectively.

Goriely et al. (2009) screened 30 spermatocytic seminomas (see 273300)
for mutations in 17 candidate genes, and in 2 tumors they identified
apparent homozygosity for a C-A transversion in the HRAS gene that
resulted in the Q61K substitution.

.0003
COSTELLO SYNDROME
MYOPATHY, CONGENITAL, WITH EXCESS OF MUSCLE SPINDLES, INCLUDED;;
EPIDERMAL NEVUS WITH UROTHELIAL CANCER, SOMATIC, INCLUDED;;
NEVUS SEBACEOUS, SOMATIC, INCLUDED
HRAS, GLY12SER

Costello Syndrome

In 3 Japanese and in 4 Italian patients with Costello syndrome (218040),
Aoki et al. (2005) identified a germline 34G-A transition in the HRAS
gene that caused a gly12-to-ser (G12S) amino acid substitution.

Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical
diagnosis of Costello syndrome and identified mutations in 37 (86%);
G12S was the most common mutation, found in 30 of the 37
mutation-positive patients.

Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated
patients with Costello syndrome. By analyzing the flanking genomic
region, the authors determined that all patients had de novo mutations
inherited from the father. There was an advanced age at conception in
affected fathers transmitting the mutation. The phenotype was
homogeneous.

In a male infant with severe Costello syndrome, Lo et al. (2008)
identified the G12S mutation in the HRAS gene. The patient had
persistent neonatal hypoglycemia, hypocalcemia, right ventricular
hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric
stenosis and inguinal hernia repair at age 3 months. He had complex
upper and lower airway obstruction with a floppy tongue, narrow
subglottic opening, and tracheobronchomalacia, requiring a tracheostomy
with intermittent ventilatory support. Deterioration of his respiratory
function led to the discovery of a pulmonary rhabdomyosarcoma, and he
died at 2.25 years of age.

Congenital Myopathy with Excess of Muscle Spindles

Van der Burgt et al. (2007) identified a heterozygous G12S mutation in
the HRAS gene in a patient with congenital myopathy with excess of
muscle spindles (see 218040), a phenotypic variant of Costello syndrome.
The patient, originally reported by Selcen et al. (2001), died at age 14
months of cardiorespiratory failure. He had generalized muscle weakness,
areflexia, joint contractures, and clubfeet.

Epidermal Nevus and Urothelial Cancer

Hafner et al. (2011) reported a 49-year-old man who had widespread
mosaicism for a G12S mutation present in tissues derived from endoderm,
ectoderm, and mesoderm, suggesting an embryonic mutation. The patient
presented at 49 years of age with widespread congenital epidermal nevus
(162900). At 19 years of age a urothelial cell carcinoma was detected in
the bladder, and 2 new tumors were identified at 48 years of age. At age
49 a single metastatic lesion was identified in lung.

Nevus Sebaceous

Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of
65 nevus sebaceous tumors (see 162900).

.0004
COSTELLO SYNDROME
HRAS, GLY12ALA

In 1 Japanese and 1 Italian patient with Costello syndrome (218040),
Aoki et al. (2005) found a germline 35G-C transversion in the HRAS gene
that caused a gly12-to-ala (G12A) amino acid substitution.

.0005
COSTELLO SYNDROME
HRAS, GLY13ASP

In 2 Japanese patients with Costello syndrome (218040), Aoki et al.
(2005) found a germline 38G-A transition in the HRAS gene that caused a
gly13-to-asp (G13D) amino acid substitution.

.0006
COSTELLO SYNDROME
HRAS, LYS117ARG

In a 9-year-old girl with Costello syndrome (218040), Kerr et al. (2006)
identified a de novo 350A-G transition in the HRAS gene, resulting in a
lys117-to-arg (K117R) substitution. The patient's physical phenotype was
unusual in that she had microretrognathism and both her plantar and
palmar creases were less pronounced than usually seen in Costello
syndrome. Her behavioral phenotype included autistic traits with verbal
stereotypies and hand biting. Otherwise she had classic features of
Costello syndrome with cardiac involvement (cardiomyopathy and
ventricular septal defect) but no neurologic malformation. The mutation
was not found in either of her parents.

Denayer et al. (2008) identified a de novo K117R mutation in a
6-year-old girl with typical Costello syndrome. Behavioral features
included moderate mental retardation with a friendly personality and no
autistic features. In vitro functional expression studies showed
increased levels of phosphorylated proteins consistent with constitutive
activation of the RAS/MAPK pathways. Recombinant K117R showed normal
intrinsic GTP hydrolysis and responsiveness to GTPase-activating
proteins, but the nucleotide disassociation rate was increased 80-fold.
Crystal structure data indicated an altered interaction pattern of the
side chain that was associated with unfavorable nucleotide binding
properties.

.0007
COSTELLO SYNDROME
HRAS, GLY13CYS

Sol-Church et al. (2006) found that 1 of 42 patients with Costello
syndrome (218040) and heterozygous de novo missense mutations involving
either glycine-12 or -13 of the HRAS gene carried a gly13-to-cys (G13C)
substitution (37G-A).

Piccione et al. (2009) reported a premature male infant born at 29
weeks' gestation due to fetal distress who was found to have Costello
syndrome due to the G13C mutation. The characteristic facial features
were not apparent until about 4 months of age, when he was noted to have
relative macrocephaly, coarse face with hypertelorism, downslanting
palpebral fissures, epicanthal folds, prominent eyes, short nose,
low-set ears, large mouth, short neck, loose skin of hands and feet,
sparse hair, hyperpigmented skin, deep palmar creases, joint laxity,
reduced subcutaneous adipose tissue, and bilateral cryptorchidism. At 11
months of age, he had delayed motor development with central hypotonia,
but adequate mental and speech development. Papillomata were not
present. Piccione et al. (2009) noted that the distinctive features of
Costello syndrome may be absent during the first months of life,
especially in preterm infants who often have failure to thrive and
decreased subcutaneous adipose tissue. The striking facial features of
the disorder become more evident after the critical neonatal period.

Gripp et al. (2011) examined 12 individuals with Costello syndrome due
to the G13C mutation and compared the phenotype to those with the G12S
(190020.0003) mutation. Individuals with G13C had many typical findings
including polyhydramnios, failure to thrive, hypertrophic
cardiomyopathy, macrocephaly, posterior fossa crowding, and
developmental delay. Their facial features were less coarse and short
stature was less severe. Statistically significant differences included
the absence of several common features, including multifocal atrial
tachycardia, ulnar deviation of the wrist, and papillomata; a noteworthy
absence of malignant tumors did not reach statistical significance.
There were some novel ectodermal findings associated with the G13C
mutation, including loose anagen hair and long eyelashes requiring
trimming (termed 'dolichocilia').

.0008
COSTELLO SYNDROME
HRAS, ALA146THR

In 1 of 9 unrelated patients with Costello syndrome (218040), Zampino et
al. (2007) identified a de novo 436G-A transition in the HRAS gene,
resulting in an ala146-to-thr (A146T) substitution The mutation was of
paternal origin. The patient had unusual features, including normal
neonatal growth, microcephaly, normal ears, and thin, but not curly,
hair. Crystallographic information indicated that the A146T substitution
occurs in a hydrophobic pocket involved in binding to the purine ring of
GTP/GDP and likely destabilizes the binding of GTP and GDP. Since GTP
has a higher cytoplasmic concentration and would therefore be more
likely to bind to the protein, the A146T mutation may result in a gain
of function.

.0009
MYOPATHY, CONGENITAL, WITH EXCESS OF MUSCLE SPINDLES
HRAS, GLU63LYS

In a 7-month-old girl with congenital myopathy with excess of muscle
spindles (see 218040), a variant of Costello syndrome, van der Burgt et
al. (2007) identified a heterozygous 187G-A transition in the HRAS gene,
resulting in a glu63-to-lys (E63K) substitution. The patient, originally
reported by Stassou et al. (2005), had hypertrophic obstructive
cardiomyopathy, hypotonia, contractures, and clubfeet, and died at age 7
months of respiratory failure.

.0010
MYOPATHY, CONGENITAL, WITH EXCESS OF MUSCLE SPINDLES
HRAS, GLN22LYS

In a 13-month-old boy with congenital myopathy with excess of muscle
spindles (see 218040), a variant of Costello syndrome, van der Burgt et
al. (2007) identified a heterozygous 64C-A transversion in the HRAS
gene, resulting in a gln22-to-lys (Q22K) substitution. The patient had
mild hypertrophic cardiomyopathy, generalized hypotonia, delayed motor
development, and poor feeding.

.0011
COSTELLO SYNDROME
HRAS, THR58ILE

In a boy with Costello syndrome (218040), Gripp et al. (2008) identified
a heterozygous de novo 173C-T transition in exon 3 of the HRAS gene,
resulting in a thr58-to-ile (T58I) substitution in a highly conserved
residue in the switch II region of small GTPases. Neither parent carried
the mutation, which was present on the paternal allele. At the time of
birth, the father and mother were 45 and 34 years old, respectively. The
facial features of the patient were less coarse than typical Costello
syndrome, but he showed other typical features, including failure to
thrive, cognitive impairment, lax skin, deep palmar creases, and pyloric
stenosis.

.0012
COSTELLO SYNDROME
HRAS, ALA146VAL

In a girl with Costello syndrome (218040), Gripp et al. (2008)
identified a heterozygous 437C-T transition in exon 4 of the HRAS gene,
resulting in an ala146-to-val (A146V) substitution. The facial features
of the patient were less coarse than usually seen in Costello syndrome,
but she also showed other typical features, including hypertrophic
cardiomyopathy, deep palmar creases, and delayed development. Another
HRAS mutation resulting in Costello syndrome has been reported in this
codon (A146T; 190020.0008).

.0013
COSTELLO SYNDROME, SEVERE
NEVUS SEBACEOUS, SOMATIC, INCLUDED
HRAS, GLY12ASP

In 2 infants with severe Costello syndrome (218040) including neonatal
hypoglycemia and respiratory failure, Lo et al. (2008) identified 35G-A
transition in the HRAS gene, resulting in a gly12-to-asp (G12D)
substitution. One infant had paroxysmal multifocal atrial tachycardia,
atrial septal defect, and septal hypertrophy, as well as persistent
respiratory distress with tracheobronchomalacia, recurrent pneumothorax,
pneumonia, and chylothorax, and died at age 3 months due to respiratory
failure; postmortem lung histology showed findings consistent with
lymphangiectasia and alveolar/capillary dysplasia. The other infant had
hypertrophic cardiomyopathy and dysplastic pulmonary valve noted at day
1, and developed atrial fibrillation and heart failure at day 35; she
had persistent hyponatremia due to renal sodium leakage with signs of
renal failure at 6 weeks. She became ventilator dependent and died at 3
months of age from sepsis and renal failure.

Kuniba et al. (2009) reported a Japanese fetus with severe Costello
syndrome due to the G12D mutation. He was diagnosed using prenatal
3-dimensional ultrasonography at 23 weeks' gestation. Findings at that
time included polyhydramnios, severe overgrowth (+5.3 SD using a
Japanese fetal growth curve), and dysmorphic craniofacial features, such
as large head, pointed chin, wide nasal bridge, and low-set ears. In
addition, the wrists showed lateral deviation and flexion. After birth,
he developed respiratory failure, severe hypoglycemia, cardiac
hypertrophy, and renal failure, and died soon after birth. The phenotype
was similar to that reported by Lo et al. (2008) in 2 infants with the
G12D mutation, suggesting that this mutation is associated with a severe
clinical outcome and death in early infancy.

Groesser et al. (2012) identified a somatic G12D mutation in 1 (2%) of
65 nevus sebaceous tumors (see 162900).

.0014
COSTELLO SYNDROME
NEVUS SEBACEOUS, SOMATIC, INCLUDED;;
EPIDERMAL NEVUS, SOMATIC, INCLUDED
HRAS, GLY12CYS

In a male infant with severe Costello syndrome (218040), Lo et al.
(2008) identified a 34G-T transversion in the HRAS gene, resulting in a
gly12-to-cys (G12C) substitution. The patient developed respiratory
distress after delivery and required intubation and ventilatory support
secondary to small lungs and upper airway obstruction. He had an atrial
tachyarrhythmia with apparent thickening of the myocardial wall and
redundant mitral valve tissue on echocardiogram, and had echogenic
kidneys with thick-walled pelvises on ultrasound. He died at 3 months of
age due to respiratory failure.

Groesser et al. (2012) identified a somatic G12C mutation in 1 (2%) of
65 nevus sebaceous tumors (see 162900).

Hafner et al. (2012) identified a somatic G12C mutation in 1 of 72
keratinocytic epidermal nevi (162900).

.0015
COSTELLO SYNDROME
HRAS, 3-BP DUP, 110AGG

In a 5-year-old Kurdish male with a phenotype reminiscent of Costello
syndrome (218040), Gremer et al. (2010) detected a heterozygous 3-bp
duplication in exon 2 of the HRAS gene that resulted in duplication of
glutamic acid at position 37 (110_111+1dupAGG, glu37dup). The child had
hypertrophic cardiomyopathy, global developmental delay, growth
retardation, coarse facial features, and sparse hair. Mental retardation
was severe, with no speech development. Neither parent carried the
mutation. The authors also identified another patient with a similar
phenotype who also carried a duplication of glu37 caused by a different
3-nucleotide duplication (190020.0016).

.0016
COSTELLO SYNDROME
HRAS, 3-BP DUP, 108AGA

In a 6-year-old Italian boy with a phenotype reminiscent of Costello
syndrome (218040), Gremer et al. (2010) detected a heterozygous 3-bp
duplication in exon 2 of the HRAS gene that resulted in duplication of
glutamic acid at position 37 (108_110dupAGA, glu37dup). The patient had
global developmental delay, growth retardation, coarse facial features,
sparse hair, and a thickened ventricular septum. Language was absent.
Neither of his parents carried the mutation. Another duplication of
glu37 was identified in another patient (190020.0015).

.0017
NEVUS SEBACEOUS, SOMATIC
SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC, INCLUDED;;
EPIDERMAL NEVUS, SOMATIC, INCLUDED
HRAS, GLY13ARG

In 59 (91%) of 65 different nevus sebaceous (see 162900) tumors,
Groesser et al. (2012) identified a somatic 37G-C transversion in the
HRAS gene, resulting in a gly13-to-arg (G13R) substitution. Two of the
tumors also carried a somatic mutation in the KRAS gene (190070.0005 and
190070.0006, respectively), and 1 tumor had 2 HRAS mutations: G13R and
G12S (190020.0003). Nonlesional tissue from 18 individuals with the G13R
mutation showed the wildtype HRAS allele. Eight individuals developed
secondary tumors within the nevus sebaceous, including 2
syringocystadenoma papilliferum, 3 trichoblastomas, and 3
trichilemmomas, and all secondary tumors carried the same mutation as
the nevi, suggesting that they arose from cells of the nevus sebaceous.
Functional analysis of mutant cells carrying the G13R mutation showed
constitutive activation of the MAPK and PI3K-AKT signaling pathways.

Hafner et al. (2012) identified a somatic G13R mutation in 21 of 24
HRAS-mutant keratinocytic epidermal nevi (162900), making it the most
common mutation among a larger series of 72 nevi.

One patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) was
found by Groesser et al. (2012) to carry the G13R mutation in somatic
mosaic state. This patient had originally been reported by Zutt et al.
(2003). She was a 52-year-old woman who was noted at birth to have a
large, right-sided nevus sebaceous extending to her head, neck, arm, and
trunk. The scalp was also involved, resulting in alopecia. The patient
developed recurrent syringocystadenoma papilliferum and basal cell
carcinoma within the nevus. Other features included generalized growth
retardation, hypophosphatemic rickets, and precocious puberty.
Intelligence was normal. There was no family history of a similar
disorder.

*FIELD* SA
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86. Zutt, M.; Strutz, F.; Happle, R.; Habenicht, E. M.; Emmert, S.;
Haenssle, H. A.; Kretschmer, L.; Neumann, C.: Schimmelpenning-Feuerstein-Mims
syndrome with hypophosphatemic rickets. Dermatology 207: 72-76,
2003.

*FIELD* CN
Cassandra L. Kniffin - updated: 3/13/2013
Cassandra L. Kniffin - updated: 1/30/2013
Cassandra L. Kniffin - updated: 7/25/2012
Marla J. F. O'Neill - updated: 11/29/2011
Ada Hamosh - updated: 11/29/2011
George E. Tiller - updated: 11/7/2011
Cassandra L. Kniffin - updated: 4/16/2010
Cassandra L. Kniffin - updated: 2/16/2010
Ada Hamosh - updated: 7/9/2009
Ada Hamosh - updated: 1/20/2009
Marla J. F. O'Neill - updated: 11/12/2008
Ada Hamosh - updated: 9/9/2008
Ada Hamosh - updated: 7/18/2008
Cassandra L. Kniffin - updated: 6/25/2008
Cassandra L. Kniffin - updated: 3/24/2008
Cassandra L. Kniffin - updated: 3/6/2008
Ada Hamosh - updated: 11/26/2007
Patricia A. Hartz - updated: 10/11/2007
Cassandra L. Kniffin - updated: 8/28/2007
Ada Hamosh - updated: 6/29/2007
Cassandra L. Kniffin - updated: 5/16/2007
Ada Hamosh - updated: 2/8/2007
Victor A. McKusick - updated: 8/24/2006
Marla J. F. O'Neill - updated: 6/20/2006
Patricia A. Hartz - updated: 4/10/2006
Victor A. McKusick - updated: 9/21/2005
Stylianos E. Antonarakis - updated: 3/28/2005
John A. Phillips, III - updated: 9/11/2003
John A. Phillips, III - updated: 9/2/2003
Ada Hamosh - updated: 2/4/2003
Ada Hamosh - updated: 9/30/2002
Stylianos E. Antonarakis - updated: 9/9/2002
Patricia A. Hartz - updated: 8/5/2002
Ada Hamosh - updated: 6/27/2001
Ada Hamosh - updated: 7/28/1999
Stylianos E. Antonarakis - updated: 3/18/1999
Victor A. McKusick - edited: 3/10/1997

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

*FIELD* ED
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carol: 5/28/1993
supermim: 3/16/1992

MIM 218040
*RECORD*
*FIELD* NO
218040
*FIELD* TI
#218040 COSTELLO SYNDROME
;;FACIOCUTANEOSKELETAL SYNDROME;;
FCS SYNDROME
MYOPATHY, CONGENITAL, WITH EXCESS OF MUSCLE SPINDLES, INCLUDED; CMEMS,
read moreINCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
Costello syndrome can be caused by mutations in the HRAS gene (190020).
A variant of Costello syndrome, congenital myopathy with excess of
muscle spindles, is also caused by mutation in HRAS.

Costello syndrome shows phenotypic overlap with cardiofaciocutaneous
syndrome (CFC; 115150) and Noonan syndrome (163950).

DESCRIPTION

Costello syndrome is a rare multiple congenital anomaly syndrome
associated in all cases with a characteristic coarse facies, short
stature, distinctive hand posture and appearance, severe feeding
difficulty, and failure to thrive. Other features include cardiac
anomalies and developmental disability. Facial warts, particularly
nasolabial, are often present in childhood (Kerr et al., 2006).

In patients with a clinical diagnosis of Costello syndrome, Zenker et
al. (2007) identified mutations in the KRAS gene, but noted that these
patients may later develop features of CFC syndrome. In either case, the
findings underscore the central role of Ras in the pathogenesis of these
phenotypically related disorders (Zenker et al., 2007). However, Kerr et
al. (2008) commented that the diagnosis of Costello syndrome should only
be used to refer to patients with mutations in the HRAS gene.

CLINICAL FEATURES

Costello (1977) described 2 unrelated children with a syndrome
comprising short stature, redundant skin of the neck, palms, soles, and
fingers, curly hair, papillomata around the mouth and nares, and mental
retardation. Der Kaloustian et al. (1991) reported a boy with the same
syndrome. The parents were not consanguineous in any of the 3 cases. The
patient of Der Kaloustian et al. (1991) had an aged facial appearance
with thin anterior hair of the head. Epicanthal folds, large, depressed
nasal bridge, and large earlobes were noted. The verrucal lesions were
present around the anus as well as around the mouth and nares. The loose
skin over the hands and feet was also thickened and the palms and soles
were hyperkeratotic. The skin color was generally dark. Some
similarities to the cardiofaciocutaneous syndrome (CFC; 115150) and
Noonan syndrome (163950) were noted.

Martin and Jones (1991) reported a 15-year-old girl with mental
retardation, short stature, coarse face, thick and loose skin of the
hands and feet, deep plantar and palmar creases, and nasal papillomata.
Berberich et al. (1991) reported 3 patients, 2 of whom were sibs, with a
presumably new syndrome of failure to thrive, cardiomyopathy, and
furrowing of palmar creases. Later these cases were diagnosed as
Costello syndrome (Der Kaloustian, 1993; Zampino et al., 1993).
Additional patients were reported by Say et al. (1993), Teebi and
Shaabani (1993), Philip and Mancini (1993), and Zampino et al. (1993).
Zampino et al. (1993) provided photographs of a 24-year-old patient. Di
Rocco et al. (1993) reported 2 unrelated patients, a 5-year-old girl and
a 3-year-old boy, with Costello syndrome and sialuria. Di Rocco et al.
(1993) suggested that urine and fibroblast sialic acid should be tested
in other Costello syndrome patients. In both of their patients, feeding
problems and abnormal speech were related to an oral motor apraxia. The
girl also had acanthosis nigricans and abnormal glucose metabolism
(fasting hypoglycemia and postprandial hyperglycemia).

Borochowitz et al. (1992) reported 5 unrelated patients, 1 male and 4
females, with a previously undefined multiple congenital
anomalies/mental retardation (MCA/MR) syndrome which they designated the
faciocutaneoskeletal (FCS) syndrome. The features included mental
retardation with specific sociable, humorous behavior, characteristic
facial appearance, generally excessive skin, postnatal growth failure,
and skeletal abnormalities. Consanguinity was noted in 2 patients,
suggesting autosomal recessive inheritance. Coarse facies, wide hirsute
forehead, wide anteverted nostrils, and thick lips were pictured. Martin
and Jones (1993), Der Kaloustian (1993), Teebi (1993), Philip and
Mancini (1993), and Zampino et al. (1993) suggested that the FCS
syndrome described by Borochowitz et al. (1992) is the same as the
Costello syndrome. Borochowitz et al. (1993) concluded, on the other
hand, that 'it is premature to reach a definite conclusion at this
stage.' Patton and Baraitser (1993) reviewed 5 cases from their previous
paper on cutis laxa (see 219200) (Patton et al., 1987) and concluded
that the appropriate diagnosis was in fact Costello syndrome.
Independently, Davies and Hughes (1994) reviewed case 7 from the same
paper and, based on both history and clinical examination, made 'an
unequivocal diagnosis of Costello syndrome.' In a longer report, Davies
and Hughes (1994) described the development of one of the patients of
Patton et al. (1987) for more than 10 years and again emphasized that
Costello syndrome should be included in the differential diagnosis of
cutis laxa in association with postnatal growth retardation and
developmental delay.

Izumikawa et al. (1993) reported the case of a 3-year-old boy who had
typical clinical features except for the absence of nasal papillomas and
who also had cardiac anomalies with extrasystoles and thick mitral
valves. Kondo et al. (1993) emphasized nasal papillomata as particularly
characteristic of Costello syndrome and pointed out that the age at
development ranged from 2 to 15 years in reported cases.

Fryns et al. (1994) described 2 unrelated patients with Costello
syndrome, a 12-year-old girl and a 3.5-year-old boy. Severe postnatal
growth retardation was the first clinical sign. Characteristic facial
changes, loose and hyperelastic skin, and papillomata became
progressively more evident with age. The patients presented a pleasant,
happy nature and were mildly to moderately mentally retarded. Okamoto et
al. (1994) reported the case of a Japanese patient. A fundoplication was
performed at the age of 11 months to treat severe gastroesophageal
reflux. The infant had congenital bilateral subluxation of the hips. At
the age of 7 years, there was generalized pigmentation and acanthosis
nigricans around the neck and axilla. Endocrinologic evaluation
demonstrated partial deficiency of growth hormone. Stating that 16 cases
had been reported, Torrelo et al. (1995) presented the case of a
15-year-old girl and emphasized the cutaneous manifestations of the
disorder.

Umans et al. (1995) described the natural history of the Costello
syndrome in a child followed from birth to the age of 12 years. Severe
feeding difficulties and poor sucking with swallowing difficulties are
features. The history of polyhydramnios in almost all pregnancies
indicates that diminished swallowing starts very early in fetal life.
Generalized lymphoedema was noted at birth and hypotonia is a feature.

Mori et al. (1996) described a case of Costello syndrome. The main
clinical findings were loose skin of the neck, hands, and feet, deep
palmar and plantar creases, typical 'coarse' face with thick lips and
macroglossia, relative macrocephaly, mental retardation, short stature,
arrhythmia, large size for gestational age, and poor feeding. The infant
died of rhabdomyolysis at the age of 6 months. The major pathologic
findings were fine, disrupted, and loosely-constructed elastic fibers in
the skin, tongue, pharynx, larynx, and upper esophagus, but not in the
bronchi, alveoli, aorta, or coronary arteries. The degeneration of
elastic fibers was confirmed in the skin of a second Costello syndrome
patient, that described previously by Yoshida et al. (1993). Autopsy
also showed degeneration of the atrial conduction system, calcification
and ballooning of skeletal muscle fibers with infiltration of
macrophages, and myoglobin deposits in the collecting ducts of the
kidney, consistent with rhabdomyolysis. They analyzed the clinical
findings in 14 cases.

Costello (1996) provided an update on the original cases and commented
on other reported examples of this syndrome. Case 1 was reviewed at the
age of 32 years. In summary, he had been known to have hypertension
since the age of 17 years. Surgical operation had been required for
recurrent inguinal hernia, ruptured cornea associated with keratoconus
in the left eye, and hemorrhoidectomy. Duodenal ulcer and
gastroesophageal reflux were diagnosed at age 20 following an episode of
hematemesis and melena. Case 2 was reviewed at the age of 27 years. In
summary, she had been asthmatic since age 18 years. Mammography at age
21 suggested severe fibroadenosis; warty hyperkeratosis of the nipples
and lichenified eczema of the neck were noted. A cardiologic assessment
was made at age 22 for a systolic murmur. Costello (1996) presented a
table of manifestations frequently seen in Costello syndrome and also in
Noonan syndrome and/or CFC syndrome, as well as a table of
manifestations frequently seen in Costello syndrome but infrequent or
absent in the other 2 syndromes. Out of 16 cases reviewed, 13 had
low-set ears with large/thick lobes, 13 had thick lips, 12 had nasal
papillomas and/or papillomas elsewhere, 16 had loose skin of the hands
and feet, 14 had deep palmar creases, 12 had hyperkeratotic palms and
soles, and 12 had hyperextensible fingers. Costello (1996) concluded
that it is possible to make the clinical diagnosis of Costello syndrome
with confidence. In particular, it is possible to differentiate Costello
syndrome clearly from Noonan and CFC syndromes.

Siwik et al. (1998) reviewed the cardiac manifestations of Costello
syndrome in 30 patients, 18 of whom had at least 1 cardiac abnormality.
Of these 18, 9 had structural heart disease, 6 had hypertrophic
cardiomyopathy (mean age of onset 6.5 years, range 5 months to 20
years), and 5 had tachyarrhythmias. The authors recommended cardiac
evaluation for any patient in whom the diagnosis of Costello syndrome
has been established, and subsequent follow-up of affected individuals
for the development of hypertrophic cardiomyopathy.

Lin et al. (2002) reviewed the cardiac abnormalities in 94 patients with
Costello syndrome and found the following in 59 (63%) patients:
cardiovascular malformation in 30% (most commonly pulmonic stenosis),
cardiac hypertrophy in 34%, and rhythm disturbances in 33% (most
commonly atrial tachycardia). Most (68%) of the patients with a rhythm
abnormality had a cardiovascular malformation, cardiac hypertrophy, or
both. The authors recommended baseline and additional cardiac
evaluations in all patients with Costello syndrome.

Van Eeghen et al. (1999) reported the case of a 34-year-old woman with
the diagnosis of Costello syndrome. Features included mental
retardation, short stature, macrocephaly, 'coarse' face, hoarse voice,
and redundant skin with deep palmar and plantar creases. She had
wart-like lesions of the skin.

Feingold (1999) reported a child with Costello syndrome who developed an
alveolar rhabdomyosarcoma of the right foot at the age of 6 months.

Kerr et al. (1998) reported 2 children diagnosed with Costello syndrome
in the first months of life who developed retroperitoneal embryonal
rhabdomyosarcoma. They suggested that increased risk of malignancy may
be part of Costello syndrome. Moroni et al. (2000) reported a patient
with Costello syndrome who developed an intrathoracic
ganglioneuroblastoma. They cited several other patients with tumors and
suggested that neural crest neoplasia may be a significant risk factor
for children with Costello syndrome.

Franceschini et al. (1999) reported a 12-year-old boy with Costello
syndrome who was born to consanguineous parents. At age 11 years, this
patient developed bladder carcinoma, a rare event in childhood,
supporting an increased risk of malignancy in this syndrome. Gripp et
al. (2000) likewise reported a case of transitional cell carcinoma of
the bladder in a patient with Costello syndrome. Birth weight and birth
length had been greater than the 95th centile but at the 50th centile
within weeks or months. Gastrostomy tube placement was required at 6
months because of feeding problems and failure to thrive. Redundancy of
skin folds of palms, labia majora, and other body areas was noted at
that time. Biventricular concentric hypertrophic cardiomyopathy with
asymmetric septal hypertrophy and a large pressure gradient from the
left ventricle to the aorta were seen. Treatment with the beta blocker
propranolol over a period of several years led to relief of the left
ventricular outflow tract obstruction. Papillomata (squamous acanthomas)
of the cheeks were noted at age 4; perineal papillomata developed at age
14. Hair growth was extremely slow requiring trims once a year. Nails
were thin and dysplastic. Body odor was a persistent problem. The
bladder cancer was discovered at the age of 14 years.

Gripp et al. (2002) reported 5 new cases of rhabdomyosarcoma in Costello
syndrome, bringing the number of reported cases of solid tumors to 17.
They pointed out that the frequency is in the same order of magnitude as
that of solid tumors in Beckwith-Wiedemann syndrome (BWS; 130650) and
may justify tumor screening. Based on the recommendations for screening
BWS patients, they proposed a screening protocol consisting of
ultrasound examination of the abdomen and pelvis every 3 to 6 months
until age 8 to 10 years looking for rhabdomyosarcoma and abdominal
neuroblastoma; urine catecholamine metabolite analysis every 6 to 12
months until age 5 years for neuroblastoma; and urinalysis for hematuria
annually for bladder carcinoma after age 10 years. In 8 of the 10 cases
of Costello syndrome with rhabdomyosarcoma, the tumor originated from
the abdomen, pelvis, or urogenital areas. Prior diagnosis of Costello
syndrome was a prerequisite for the implementation of any screening
protocol. Conversely, the diagnosis of Costello syndrome should be
considered in individuals with rhabdomyosarcoma and physical findings
suggestive of Costello syndrome. DeBaun (2002) reviewed the usefulness
of screening in Costello syndrome.

Ioan and Fryns (2002) described Costello syndrome in a brother and
sister, with minor manifestations in their mother. The sibs had severe
mental and motor retardation, feeding difficulties, failure to thrive in
the first months of life, coarse facial appearance, skin hyperlaxity,
and skeletal deformities. The mother presented with mild to moderate
mental retardation, short stature, facial fullness, and wart-like
lesions on her face.

Hennekam (2003) stated that 115 cases of Costello syndrome had been
described. He summarized clinical data on 73 of the cases and
illustrated the characteristic facial appearance and palm of the hand.

Kawame et al. (2003) retrospectively reviewed the clinical records and
findings in 5 girls and 5 boys with Costello syndrome. All showed
significant postnatal growth retardation and severe feeding difficulties
leading to failure to thrive from early infancy. All required tube
feeding and some needed high-calorie formulas for variable periods.
Developmental quotients/IQs in 7 children were 50 or less, and 3 were in
the mildly retarded range. Five had seizures. Although happy and
sociable personality had previously been established as characteristic
of the disorder, Kawame et al. (2003) noted that during infancy, all 10
children showed significant irritability, including hypersensitivity to
sound and tactile stimuli, sleep disturbance, and excessive shyness with
strangers. These symptoms usually disappeared around 2 to 4 years of
age. Other clinical features were cardiac abnormalities in 8,
musculoskeletal abnormalities in all 10, and ophthalmologic
manifestations in 5. Only 3 girls had papillomata.

Axelrad et. al. (2004) performed standardized testing on 18 individuals
with Costello syndrome. The Leiter International Performance
Scale-Revised, a standardized nonverbal measure of intellectual ability,
revealed a mean brief-IQ score of 57 (SD 12.5), within the range of mild
mental retardation. In total, 17% of the participants had IQ scores
within the severe range of mental retardation, 28% had IQ scores within
the moderate range, 39% within the mild range, and 17% within the
borderline range of intellectual functioning. Receptive language skills
as assessed by the Peabody picture vocabulary test, 3rd edition, ranged
from average functioning to 4 SD below the mean. Delays found on the
Vineland adaptive behavior scales in the daily living skills,
communication, and motor skills domains were comparable to the results
seen in the Leiter brief-IQ. However, in the adaptive area of
socialization, less than 50% participants fell in the low range of
delay, and 25% of participants showed no delay in this domain. Axelrad
et. al. (2004) concluded that their study provides evidence supporting
anecdotal data that Costello patients are quite social despite their
cognitive difficulties.

White et al. (2005) reviewed the clinical findings of 17 adults with
Costello syndrome and found the major health problems to be bladder
carcinoma, benign tumors including benign breast disease, Chiari
malformations, gastroesophageal reflux, pubertal delay, and
osteoporosis. Intellectual disability was mild to moderate in 14 of the
patients and severe in 3.

Piccione et al. (2009) reported a premature male infant born at 29
weeks' gestation due to fetal distress who was found to have Costello
syndrome confirmed by genetic analysis (G13C; 190020.0007). At birth, he
was asystolic, neurologically depressed, had no spontaneous respiration,
and had bilateral pneumothoraces. Further studies showed periventricular
hyperechogenicity, septum pellucidum cysts, small choroid plexus
hemorrhage, abdominal ascites, and atrial septal defect. At 4 months of
age, he was noted to have relative macrocephaly, coarse face with
hypertelorism, downslanting palpebral fissures, epicanthal folds,
prominent eyes, short nose, low-set ears, large mouth, short neck, loose
skin of hands and feet, sparse hair, hyperpigmented skin, deep palmar
creases, joint laxity, reduced subcutaneous adipose tissue, and
bilateral cryptorchidism. These features led to the clinical diagnosis
of Costello syndrome. At 11 months of age, he had delayed motor
development with central hypotonia, but adequate mental and speech
development. Papillomata were not present. Piccione et al. (2009) noted
that the distinctive features of Costello syndrome may be absent during
the first months of life, especially in preterm infants who often have
failure to thrive and decreased subcutaneous adipose tissue. The
striking facial features of the disorder become more evident after the
critical neonatal period.

Smith et al. (2009) reported a female infant with Costello syndrome born
at 27 weeks' gestation in a pregnancy complicated by mild polyhydramnios
and preterm labor. She had fetal overgrowth, large anterior fontanel,
low-set thickened and posteriorly rotated ears, and coarse facies. She
developed an arrhythmia with multiple ectopic foci (chaotic atrial
rhythm) at 4 weeks of age. Cardiac examination showed a hyperdynamic
precordium with a systolic heart murmur, and echocardiogram showed
concentric hypertrophic cardiomyopathy with pulmonary valve stenosis.
Other features included hepatomegaly, hand posturing with ulnar
deviation of the wrist, and hypoplastic labia. She died at 6 months of
age from complications of cardiac arrhythmia and bronchopulmonary
dysplasia. Genetic analysis identified a G12S mutation in the HRAS gene
(190020.0003). Smith et al. (2009) emphasized the neonatal cardiac
morbidity and mortality associated with Costello syndrome.

- Congenital Myopathy With Excess of Muscle Spindles

De Boode et al. (1996) reported 2 unrelated patients with progressive
hypertrophic obstructive cardiomyopathy, Noonan syndrome-like facial
anomalies, and increased density of muscle spindles in skeletal muscle
biopsies. Both showed polyhydramnios on prenatal ultrasound and 1 had
fetal hydrops. Death occurred at ages 3 weeks and 10 months,
respectively.

Selcen et al. (2001) reported an infant with congenital weakness,
hypotonia, arthrogryposis, atrial tachycardia, hypertrophic
cardiomyopathy, and marked excess of muscle spindles on biopsy. He died
at age 14 months from cardiorespiratory failure. Postmortem examination
showed organomegaly. He also had bifrontal hallowing with fat pads
below, triangular mouth, high-arched palate, and congenital
neuroblastoma.

Stassou et al. (2005) reported a preterm neonate with arthrogryposis,
hydrops fetalis, hypertrophic cardiomyopathy, and flaccid quadriplegia.
Skeletal muscle biopsy showed increased muscle spindles encapsulated by
fibrous tissue within most of the muscle fascicles sampled. She died at
age 7 months.

Lin et al. (2011) reviewed the cardiac features of 61 patients with
Costello syndrome ranging in age from 1 month to 40 years, with 13
patients over age 18 years. Cardiovascular abnormalities were present in
85% of patients. The most common finding was hypertrophic cardiomyopathy
(HCM), typically subaortic septal hypertrophy, which was present in 37
(61%) of the 61 patients. Among these patients, HCM was chronic or
progressive in 14 (38%), stabilized in 11 (37%), regressed in 4 (11%),
and was unknown in 8 (22%). A congenital heart defect was present in 27
(44%) of the 61 patients, most commonly nonprogressive valvar pulmonary
stenosis. Arrhythmia occurred in 34 (56%) patients, atrial tachycardia
in 15 (25%), and aortic dilation in 4 (7%). The cardiac features of 85
patients with HRAS mutations from the literature were also assessed.
Congenital heart disease was present in 22% of patients, HCM in 68%,
arrhythmia in 40%, atrial tachycardia in 7%, and aortic dilation in 1
patient. Cardiac tissue showed myocardial fiber disarray in 7 (70%) of
10 specimens, consistent with sarcomeric dysfunction. Ten (43%) of 23
deaths among both cohorts occurred in infants less than 1 year of age,
and most of these deaths were cardiac-related. The most common HRAS
mutation was G12S (190020.0003), occurring in 84% of patients from the
study and 71% of patients from the literature.

OTHER FEATURES

Della Marca et al. (2006) found that 7 of 10 patients with Costello
syndrome had obstructive sleep apnea as demonstrated by polysomnography
and abnormally high apnea-hypopnea index. None of the patients were
obese. All patients had 1 or more sites of narrowing in the upper
airways.

Gripp et al. (2008) reported a boy with Costello syndrome and
hypertrophic pyloric stenosis. A review identified pyloric stenosis in 5
(8.6%) of 58 patients with Costello syndrome, which is an increased
frequency when compared to the general population (2.5 per 1,000).

Gripp et al. (2010) found abnormal brain imaging in 27 (96%) of 28
patients with Costello syndrome. All 28 had macrocephaly, and 14 (50%)
of 28 had ventriculomegaly, necessitating surgical intervention in 7
(25%). Twenty-seven (96%) of 28 patients had an enlarged cerebellum
causing posterior fossa crowding with cerebellar tonsillar herniation,
which progressed in 10 (59%) of 17 patients who had serial studies.
Cerebellar herniation was not seen in studies performed before age 6
months, but developed between 8 and 15 months of age. Herniation caused
Chiari type I malformation in 9 (32%) and syrinx formation in 7 (25%) of
28 patients, and 9 (32%) needed decompression intervention. Tethered
cord release was performed in 2 (7%). The symptoms associated with
tonsillar herniation resembled the most common presentation of infants
with Costello syndrome, including poor feeding, respiratory distress
with mixed central and obstructive apnea, ocular palsy, and constant
arching. Serial studies showed progression of relative macrocephaly,
frontal bossing, and cerebellar tonsillar herniation, consistent with
accelerated postnatal growth. Gripp et al. (2010) concluded that the
findings indicated that macrocephaly and posterior fossa crowding are
part of an ongoing process that occurs postnatally and results from
disproportionate brain growth, rather than a static congenital anomaly.

BIOCHEMICAL FEATURES

Gripp et al. (2004) found elevated catecholamine metabolite levels
(vanillylmandelic acid and/or homovanillic acid) in the urine of 8
patients with Costello syndrome. Imaging studies and clinical follow-up
did not lead to the identification of neuroblastoma or another
catecholamine-secreting tumor in any patient. Gripp et al. (2004)
concluded that in this patient group an elevation above the normal limit
for catecholamine metabolites is more likely to be a variant than a sign
of a neuroblastoma, and recommended that this assay not be used as a
screening test.

INHERITANCE

The vast majority of patients with Costello syndrome have de novo
heterozygous mutations in the HRAS gene (Aoki et al., 2005; Kerr et al.,
2006; Gripp et al., 2006). Studies by Lurie (1994) found a significant
increase of mean paternal age (38.0 years), suggesting sporadic
autosomal dominant mutations as the most likely cause. Rare reports of
affected sibs born to healthy parents may be explained by gonadal
mosaicism.

The molecular evidence presented by Aoki et al. (2005), viz., the
finding of heterozygous mutations in the HRAS gene (190020) in patients
with Costello syndrome, convincingly refuted the hypothesis of autosomal
recessive inheritance and favored gonadal mosaicism as the explanation
of instances of affected sibs.

- Exclusion of Autosomal Recessive Inheritance

The hypothesis of autosomal recessive inheritance of Costello syndrome
was based on 2 families with affected sibs (Berberich et al., 1991;
Zampino et al., 1993) and 2 consanguineous matings (Borochowitz et al.,
1992). Lurie (1994) reviewed 20 reported families and found that the 37
sibs of probands were all normal. In 6 families for whom pedigrees were
not available, 2 affected sib pairs were born. Even if there were no
normal offspring in these latter families, the occurrence of the
Costello syndrome in only 2 of 39 sibs virtually excludes an autosomal
recessive inheritance pattern (P = 0.999). Moreover, a significant
increase of mean paternal age (38.0 years) and paternal-maternal age
difference (7.36 years) suggests sporadic autosomal dominant mutations
as a likely cause. The 2 reported cases of affected sibs born to healthy
parents may be explained by gonadal mosaicism.

However, Franceschini et al. (1999) reported a 12-year-old boy with
Costello syndrome who was born to consanguineous (first cousins once
removed) parents, which could be considered consistent with autosomal
recessive transmission.

- Apparent Autosomal Dominant Inheritance and Somatic Mosaicism

Johnson et al. (1998) described 8 patients with Costello syndrome,
including an affected sib pair, and reviewed the literature on 29
previously reported patients. They emphasized an association with
advanced parental age, which was considered consistent with autosomal
dominant inheritance with germline mosaicism. In their study the average
paternal age was 40.3 years, with a mean maternal age of 35.8 years.
Features noted in the patients of Johnson et al. (1998) included
cataracts in 2 patients, heat intolerance and increased sweating in 3,
graying of hair in 1 (aged 8 years), and generalized amino aciduria in
3. Of all the patients reviewed, hypertrophic cardiomyopathy with valve
dysfunction was found in 65% and delayed bone age in 85%.

A review of previously reported patients suggested to Van Eeghen et al.
(1999) that the disorder is autosomal dominant, caused either by a
mutation in a single gene or by microdeletion. Ioan and Fryns (2002)
described Costello syndrome in a brother and sister, with minor
manifestations in their mother. They suggested that this was further
evidence for autosomal dominant inheritance. In a review of Costello
syndrome, Hennekam (2003) favored autosomal dominant inheritance.

Gripp et al. (2006) reported a 15-year-old girl with Costello syndrome
resulting from somatic mosaicism for the common G12S HRAS mutation
(190020.0003). Clinical features included short stature, developmental
delay, mild mitral valve prolapse without hypertrophic cardiomyopathy,
Achilles tendon contractures, sparse, thin and brittle hair, epicanthal
folds, and a wide mouth with thick lips. She also had nasal papillomata
and thickened toenails. Her skin showed areas of streaky
hyperpigmentation over trunk and extremities. Molecular analysis of
white blood cells failed to detect a mutation, but DNA derived from
buccal swabs showed the G12S mutation in 25 to 30% of cells. The wide
distribution throughout the skin suggested an early somatic mutation.

Sol-Church et al. (2009) described what they said was the first
documented transmission of an HRAS mutation from a parent with somatic
mosaicism to a child, resulting in typical Costello syndrome in the
child. The child carried a heterozygous G12S mutation on the paternal
allele. The father was noted to have features suggestive of mosaic
Costello syndrome, including severe failure to thrive in early
childhood, developmental delay, hyperkeratosis on both hands and his
left foot, papillomas on the right left perianal region and nose,
hyperpigmentation, thick ear lobes, and patches of curly hair. He did
not have structural cardiac defects. The father expressed awareness that
he and his son had similar physical and developmental traits of the
disorder. DNA testing of the father showed that he was somatic mosaic
for the G12S mutation, carrying it in 7 to 8% of his alleles, whereas
the mother did not have the mutation. The findings showed the importance
of parental evaluation, which has implications for genetic counseling.
This family had been reported in abstract form by Bodkin et al. (1999).

DIAGNOSIS

Smith et al. (2009) reviewed prenatal ultrasound findings of 17 patients
with Costello syndrome. Seven (41%) were preterm with delivery prior to
37 weeks' gestation, and the remaining 10 (59%) were term deliveries.
There were 3 main prenatal findings on ultrasound: polyhydramnios, fetal
overgrowth, and relative macrocephaly. Polyhydramnios was the most
commonly reported prenatal complication, affecting 100% of pregnancies.
Most (65%) patients had birth weight above the 90th centile, and 41%
patients had birth weights greater than the 97th centile. A fourth less
common finding was cardiac arrhythmia. Smith et al. (2009) noted that
the combination of polyhydramnios and fetal overgrowth often prompts
evaluation for maternal diabetes mellitus, but that recognition of
Costello syndrome in utero is important because of the neonatal risk of
cardiac mortality and morbidity.

Kuniba et al. (2009) provided a case report of a Japanese fetus with
severe Costello syndrome diagnosed using prenatal 3-dimensional
ultrasonography at 23 weeks' gestation. Findings at that time included
polyhydramnios, severe overgrowth (+5.3 SD using a Japanese fetal growth
curve), and dysmorphic craniofacial features, such as large head,
pointed chin, wide nasal bridge, and low-set ears. In addition, the
wrists showed lateral deviation and flexion. Molecular analysis via
amniocentesis identified an uncommon G12D mutation in the HRAS gene
(190020.0013). After birth, he developed respiratory failure, severe
hypoglycemia, cardiac hypertrophy, and renal failure, and died soon
after birth. The phenotype was similar to that reported by Lo et al.
(2008) in 2 infants with the G12D mutation, suggesting that this
mutation is associated with a severe clinical outcome and death in early
infancy.

CYTOGENETICS

Czeizel and Timar (1995) described the case of a Hungarian girl with
Costello syndrome in association with an apparently balanced
translocation: 46,XX t(1;22)(q25;q11). The patient showed excessive
generalized skin, more pronounced in the palms, 'wash woman's hands,'
and soles, with elastolysis confirmed by histologic examination. The
long tubular bones were osteoporotic. Spina bifida occulta was
demonstrated in L5 and S1. Mental retardation was mild. She had a
particularly sociable and humorous personality.

Sutajova et al. (2004) studied further the female patient originally
reported by Czeizel and Timar (1995) who was diagnosed with Costello
syndrome and who carried an apparently balanced translocation, t(1;22).
They showed that there were 2 derivative chromosomes 1 in her peripheral
blood lymphocytes, in one of which the coding region of the PDGFB gene
(190040), which maps to 22q13.1, was disrupted. In 18 patients with
Costello syndrome, no pathogenic mutations were found in any of the
genes belonging to the PDGF or PDGFR (see 173490) gene families.
Reevaluation of the clinical features of the translocation patient
challenged the diagnosis of Costello syndrome. Sutajova et al. (2004)
speculated, however, that the biologic consequences of the mutant PDGFB
allele contributed to the unique disease phenotype of the patient.

Maroti et al. (2002) defined the location of the breakpoint regions of
the 1;22 translocation. FISH analysis refined the cytogenetic breakpoint
from 22q11 to 22q13.1. Suri and Garrett (1998) described a patient with
Costello syndrome with acoustic neurinoma and cataract, both of which
are features of neurofibromatosis type 2 (NF2; 101000). Although they
did not find a deletion or point mutation of the NF2 gene, located in
22q12.2, it was suggested that the gene for Costello syndrome might be
close to NF2. If the Costello gene is located on 22q13.1, an inversion
might have happened in the Costello/NF2 patient that escaped detection
by conventional cytogenetic analysis. Maroti et al. (2002) confirmed the
1q25 location of the other breakpoint.

PATHOGENESIS

Disruption of elastic fiber production, such as is observed in Costello
syndrome, may arise either from low production of tropoelastin (see
130160) and microfibrillar proteins, or from their inadequate secretion
and extracellular assembly. Hinek et al. (2000) undertook a study to
assess the major steps of elastogenesis in fibroblasts derived from 6
children with Costello syndrome and from 3 age-matched normal children.
Their data indicated that fibroblasts from patients with Costello
syndrome produce normal levels of soluble tropoelastin and properly
deposit an extracellular microfibrillar scaffold but are unable to
assemble elastic fibers, because of a secondary deficiency in the 67-kD
elastin-binding protein, which the authors called EBP. EBP is an
enzymatically inactive spliced variant of beta-galactosidase (see
230500) (Hinek et al., 1993; Privitera et al., 1998) that binds to the
repeating hydrophobic domains on elastin. Because the normal association
between tropoelastin and EBP can be disrupted by contact with
galactosugar-bearing moieties, and because the fibroblasts from patients
with Costello syndrome showed an unusual accumulation of chondroitin
sulfate-bearing proteoglycans (CD44 (107269) and biglycan (301870)),
Hinek et al. (2000) postulated that a chondroitin sulfate may induce
shedding of EBP from Costello cells and prevent normal recycling of this
reusable tropoelastin chaperone. This conclusion was further supported
by the fact that exposure to chondroitinase ABC, an enzyme capable of
chondroitin sulfate degradation, restored normal production of elastic
fibers by fibroblasts from patients with Costello syndrome.

In histologic and immunohistochemical analyses of postmortem heart
tissue from 3 children with Costello syndrome, Hinek et al. (2005)
observed that cardiomyocytes from all 3 were characterized by
pericellular and intracellular accumulation of chondroitin
6-sulfate-bearing glycosaminoglycans, with lower than normal deposition
of chondroitin 4-sulfate. Their endocardia showed the presence of
multiple foci of collagen-rich fibrotic tissue with a marked reduction
of elastic fibers, and there were thin, short, and fragmented elastic
fibers in the myocardial stroma, pericardium, and cardiac valves,
coinciding with lowered expression of EBP. Hinek et al. (2005) proposed
that an imbalance in sulfation of chondroitin sulfate molecules and
subsequent accumulation of chondroitin 6-sulfate in cardiomyocytes
contribute to the development of the hypertrophic cardiomyopathy of
Costello syndrome.

MOLECULAR GENETICS

Because of phenotypic overlap between Costello syndrome and Noonan
syndrome (163950), and because mutations in the SHP2/PTPN11 gene
(176876) had been demonstrated in the latter, Tartaglia et al. (2003)
screened a cohort of 27 patients with clinically diagnosed Costello
syndrome for PTPN11 mutations; they found none. The previous exclusion
of PTPN11 mutations in cardiofaciocutaneous syndrome by Ion et al.
(2002) indicates that these 3 syndromes are distinct. Troger et al.
(2003) likewise found no mutation in the PTPN11 gene in 18 patients with
Costello syndrome.

Gain-of-function mutant SHP2 proteins identified in Noonan syndrome have
enhanced phosphatase activity, which results in activation of a RAS-MAPK
cascade in a cell-specific manner. Aoki et al. (2005) hypothesized that
genes mutated in Costello syndrome and in PTPN11-negative Noonan
syndrome encode molecules that function upstream or downstream of SHP2
in signal pathways. Among these molecules, they sequenced the entire
coding region of 4 RAS genes in genomic DNA from 13 individuals with
Costello syndrome and 28 individuals with PTPN11-negative Noonan
syndrome. In 12 of the 13 individuals with Costello syndrome, they found
a heterozygous mutation in the HRAS gene (190020.0001,
190020.0003-190020.0005). All 4 of the mutations had previously been
identified somatically in various tumors. Examination of genomic DNA
from unaffected parents in 4 families identified no mutations,
suggesting that mutations in the affected individuals arose de novo,
although the possibility of germline mosaicism in a parent could not be
excluded. No mutations in KRAS (190070), NRAS (164790), HRAS, or ERAS
(300437) were observed in the 28 individuals with Noonan syndrome or in
1 individual with Costello syndrome. The observations suggested that
germline mutations in HRAS perturb human development and increase
susceptibility to tumors.

Gripp et al. (2006) and Estep et al. (2006) simultaneously analyzed the
HRAS gene in samples collected at International Costello Syndrome
meetings over several years and identified heterozygous mutations in 33
of 40 and 33 of 36 patients diagnosed with Costello syndrome,
respectively (20 patients participated in both studies, for a total of
56 different patients). All mutations were in codons 12 and 13; the
majority in both studies (91% and 91%, respectively) were a G12S
substitution (190020.0003). Gripp et al. (2006) analyzed 19 sets of
parents, none of whom carried the mutation, confirming the de novo
nature of mutations in Costello syndrome patients. Estep et al. (2006)
also analyzed 8 well-characterized patients diagnosed with
cardiofaciocutaneous syndrome (CFC; 115150) and found no mutations in
the HRAS coding region, supporting a distinct etiology between the
Costello and CFC syndromes. In a detailed review of these reports, Lin
et al. (2008) noted that Gripp et al. (2006) and Estep et al. (2006) had
described a total of 49 patients, not 56 as originally stated. Lin et
al. (2008) also provided a detailed list of the clinical features of
these patients and emphasized the need for a central registry in order
to keep track of biologic material.

In 2 patients originally diagnosed with Costello syndrome but with
features overlapping those of CFC, in whom no HRAS mutations were found
(Estep et al., 2006), Rauen (2006) identified missense mutations in the
BRAF gene (164757.0020 and 164757.0021, respectively). Rauen (2006)
stated that Costello syndrome and CFC can be distinguished by mutation
analysis of genes in the RAS/MAPK pathway.

Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical
diagnosis of Costello syndrome and identified mutations in 37 (86%). The
mutations were de novo in all cases in which DNA samples were available
from the parents. The most common mutation was G12S, which was found in
30 of 37 mutation-positive patients. All of the mutation-positive cases
had failure to thrive as well as the facial appearance and hands
characteristic of Costello syndrome; macrocephaly was found in 32
mutation-positive cases. In a patient with autistic features and
microretrognathism, Kerr et al. (2006) identified a substitution in a
novel region of HRAS (K117R; 190020.0006). Kerr et al. (2006) stated
that, together with previously published series (Aoki et al., 2005 and
Gripp et al., 2006), mutations in HRAS had been found in 82 (85%) of 96
patients with a clinical diagnosis of Costello syndrome and that
overall, the frequency of malignancy in the published mutation-positive
cases was 11%.

Zampino et al. (2007) identified the common G12S mutation in 8 of 9
unrelated patients with Costello syndrome; the ninth child had a
different mutation (190020.0008). All mutations were de novo, paternally
inherited and associated with advanced paternal age. None of 36 patients
with Noonan syndrome or 4 with CFC syndrome had a mutation in the HRAS
gene.

Zenker et al. (2007) identified 2 different heterozygous mutations in
the KRAS gene (190070.0017-190070.0018) in 2 unrelated infants with
Costello syndrome. Both patients had coarse facies, loose and redundant
skin with deep palmar creases, heart defects, failure to thrive, and
moderate mental retardation. Zenker et al. (2007) noted that the
patients may later develop features of CFC, which is commonly associated
with KRAS mutations, but emphasized that the findings underscored the
central role of Ras in the pathogenesis of these phenotypically related
disorders.

In a 20-year-old woman with clinical features typical of Costello
syndrome and additional findings seen in Noonan syndrome, who was
negative for mutations in the PTPN11 and HRAS genes, Bertola et al.
(2007) identified a mutation in the KRAS gene (K5E; 190070.0019) that
was not found in her unaffected mother or brother or in 100 controls.
The patient was diagnosed with hypertrophic cardiomyopathy soon after
birth, and evolved with severe developmental delay; lymphedema began in
her lower extremities at age 15 years, and at age 18 years she developed
nasal papillomata. The initial diagnosis was Noonan syndrome, but the
presence of relative macrocephaly, coarse facial features, loose skin in
the hands and feet with deep creases, dark skin, and particularly the
development of nasal papillomata led to the diagnosis of Costello
syndrome. Bertola et al. (2007) noted that this mutation was in the same
codon as that of 1 of the patients reported by Zenker et al. (2007)
(K5N; 190070.0017).

Van der Burgt et al. (2007) identified mutations in the HRAS gene (see,
e.g., 190020.0001; 190020.0003; 190020.0009; 190020.0010) in patients
with congenital myopathy with excess muscle spindles, a variant of
Costello syndrome. Three of the patients had been reported by de Boode
et al. (1996), Selcen et al. (2001), and Stassou et al. (2005).

Schulz et al. (2008) identified mutations in the HRAS gene in 28 (90.3%)
of 31 patients with Costello syndrome. All mutations occurred in codons
12 or 13, and the HRAS mutations in 14 informative families could all be
traced to the paternal allele. G12S was the most common mutation,
occurring in 82.1% of patients. The phenotype was relatively
homogeneous.

In 2 unrelated patients with Costello syndrome, Gripp et al. (2008)
identified 2 different novel mutations in the HRAS gene (190020.0011;
190020.0012). The facial features of both patients were less coarse than
typically seen in Costello syndrome.

Lo et al. (2008) described 4 infants with an unusually severe Costello
syndrome, in whom they identified 3 mutations in the HRAS gene
(190020.0003, 190020.0013, and 190020.0014, respectively). The authors
stated that hypoglycemia, renal abnormalities, severe early
cardiomyopathy, congenital lung and airway abnormalities, pleural and
pericardial effusion, chylous ascites, and pulmonary lymphangectasia are
part of the clinical spectrum seen in Costello syndrome, and noted that
lung pathology resembling alveolar capillary dysplasia was reported in 1
case.

GENOTYPE/PHENOTYPE CORRELATIONS

Gripp et al. (2007) reported 13 unrelated patients ages 0 to 8 years
with a clinical diagnosis of Costello syndrome, Costello-like syndrome,
or thought to have either CFC syndrome or Costello syndrome who were
negative for mutations in the HRAS gene. De novo heterozygous BRAF or
MEK1 mutations were identified in 8 and 5 patients, respectively. In a
comparison to a group of previously published patients with HRAS
mutations, Gripp et al. (2007) found several significant clinical
differences between the 2 groups. Patients with an HRAS mutation and
Costello syndrome tended to have polyhydramnios, ulnar deviation, growth
hormone deficiency, and tachycardia more frequently than patients with
BRAF or MEK1 mutations. Those with BRAF or MEK1 mutations had more
cardiovascular malformations. Although the presence of more than 1
papilloma strongly suggested Costello syndrome over CFC, the authors
noted that these lesions typically develop over time and thus may not be
very helpful in the differential diagnosis of younger children. Gripp et
al. (2007) concluded that the 13 patients in their study had CFC
syndrome and not Costello syndrome, based on the clinical and molecular
findings. The authors noted the phenotypic overlap between the 2
disorders, but suggested that Costello syndrome be reserved for patients
with HRAS mutations.

Gripp et al. (2011) examined 12 individuals with Costello syndrome due
to the HRAS G13C (190020.0007) mutation and compared the phenotype to
those with the HRAS G12S (190020.0003) mutation. Individuals with G13C
had many typical findings including polyhydramnios, failure to thrive,
hypertrophic cardiomyopathy, macrocephaly, posterior fossa crowding, and
developmental delay. Their facial features were less coarse and short
stature was less severe. Statistically significant differences included
the absence of several common features, including multifocal atrial
tachycardia, ulnar deviation of the wrist, and papillomata; a noteworthy
absence of malignant tumors did not reach statistical significance.
There were some novel ectodermal findings associated with the G13C
mutation, including loose anagen hair and long eyelashes requiring
trimming (termed 'dolichocilia').

McCormick et al. (2013) developed a severity score for Costello syndrome
based on various criteria, including feeding difficulties, cardiac
abnormalities, orthopedic abnormalities, neurologic abnormalities,
malignancies, bone density, and stature as well as mortality, and
assessed 78 individuals blind to genotype. They then compared this to
genotypes of the individuals and found that individuals with the G12A
(190020.0004) and the G12C (190020.0014) HRAS mutations were more
severely affected than those with other HRAS mutations.

ANIMAL MODEL

Schuhmacher et al. (2008) generated a mouse model of Costello syndrome
by introduction of an oncogenic gly12-to-val mutation (190020.0001) in
the mouse Hras gene. Mutant mice developed hyperplasia of the mammary
gland, but tumor development was rare. The mice showed some phenotypic
features similar to those of Costello syndrome, including facial
dysmorphism and cardiomyopathy. Mutant mice also developed systemic
hypertension, extensive vascular remodeling, and fibrosis in both the
heart and the kidneys resulting from abnormal upregulation of the
renin-angiotensin II system, which responded to treatment with
captopril.

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31. Gripp, K. W.; Stabley, D. L.; Nicholson, L.; Hoffman, J. D.; Sol-Church,
K.: Somatic mosaicism for an HRAS mutation causes Costello syndrome. Am.
J. Med. Genet. 140A: 2163-2169, 2006.

32. Hennekam, R. C. M.: Costello syndrome: an overview. Am. J. Med.
Genet. 117C: 42-48, 2003.

33. Hinek, A.; Rabinovitch, M.; Keeley, F.; Okamura-Oho, Y.; Callahan,
J.: The 67-kD elastin/laminin-binding protein is related to an enzymatically
inactive, alternatively spliced form of beta-galactosidase. J. Clin.
Invest. 91: 1198-1205, 1993.

34. Hinek, A.; Smith, A. C.; Cutiongco, E. M.; Callahan, J. W.; Gripp,
K. W.; Weksberg, R.: Decreased elastin deposition and high proliferation
of fibroblasts from Costello syndrome are related to functional deficiency
in the 67-kD elastin-binding protein. Am. J. Hum. Genet. 66: 859-872,
2000.

35. Hinek, A.; Teitell, M. A.; Schoyer, L.; Allen, W.; Gripp, K. W.;
Hamilton, R.; Weksberg, R.; Kluppel, M.; Lin, A. E.: Myocardial storage
of chondroitin sulfate-containing moieties in Costello syndrome patients
with severe hypertrophic cardiomyopathy. Am. J. Med. Genet. 133A:
1-12, 2005.

36. Ioan, D. M.; Fryns, J. P.: Costello syndrome in two siblings
and minor manifestations in their mother: further evidence for autosomal
dominant inheritance? Genet. Counsel. 13: 353-356, 2002.

37. Ion, A.; Tartaglia, M.; Song, X.; Kalidas, K.; van der Burgt,
I.; Shaw, A. C.; Ming, J. E.; Zampino, G.; Zackai, E. H.; Dean, J.
C. S.; Somer, M.; Parenti, G.; Crosby, A. H.; Patton, M. A.; Gelb,
B. D.; Jeffery, S.: Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous
(CFC) syndrome. Hum. Genet. 111: 421-427, 2002.

38. Izumikawa, Y.; Naritomi, K.; Tohma, T.; Shiroma, N.; Hirayama,
K.: The Costello syndrome: a boy with thick mitral valves and arrhythmias. Jpn.
J. Hum. Genet. 38: 329-334, 1993.

39. Johnson, J. P.; Golabi, M.; Norton, M. E.; Rosenblatt, R. M.;
Feldman, G. M.; Yang, S. P.; Hall, B. D.; Fries, M. H.; Carey, J.
C.: Costello syndrome: phenotype, natural history, differential diagnosis,
and possible cause. J. Pediat. 133: 441-448, 1998.

40. Kawame, H.; Matsui, M.; Kurosawa, K.; Matsuo, M.; Masuno, M.;
Ohashi, H.; Fueki, N.; Aoyama, K.; Miyatsuka, Y.; Suzuki, K.; Akatsuka,
A.; Ochiai, Y.; Fukushima, Y.: Further delineation of the behavioral
and neurologic features in Costello syndrome. Am. J. Med. Genet. 118A:
8-14, 2003.

41. Kerr, B.; Allanson, J.; Delrue, M. A.; Gripp, K. W.; Lacombe,
D.; Lin, A. E.; Rauen, K. A.: The diagnosis of Costello syndrome:
nomenclature in Ras/MAPK pathway disorders. (Letter) Am. J. Med.
Genet. 146A: 1218-1220, 2008.

42. Kerr, B.; Delrue, M.-A.; Sigaudy, S.; Perveen, R.; Marche, M.;
Burgelin, I.; Stef, M.; Tang, B.; Eden, O. B.; O'Sullivan, J.; De
Sandre-Giovannoli, A.; Reardon, W.; and 14 others: Genotype-phenotype
correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J.
Med. Genet. 43: 401-405, 2006.

43. Kerr, B.; Eden, O. B.; Dandamudi, R.; Shannon, N.; Quarrell, O.;
Emmerson, A.; Ladusans, E.; Gerrard, M.; Donnai, D.: Costello syndrome:
two cases with embryonal rhabdomyosarcoma. J. Med. Genet. 35: 1036-1039,
1998.

44. Kondo, I.; Tamanaha, K.; Ashimine, K.: The Costello syndrome:
report of a case and review of the literature. Jpn. J. Hum. Genet. 38:
433-436, 1993.

45. Kuniba, H.; Pooh, R. K.; Sasaki, K.; Shimokawa, O.; Harada, N.;
Kondoh, T.; Egashira, M.; Moriuchi, H.; Yoshiura, K.; Niikawa, N.
: Prenatal diagnosis of Costello syndrome using 3D ultrasonography
amniocentesis confirmation of the rare HRAS mutation G12D. (Letter) Am.
J. Med. Genet. 149A: 785-787, 2009.

46. Lin, A. E.; Alexander, M. E.; Colan, S. D.; Kerr, B.; Rauen, K.
A.; Noonan, J.; Baffa, J.; Hopkins, E.; Sol-Church, K.; Limongelli,
G.; Digilio, M. C.; Marino, B.; and 11 others: Clinical, pathological,
and molecular analyses of cardiovascular abnormalities in Costello
syndrome: a Ras/MAPK pathway syndrome. Am. J. Med. Genet. 155A:
486-507, 2011.

47. Lin, A. E.; Grossfeld, P. D.; Hamilton, R. M.; Smoot, L.; Gripp,
K. W.; Proud, V.; Weksberg, R.; Wheeler, P.; Picker, J.; Irons, M.;
Zackai, E.; Marino, B.; Scott, C. I., Jr.; Nicholson, L.: Further
delineation of cardiac abnormalities in Costello syndrome. Am. J.
Med. Genet. 111: 115-129, 2002.

48. Lin, A. E.; Rauen, K. A.; Gripp, K. W.; Carey, J. C.: Clarification
of previously reported Costello syndrome patients. (Letter) Am. J.
Med. Genet. 146A: 940-943, 2008.

49. Lo, I. F. M.; Brewer, C.; Shannon, N.; Shorto, J.; Tang, B.; Black,
G.; Soo, M. T.; Ng, D. K. K.; Lam, S. T. S.; Kerr, B.: Severe neonatal
manifestations of Costello syndrome. (Letter) J. Med. Genet. 45:
167-171, 2008.

50. Lurie, I. W.: Genetics of the Costello syndrome. Am. J. Med.
Genet. 52: 358-359, 1994.

51. Maroti, Z.; Kutsche, K.; Sutajova, M.; Gal, A.; Nothwang, H. G.;
Czeizel, A. E.; Timar, L.; Solyom, E.: Refinement and delineation
of the breakpoint regions of a chromosome 1;22 translocation in a
patient with Costello syndrome. Am. J. Med. Genet. 109: 234-237,
2002.

52. Martin, R. A.; Jones, K. L.: Delineation of the Costello syndrome. Am.
J. Med. Genet. 41: 346-349, 1991.

53. Martin, R. A.; Jones, K. L.: Facio-cutaneous-skeletal syndrome
is the Costello syndrome. (Letter) Am. J. Med. Genet. 47: 169 only,
1993.

54. McCormick, E. M.; Hopkins, E.; Conway, L.; Catalano, S.; Hossain,
J.; Sol-Church, K.; Stabley, D. L.; Gripp, K. W.: Assessing genotype-phenotype
correlation in Costello syndrome using a severity score. Genet. Med. 15:
554-557, 2013.

55. Mori, M.; Yamagata, T.; Mori, Y.; Nokubi, M.; Saito, K.; Fukushima,
Y.; Momoi, M. Y.: Elastic fiber degeneration in Costello syndrome. Am.
J. Med. Genet. 61: 304-309, 1996.

56. Moroni, I.; Bedeschi, F.; Luksch, R.; Casanova, M.; D'Incerti,
L.; Uziel, G.; Selicorni, A.: Costello syndrome: a cancer predisposing
syndrome? Clin. Dysmorph. 9: 265-268, 2000.

57. Okamoto, N.; Chiyo, H.; Imai, K.; Otani, K.; Futagi, Y.: A Japanese
patient with the Costello syndrome. Hum. Genet. 93: 605-606, 1994.

58. Patton, M. A.; Baraitser, M.: Cutis laxa and the Costello syndrome. J.
Med. Genet. 30: 622, 1993.

59. Patton, M. A.; Tolmie, J.; Ruthnum, P.; Bamforth, S.; Baraitser,
M.; Pembrey, M.: Congenital cutis laxa with retardation of growth
and development. J. Med. Genet. 24: 556-561, 1987.

60. Philip, N.; Mancini, J.: Costello syndrome and facio-cutaneous-skeletal
syndrome. Am. J. Med. Genet. 47: 174-175, 1993.

61. Piccione, M.; Piro, E.; Pomponi, M. G.; Matina, F.; Pietrobono,
R.; Candela, E.; Gabriele, B.; Neri, G.; Corsello, G.: A premature
infant with Costello syndrome due to a rare G13C HRAS mutation. Am.
J. Med. Genet. 149A: 487-489, 2009.

62. Privitera, S.; Prody, C. A.; Callahan, J. W.; Hinek, A.: The
67-kDa enzymatically inactive alternatively spliced variant of beta-galactosidase
is identical to the elastin/laminin-binding protein. J. Biol. Chem. 273:
6319-6326, 1998.

63. Rauen, K. A.: Distinguishing Costello versus cardio-facio-cutaneous
syndrome: BRAF mutations in patients with a Costello phenotype. (Letter) Am.
J. Med. Genet. 140A: 1681-1683, 2006.

64. Say, B.; Gucsavas, M.; Morgan, H.; York, C.: The Costello syndrome. Am.
J. Med. Genet. 47: 163-165, 1993.

65. Schuhmacher, A. J.; Guerra, C.; Sauzeau, V.; Canamero, M.; Bustelo,
X. R.; Barbacid, M.: A mouse model for Costello syndrome reveals
an Ang II-mediated hypertensive condition. J. Clin. Invest. 118:
2169-2179, 2008.

66. Schulz, A. L.; Albrecht, B.; Arici, C.; van der Burgt, I.; Buske,
A.; Gillessen-Kaesbach, G.; Heller, R.; Horn, D.; Hubner, C. A.; Korenke,
G. C.; Konig, R.; Kress, W.; and 15 others: Mutation and phenotypic
spectrum in patients with cardio-facio-cutaneous and Costello syndrome Clin.
Genet. 73: 62-70, 2008.

67. Selcen, D.; Kupsky, W. J.; Benjamins, D.; Nigro, M. A.: Myopathy
with muscle spindle excess: a new congenital neuromuscular syndrome? Muscle
Nerve 24: 138-143, 2001. Note: Erratum: Muscle Nerve 24: 445 only,
2001.

68. Siwik, E. S.; Zahka, K. G.; Wiesner, G. L.; Limwongse, C.: Cardiac
disease in Costello syndrome. Pediatrics 101: 706-709, 1998.

69. Smith, L. P.; Podraza, J.; Proud, V. K.: Polyhydramnios, fetal
overgrowth, and macrocephaly: prenatal ultrasound findings of Costello
syndrome. Am. J. Med. Genet. 149A: 779-784, 2009.

70. Sol-Church, K.; Stabley, D. L.; Demmer, L. A.; Agbulos, A.; Lin,
A. E.; Smoot, L.; Nicholsonm, L.; Gripp, K. W.: Male-to-male transmission
of Costello syndrome: G12S HRAS germline mutation inherited from a
father with somatic mosaicism. Am. J. Med. Genet. 149A: 315-321,
2009.

71. Stassou, S.; Nadroo, A.; Schubert, R.; Chin, S.; Gudavalli, M.
: A new syndrome of myopathy with muscle spindle excess. J. Perinat.
Med. 33: 179-182, 2005.

72. Suri, M.; Garrett, C.: Costello syndrome with acoustic neuroma
and cataract. Is the Costello locus linked to neurofibromatosis type
2 on 22q? Clin. Dysmorph. 7: 149-151, 1998.

73. Sutajova, M.; Neukirchen, U.; Meinecke, P.; Czeizel, A. E.; Timar,
L.; Solyom, E.; Gal, A.; Kutsche, K.: Disruption of the PDGFB gene
in a 1;22 translocation patient does not cause Costello syndrome. Genomics 83:
883-892, 2004.

74. Tartaglia, M.; Cotter, P. D.; Zampino, G.; Gelb, B. D.; Rauen,
K. A.: Exclusion of PTPN11 mutations in Costello syndrome: further
evidence for distinct genetic etiologies for Noonan, cardio-facio-cutaneous
and Costello syndromes. Clin. Genet. 63: 423-426, 2003.

75. Teebi, A. S.: Costello or facio-cutaneous-skeletal syndrome?
(Letter) Am. J. Med. Genet. 47: 172, 1993.

76. Teebi, A. S.; Shaabani, I. S.: Further delineation of Costello
syndrome. Am. J. Med. Genet. 47: 166-168, 1993.

77. Torrelo, A.; Lopez-Avila, A.; Mediero, I. G.; Zambrano, A.: Costello
syndrome. J. Am. Acad. Derm. 32: 904-907, 1995.

78. Troger, B.; Kutsche, K.; Bolz, H.; Luttgen, S.; Gal, A.; Almassy,
Z.; Caliebe, A.; Freisinger, P.; Hobbiebrunken, E.; Morlot, M.; Stefanova,
M.; Streubel, B.; Wieczorek, D.; Meinecke, P.: No mutation in the
gene for Noonan syndrome, PTPN11, in 18 patients with Costello syndrome.
(Letter) Am. J. Med. Genet. 121A: 82-84, 2003.

79. Umans, S.; Decock, P.; Fryns, J. P.: Costello syndrome: the natural
history of a true postnatal growth retardation syndrome. Genet. Counsel. 6:
121-125, 1995.

80. van der Burgt, I.; Kupsky, W.; Stassou, S.; Nadroo, A.; Barroso,
C.; Diem, A.; Kratz, C. P.; Dvorsky, R.; Ahmadian, M. R.; Zenker,
M.: Myopathy caused by HRAS germline mutations: implications for
disturbed myogenic differentiation in the presence of constitutive
Hras activation. (Letter) J. Med. Genet. 44: 459-462, 2007.

81. van Eeghen, A. M.; van Gelderen, I.; Hennekam, R.C.M.: Costello
syndrome: report and review. Am. J. Med. Genet. 82: 187-193, 1999.

82. White, S. M.; Graham, J. M., Jr.; Kerr, B.; Gripp, K.; Weksberg,
R.; Cytrynbaum, C.; Reeder, J. L.; Stewart, F. J.; Edwards, M.; Wilson,
M.; Bankier, A.: The adult phenotype in Costello syndrome. Am. J.
Med. Genet. 136A: 128-135, 2005. Note: Erratum: Am. J. Med. Genet. 139A:
55 only, 2005.

83. Yoshida, R.; Fukushima, Y.; Ohashi, H.; Asoh, M.; Fukuyama, Y.
: The Costello syndrome: are nasal papillomata essential? Jpn. J.
Hum. Genet. 38: 437-444, 1993.

84. Zampino, G.; Mastroiacovo, P.; Ricci, R.; Zollino, M.; Segni,
G.; Martini-Neri, M. E.; Neri, G.: Costello syndrome: further clinical
delineation, natural history, genetic definition, and nosology. Am.
J. Med. Genet. 47: 176-183, 1993.

85. Zampino, G.; Pantaleoni, F.; Carta, C.; Cobellis, G.; Vasta, I.;
Neri, C.; Pogna, E. A.; De Feo, E.; Delogu, A.; Sarkozy, A.; Atzeri,
F.; Selicorni, A.; Rauen, K. A.; Cytrynbaum, C. S.; Weksberg, R.;
Dallapiccola, B.; Ballabio, A.; Gelb, B. D.; Neri, G.; Tartaglia,
M.: Diversity, parental germline origin, and phenotypic spectrum
of de novo HRAS missense changes in Costello syndrome. Hum. Mutat. 28:
265-272, 2007.

86. Zenker, M.; Lehmann, K.; Schulz, A. L.; Barth, H.; Hansmann, D.;
Koenig, R.; Korinthenberg, R.; Kreiss-Nachtsheim, M.; Meinecke, P.;
Morlot, S.; Mundlos, S.; Quante, A. S.; Raskin, S.; Schnabel, D.;
Wehner, L.-E.; Kratz, C. P.; Horn, D.; Kutsche, K.: Expansion of
the genotypic and phenotypic spectrum in patients with KRAS germline
mutations. J. Med. Genet. 44: 131-135, 2007.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Isolated cases

GROWTH:
[Height];
Increased birth length;
Short stature;
[Weight];
Increased birth weight;
[Other];
Fetal overgrowth;
Failure to thrive;
Postnatal onset growth deficiency

HEAD AND NECK:
[Head];
Macrocephaly;
Large anterior fontanelle;
[Face];
Coarse facies;
Full cheeks;
Micrognathia;
Pointed chin;
[Ears];
Low-set ears;
Thickened lobes;
Posteriorly rotated ears;
[Eyes];
Hypertelorism;
Epicanthal folds;
Downslanting palpebral fissures;
Strabismus;
Ptosis;
[Nose];
Depressed nasal bridge;
Anteverted nostrils;
[Mouth];
Thick lips;
Macroglossia;
High-arched palate;
[Neck];
Short neck;
Webbed neck;
Loose, redundant neck skin

CARDIOVASCULAR:
[Heart];
Hypertrophic cardiomyopathy;
Pulmonic stenosis;
Mitral valve prolapse;
Ventricular septal defect;
Atrial septal defect;
Dysrhythmias;
Arrhythmias

RESPIRATORY:
Obstructive sleep apnea;
[Airways];
Tracheomalacia;
Bronchomalacia;
[Lung];
Pneumothorax, recurrent;
Lymphangiectasia;
Alveolar/capillary dysplasia;
Small lungs;
Respiratory failure

CHEST:
[External features];
Barrel chest;
Pectus carinatum

ABDOMEN:
[Gastrointestinal];
Poor suck in infancy;
Pyloric stenosis, hypertrophic

GENITOURINARY:
[Kidneys];
Dilated calyces (in some patients);
Echogenic kidneys with thick-walled pelvises (in some patients);
Renal failure (in some patients)

SKELETAL:
[Limbs];
Restricted elbow motion;
Tight Achilles tendon;
[Hands];
Deep palmar creases;
Hyperextensible finger;
Wide distal phalanges;
Palmar nevi;
[Feet];
Deep plantar creases;
Clubfeet

SKIN, NAILS, HAIR:
[Skin];
Cutis laxa (especially hands and feet);
Loose, redundant skin;
Dark skin pigmentation;
Papillomas (perioral, nasal, and anal regions);
Acanthosis nigricans;
Palmar nevi;
Deep palmar creases;
[Nails];
Thin, deep-set nails;
Koilonychia;
Brittle nails;
[Hair];
Curly hair;
Sparse hair;
Thin anterior head hair

NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Sleep disorder;
Mental retardation;
Cerebral atrophy;
Ventriculomegaly;
Hydrocephalus;
Posterior fossa crowding, progressive;
Enlarged cerebellum;
Cerebellar tonsillar herniation;
Chiari I malformation

VOICE:
Hoarse voice

NEOPLASIA:
Epithelioma;
Bladder carcinoma;
Rhabdomyosarcoma;
Vestibular schwannoma

PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Polyhydramnios;
[Delivery];
Preterm delivery

LABORATORY ABNORMALITIES:
Hypoglycemia

MISCELLANEOUS:
Majority of cases are sporadic;
Characteristic facial features become more apparent with age;
Associated with advanced paternal age;
Sudden death;
Phenotypic overlap with Noonan syndrome 3 (609942) or cardiofaciocutaneous
syndrome (115150)

MOLECULAR BASIS:
Caused by mutation in the V-Ha-RAS Harvey rat sarcoma viral oncogene
homolog gene (HRAS, 190020.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 06/28/2011
Cassandra L. Kniffin - updated: 4/16/2010
Marla J. F. O'Neill - updated: 9/25/2009
Cassandra L. Kniffin - updated: 3/24/2008
Cassandra L. Kniffin - updated: 3/2/2007
Cassandra L. Kniffin - updated: 2/9/2006
Kelly A. Przylepa - revised: 4/4/2003

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

*FIELD* ED
ckniffin: 06/28/2011
wwang: 5/12/2011
ckniffin: 4/16/2010
ckniffin: 2/8/2010
joanna: 9/25/2009
joanna: 4/10/2009
ckniffin: 3/24/2008
ckniffin: 3/19/2008
ckniffin: 1/9/2008
joanna: 5/23/2007
ckniffin: 5/16/2007
ckniffin: 3/2/2007
ckniffin: 2/9/2006
joanna: 3/30/2004
joanna: 4/4/2003
alopez: 2/19/2002

*FIELD* CN
Ada Hamosh - updated: 11/12/2013
Cassandra L. Kniffin - updated: 3/13/2013
Cassandra L. Kniffin - updated: 9/11/2012
Cassandra L. Kniffin - updated: 6/28/2011
Cassandra L. Kniffin - updated: 4/16/2010
Cassandra L. Kniffin - updated: 2/16/2010
Marla J. F. O'Neill - updated: 6/1/2009
Cassandra L. Kniffin - updated: 3/3/2009
Marla J. F. O'Neill - updated: 11/12/2008
Cassandra L. Kniffin - updated: 6/25/2008
Cassandra L. Kniffin - updated: 4/14/2008
Cassandra L. Kniffin - updated: 3/24/2008
Cassandra L. Kniffin - updated: 8/28/2007
Cassandra L. Kniffin - updated: 5/16/2007
Cassandra L. Kniffin - updated: 3/2/2007
Marla J. F. O'Neill - updated: 9/26/2006
Marla J. F. O'Neill - updated: 6/20/2006
Cassandra L. Kniffin - updated: 2/8/2006
Marla J. F. O'Neill - updated: 1/25/2006
Marla J. F. O'Neill - updated: 12/28/2005
Kelly A. Przylepa - updated: 11/8/2005
Marla J. F. O'Neill - updated: 10/19/2005
Victor A. McKusick - updated: 9/21/2005
Marla J. F. O'Neill - updated: 7/20/2004
Victor A. McKusick - updated: 5/6/2004
Victor A. McKusick - updated: 8/25/2003
Victor A. McKusick - updated: 6/4/2003
Victor A. McKusick - updated: 4/16/2003
Victor A. McKusick - updated: 3/7/2003
Victor A. McKusick - updated: 12/31/2002
Deborah L. Stone - updated: 10/25/2002
Victor A. McKusick - updated: 5/21/2002
Victor A. McKusick - updated: 2/8/2002
Ada Hamosh - updated: 2/6/2001
Victor A. McKusick - updated: 3/22/2000
Victor A. McKusick - updated: 2/24/2000
Sonja A. Rasmussen - updated: 10/5/1999
Michael J. Wright - updated: 8/13/1999
Victor A. McKusick - updated: 2/14/1999
Michael J. Wright - updated: 2/12/1999
Victor A. McKusick - updated: 1/25/1999
Ada Hamosh - updated: 6/15/1998
Victor A. McKusick - updated: 2/19/1998
Iosif W. Lurie - updated: 10/2/1996

*FIELD* CD
Victor A. McKusick: 11/20/1991

*FIELD* ED
alopez: 11/12/2013
alopez: 7/10/2013
carol: 3/14/2013
ckniffin: 3/13/2013
carol: 2/27/2013
ckniffin: 9/11/2012
alopez: 1/20/2012
wwang: 7/13/2011
ckniffin: 6/28/2011
joanna: 5/17/2011
wwang: 4/30/2010
ckniffin: 4/16/2010
wwang: 2/18/2010
ckniffin: 2/16/2010
ckniffin: 2/4/2010
joanna: 9/16/2009
wwang: 6/3/2009
terry: 6/1/2009
wwang: 3/5/2009
ckniffin: 3/3/2009
wwang: 11/14/2008
terry: 11/12/2008
wwang: 9/12/2008
ckniffin: 9/8/2008
carol: 8/22/2008
ckniffin: 6/25/2008
carol: 5/5/2008
ckniffin: 4/14/2008
wwang: 4/3/2008
ckniffin: 3/24/2008
wwang: 3/18/2008
ckniffin: 3/17/2008
ckniffin: 9/12/2007
carol: 9/10/2007
ckniffin: 9/10/2007
carol: 9/6/2007
ckniffin: 8/28/2007
wwang: 5/22/2007
ckniffin: 5/16/2007
carol: 3/8/2007
ckniffin: 3/2/2007
wwang: 9/27/2006
terry: 9/26/2006
carol: 8/28/2006
wwang: 6/20/2006
terry: 6/20/2006
wwang: 2/13/2006
ckniffin: 2/8/2006
wwang: 2/2/2006
terry: 1/25/2006
wwang: 12/29/2005
terry: 12/28/2005
alopez: 11/8/2005
wwang: 10/24/2005
terry: 10/19/2005
alopez: 10/14/2005
alopez: 9/26/2005
alopez: 9/23/2005
terry: 9/21/2005
terry: 4/18/2005
carol: 7/20/2004
tkritzer: 5/11/2004
terry: 5/6/2004
mgross: 3/17/2004
tkritzer: 8/27/2003
terry: 8/25/2003
tkritzer: 6/11/2003
terry: 6/4/2003
tkritzer: 4/28/2003
terry: 4/16/2003
carol: 3/18/2003
tkritzer: 3/18/2003
terry: 3/7/2003
cwells: 2/11/2003
terry: 12/31/2002
carol: 10/25/2002
cwells: 6/4/2002
terry: 5/21/2002
alopez: 2/19/2002
terry: 2/8/2002
mcapotos: 2/12/2001
terry: 2/6/2001
carol: 11/13/2000
mgross: 4/3/2000
terry: 3/22/2000
alopez: 2/28/2000
terry: 2/24/2000
carol: 10/5/1999
terry: 8/13/1999
terry: 6/11/1999
mgross: 3/16/1999
mgross: 2/17/1999
mgross: 2/16/1999
carol: 2/14/1999
terry: 2/12/1999
carol: 2/5/1999
mgross: 2/5/1999
terry: 1/25/1999
alopez: 6/15/1998
terry: 2/19/1998
terry: 7/9/1997
carol: 6/3/1997
carol: 10/2/1996
mark: 9/19/1996
mark: 4/25/1996
terry: 4/18/1996
mark: 2/22/1996
terry: 2/19/1996
mark: 7/16/1995
carol: 2/3/1995
jason: 7/27/1994
mimadm: 2/19/1994
carol: 11/29/1993
carol: 11/22/1993

MIM 607464
*RECORD*
*FIELD* NO
607464
*FIELD* TI
#607464 THYROID CARCINOMA, HURTHLE CELL
;;HURTHLE CELL THYROID NEOPLASIA
*FIELD* TX
read moreA number sign (#) is used with this entry because Hurthle cell tumors
are associated with chromosomal abnormalities or mutations in the RAS
gene (190020), the PAX8/PPARG fusion gene (see 167415), or the NDUFA13
gene (609435).

DESCRIPTION

Hurthle cell carcinoma of the thyroid accounts for approximately 3% of
all thyroid cancers. Although they are classified as variants of
follicular neoplasms, they are more often multifocal and somewhat more
aggressive and are less likely to take up iodine than are other
follicular neoplasms (Sanders and Silverman, 1998).

Hurthle cell tumors, also known as oxyphil cell tumors, are composed of
cells with increased numbers of mitochondria, which corresponds
morphologically to their voluminous, granular, eosinophilic cytoplasm
(Maximo et al., 2005).

CYTOGENETICS

Chromosomal aberrations by comparative genomic hybridization (CGH) are
common in Hurthle cell neoplasms. However, the relationship between the
chromosomal aberrations by CGH and tumor behavior was obscure. Wada et
al. (2002) investigated chromosomal aberrations in primary Hurthle cell
neoplasms (13 carcinomas and 15 adenomas) using CGH and correlated the
aberrations identified with tumor node metastasis stage, tumor
differentiation, capsular invasion, and tumor recurrence. Chromosomal
aberrations were found in 62% (8 of 13) of carcinomas and 60% (9 of 15)
of adenomas. Overall, common chromosomal gains were found on 5p (29%),
5q (36%), 7 (29%), 12p (14%), 12q (21%), 17p (29%), 17q (32%), 19p
(32%), 19q (25%), 20p (21%), 20q (29%), and 22q (18%). Five of the 8
(63%) patients with aberrations developed recurrence, whereas 0 of 5
patients without aberrations developed recurrence. The authors concluded
that chromosomal gains by CGH on 5p, 7, 12p, 12q, 19p, 19q, 20p, and 20q
in Hurthle cell carcinomas are associated with tumor recurrence. They
also concluded that such chromosomal aberrations may be predictive for
recurrent disease in patients with Hurthle cell thyroid carcinoma.

MAPPING

Both papillary and follicular thyroid carcinomas may subsequently
acquire further somatic genetic changes, which can result in tumor
dedifferentiation and clinical progression. Certain chromosomal regions
seem to be preferentially involved, suggesting that they may harbor
tumor suppressor genes. The 17p13 region has been suggested to harbor a
novel oncogene or tumor suppressor gene that plays a role in thyroid
carcinoma progression. Farrand et al. (2002) studied a large cohort of
clinically and histologically well characterized tumors, mainly typical
follicular thyroid carcinoma and oxyphilic follicular thyroid carcinoma
(Hurthle cell carcinoma), using a series of well mapped and closely
spaced microsatellite markers. They confirmed a high 17p13 LOH rate in
follicular thyroid carcinomas (18 of 20) and Hurthle cell carcinomas (13
of 19) and showed an association between 17p13 LOH and advanced tumor
grade. In the Hurthle cell carcinomas the authors identified a narrow
minimal common deleted region between D17S1308 (285 kb from pter) and
D17S695 (696 kb from pter). This region was flanked centromerically by a
breakpoint cluster, further suggesting nonrandom deletion. Farrand et
al. (2002) concluded that these data suggest that a tumor suppressor
gene, involved in Hurthle cell carcinoma pathogenesis, is contained
within the D17S1308-D17S695 interval.

MOLECULAR GENETICS

Nikiforova et al. (2003) analyzed a series of 88 conventional follicular
and Hurthle cell thyroid tumors for RAS (e.g., 190020) mutations and
PAX8-PPARG (see 167415) rearrangements for galectin-3 (153619) and
mesothelioma antibody HBME-1 expression by immunohistochemistry.
Forty-nine percent of conventional follicular carcinomas had RAS
mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both.
In follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG
rearrangement, and 48% had neither. Follicular carcinomas with RAS
mutations most often displayed an HBME-1-positive/galectin-3-negative
immunophenotype and were either minimally or overtly invasive. Hurthle
cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations.
Nikiforova et al. (2003) concluded that follicular thyroid carcinomas
can develop through different molecular pathways. While conventional
follicular thyroid carcinomas develop through at least 2 distinct and
nonoverlapping molecular pathways initiated by RAS point mutation or
PAX8-PPARG rearrangement, Hurthle cell tumors have a low frequency of
both of these genetic alterations and apparently require a unique set of
mutations for their development.

In a man with papillary thyroid carcinoma composed predominantly of
Hurthle cells, Maximo et al. (2005) identified a heterozygous germline
mutation (609435.0001) in the NDUFA13 gene, which they called GRIM19.
Heterozygous somatic mutations were identified in 3 of 26 additional
sporadic Hurthle cell tumors. There was no associated loss of
heterozygosity at the GRIM19 locus, suggesting either a
dominant-negative mechanism or haploinsufficiency. The 4 tumors with
GRIM19 mutations had significantly higher levels of ICAM1 (147840)
expression in tumor tissue versus normal tissue compared to tumors
without GRIM19 mutations. Maximo et al. (2005) postulated that loss of
GRIM19 function may lead to mitochondrial defects and mitochondrial
excess observed in Hurthle cell tumors or to defects in apoptosis.

*FIELD* RF
1. Farrand, K.; Delahunt, B.; Wang, X.-L.; McIver, B.; Hay, I. D.;
Goellner, J. R.; Eberhardt, N. L.; Grebe, S. K. G.: High resolution
loss of heterozygosity mapping of 17p13 in thyroid cancer: Hurthle
cell carcinomas exhibit a small 411-kilobase common region of allelic
imbalance, probably containing a novel tumor suppressor gene. J.
Clin. Endocr. Metab. 87: 4715-4721, 2002.

2. Maximo, V.; Botelho, T.; Capela, J.; Soares, P.; Lima, J.; Taveira,
A.; Amaro, T.; Barbosa, A. P.; Preto, A.; Harach, H. R.; Williams,
D.; Sobrinho-Simoes, M.: Somatic and germline mutation in GRIM-19,
a dual function gene involved in mitochondrial metabolism and cell
death, is linked to mitochondrion-rich (Hurthle cell) tumours of the
thyroid. Brit. J. Cancer. 92: 1892-1898, 2005.

3. Nikiforova, M. N.; Lynch, R. A.; Biddinger, P. W.; Alexander, E.
K.; Dorn, G. W., II; Tallini, G.; Kroll, T. G.; Nikiforov, Y. E.:
RAS point mutations and PAX8-PPAR-gamma rearrangement in thyroid tumors:
evidence for distinct molecular pathways in thyroid follicular carcinoma. J.
Clin. Endocr. Metab. 88: 2318-2326, 2003.

4. Sanders, L. E.; Silverman, M.: Follicular and Hurthle cell carcinoma:
predicting outcome and directing therapy. Surgery 124: 967-974,
1998.

5. Wada, N.; Duh, Q.-Y.; Miura, D.; Brunaud, L.; Wong, M. G.; Clark,
O. H.: Chromosomal aberrations by comparative genomic hybridization
in Hurthle cell thyroid carcinomas are associated with tumor recurrence. J.
Clin. Endocr. Metab. 87: 4595-4601, 2002.

*FIELD* CN
Cassandra L. Kniffin - updated: 5/27/2008
John A. Phillips, III - updated: 9/3/2004

*FIELD* CD
John A. Phillips, III: 1/8/2003

*FIELD* ED
terry: 11/08/2010
wwang: 5/29/2008
ckniffin: 5/27/2008
carol: 6/20/2006
alopez: 9/3/2004
carol: 3/18/2004
alopez: 1/8/2003