Full text data of MYH9
MYH9
[Confidence: high (present in two of the MS resources)]
Myosin-9 (Cellular myosin heavy chain, type A; Myosin heavy chain 9; Myosin heavy chain, non-muscle IIa; Non-muscle myosin heavy chain A; NMMHC-A; Non-muscle myosin heavy chain IIa; NMMHC II-a; NMMHC-IIA)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Myosin-9 (Cellular myosin heavy chain, type A; Myosin heavy chain 9; Myosin heavy chain, non-muscle IIa; Non-muscle myosin heavy chain A; NMMHC-A; Non-muscle myosin heavy chain IIa; NMMHC II-a; NMMHC-IIA)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P35579
ID MYH9_HUMAN Reviewed; 1960 AA.
AC P35579; A8K6E4; O60805; Q60FE2; Q86T83;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Myosin-9;
DE AltName: Full=Cellular myosin heavy chain, type A;
DE AltName: Full=Myosin heavy chain 9;
DE AltName: Full=Myosin heavy chain, non-muscle IIa;
DE AltName: Full=Non-muscle myosin heavy chain A;
DE Short=NMMHC-A;
DE AltName: Full=Non-muscle myosin heavy chain IIa;
DE Short=NMMHC II-a;
DE Short=NMMHC-IIA;
GN Name=MYH9;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=16106752; DOI=10.1093/dnares/12.1.53;
RA Kato S., Ohtoko K., Ohtake H., Kimura T.;
RT "Vector-capping: a simple method for preparing a high-quality full-
RT length cDNA library.";
RL DNA Res. 12:53-62(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Spinal cord;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Yamakawa H., Kikuno R.F., Nagase T., Ohara O.;
RT "Multiplex amplification and cloning of 5'-ends of cDNA by ligase-free
RT recombination: Preparation of full-lemgth cDNA clones encoding motor
RT proteins.";
RL Submitted (JAN-2007) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M.,
RA Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K.,
RA Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J.,
RA Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G.,
RA Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R.,
RA Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E.,
RA Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G.,
RA Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S.,
RA Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A.,
RA Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M.,
RA Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T.,
RA Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J.,
RA Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T.,
RA Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T.,
RA Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L.,
RA Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M.,
RA Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J.,
RA Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S.,
RA Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T.,
RA Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I.,
RA Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H.,
RA Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L.,
RA Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z.,
RA Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P.,
RA Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S.,
RA Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J.,
RA Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T.,
RA Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J.,
RA Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S.,
RA Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E.,
RA Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P.,
RA Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E.,
RA O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X.,
RA Khan A.S., Lane L., Tilahun Y., Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-1337, AND TISSUE SPECIFICITY.
RX PubMed=1912569;
RA Toothaker L.E., Gonzalez D.A., Tung N., Lemons R.S., le Beau M.M.,
RA Arnaout M.A., Clayton L.K., Tenen D.G.;
RT "Cellular myosin heavy chain in human leukocytes: isolation of 5' cDNA
RT clones, characterization of the protein, chromosomal localization, and
RT upregulation during myeloid differentiation.";
RL Blood 78:1826-1833(1991).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-1009.
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-715.
RX PubMed=1860190;
RA Simons M., Wang M., McBride O.W., Kawamoto S., Yamakawa K., Gdula D.,
RA Adelstein R.S., Weir L.;
RT "Human nonmuscle myosin heavy chains are encoded by two genes located
RT on different chromosomes.";
RL Circ. Res. 69:530-539(1991).
RN [10]
RP PROTEIN SEQUENCE OF 2-47; 67-74; 126-139; 187-199; 203-225; 241-261;
RP 290-299; 328-355; 359-387; 408-419; 476-494; 546-555; 581-613;
RP 618-637; 645-651; 657-670; 683-693; 712-718; 721-731; 746-755;
RP 765-775; 802-810; 824-829; 834-842; 861-867; 924-930; 995-1014;
RP 1042-1048; 1052-1075; 1081-1099; 1136-1162; 1166-1191; 1261-1266;
RP 1278-1295; 1302-1322; 1393-1400; 1405-1413; 1418-1433; 1484-1492;
RP 1504-1513; 1519-1525; 1529-1555; 1558-1566; 1606-1612; 1614-1638;
RP 1642-1648; 1662-1669; 1704-1724; 1794-1802; 1807-1828; 1857-1867;
RP 1899-1912; 1923-1932 AND 1951-1960, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RA Bienvenut W.V., Claeys R.;
RL Submitted (AUG-2005) to UniProtKB.
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 714-1960.
RX PubMed=1967836; DOI=10.1073/pnas.87.3.1164;
RA Saez C.G., Myers J.C., Shows T.B., Leinwand L.A.;
RT "Human nonmuscle myosin heavy chain mRNA: generation of diversity
RT through alternative polyadenylylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:1164-1168(1990).
RN [12]
RP INTERACTION WITH SVIL.
RX PubMed=12917436; DOI=10.1074/jbc.M305311200;
RA Chen Y., Takizawa N., Crowley J.L., Oh S.W., Gatto C.L., Kambara T.,
RA Sato O., Li X.-D., Ikebe M., Luna E.J.;
RT "F-actin and myosin II binding domains in supervillin.";
RL J. Biol. Chem. 278:46094-46106(2003).
RN [13]
RP ISGYLATION.
RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132;
RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J.,
RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.;
RT "Proteomic identification of proteins conjugated to ISG15 in mouse and
RT human cells.";
RL Biochem. Biophys. Res. Commun. 336:496-506(2005).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RC TISSUE=Prostate cancer;
RX PubMed=17487921; DOI=10.1002/elps.200600782;
RA Giorgianni F., Zhao Y., Desiderio D.M., Beranova-Giorgianni S.;
RT "Toward a global characterization of the phosphoproteome in prostate
RT cancer cells: identification of phosphoproteins in the LNCaP cell
RT line.";
RL Electrophoresis 28:2027-2034(2007).
RN [17]
RP INTERACTION WITH SVIL.
RX PubMed=17925381; DOI=10.1242/jcs.008219;
RA Takizawa N., Ikebe R., Ikebe M., Luna E.J.;
RT "Supervillin slows cell spreading by facilitating myosin II activation
RT at the cell periphery.";
RL J. Cell Sci. 120:3792-3803(2007).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RC TISSUE=T-cell;
RX PubMed=19367720; DOI=10.1021/pr800500r;
RA Carrascal M., Ovelleiro D., Casas V., Gay M., Abian J.;
RT "Phosphorylation analysis of primary human T lymphocytes using
RT sequential IMAC and titanium oxide enrichment.";
RL J. Proteome Res. 7:5167-5176(2008).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [20]
RP ASSOCIATION WITH END STAGE RENAL DISEASE.
RX PubMed=18794856; DOI=10.1038/ng.226;
RA Kopp J.B., Smith M.W., Nelson G.W., Johnson R.C., Freedman B.I.,
RA Bowden D.W., Oleksyk T., McKenzie L.M., Kajiyama H., Ahuja T.S.,
RA Berns J.S., Briggs W., Cho M.E., Dart R.A., Kimmel P.L., Korbet S.M.,
RA Michel D.M., Mokrzycki M.H., Schelling J.R., Simon E., Trachtman H.,
RA Vlahov D., Winkler C.A.;
RT "MYH9 is a major-effect risk gene for focal segmental
RT glomerulosclerosis.";
RL Nat. Genet. 40:1175-1184(2008).
RN [21]
RP ASSOCIATION WITH END STAGE RENAL DISEASE.
RX PubMed=18794854; DOI=10.1038/ng.232;
RA Kao W.H., Klag M.J., Meoni L.A., Reich D., Berthier-Schaad Y., Li M.,
RA Coresh J., Patterson N., Tandon A., Powe N.R., Fink N.E., Sadler J.H.,
RA Weir M.R., Abboud H.E., Adler S.G., Divers J., Iyengar S.K.,
RA Freedman B.I., Kimmel P.L., Knowler W.C., Kohn O.F., Kramp K.,
RA Leehey D.J., Nicholas S.B., Pahl M.V., Schelling J.R., Sedor J.R.,
RA Thornley-Brown D., Winkler C.A., Smith M.W., Parekh R.S.;
RT "MYH9 is associated with nondiabetic end-stage renal disease in
RT African Americans.";
RL Nat. Genet. 40:1185-1192(2008).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=18318008; DOI=10.1002/pmic.200700884;
RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D.,
RA Zou H., Gu J.;
RT "Large-scale phosphoproteome analysis of human liver tissue by
RT enrichment and fractionation of phosphopeptides with strong anion
RT exchange chromatography.";
RL Proteomics 8:1346-1361(2008).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [25]
RP ASSOCIATION WITH END STAGE RENAL DISEASE.
RX PubMed=19177153; DOI=10.1038/ki.2008.701;
RA Freedman B.I., Hicks P.J., Bostrom M.A., Cunningham M.E., Liu Y.,
RA Divers J., Kopp J.B., Winkler C.A., Nelson G.W., Langefeld C.D.,
RA Bowden D.W.;
RT "Polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9) are
RT strongly associated with end-stage renal disease historically
RT attributed to hypertension in African Americans.";
RL Kidney Int. 75:736-745(2009).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-11 AND SER-1943, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [28]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2; LYS-8; LYS-102; LYS-299;
RP LYS-1024; LYS-1357; LYS-1392; LYS-1404; LYS-1410; LYS-1459 AND
RP LYS-1638, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [29]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=20052411; DOI=10.1371/journal.pone.0008560;
RA Betapudi V.;
RT "Myosin II motor proteins with different functions determine the fate
RT of lamellipodia extension during cell spreading.";
RL PLoS ONE 5:E8560-E8560(2010).
RN [30]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1714 AND SER-1943, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [31]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [32]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [33]
RP INTERACTION WITH HTRA3.
RX PubMed=22229724; DOI=10.2144/000113798;
RA Singh H., Makino S., Endo Y., Li Y., Stephens A.N., Nie G.;
RT "Application of the wheat-germ cell-free translation system to produce
RT high temperature requirement A3 (HtrA3) proteases.";
RL BioTechniques 52:23-28(2012).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [35]
RP VARIANT DFNA17 HIS-705.
RX PubMed=11023810;
RA Lalwani A.K., Goldstein J.A., Kelley M.J., Luxford W., Castelein C.M.,
RA Mhatre A.N.;
RT "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in
RT nonmuscle myosin MYH9.";
RL Am. J. Hum. Genet. 67:1121-1128(2000).
RN [36]
RP VARIANTS MHA/FTNS/SBS LYS-93; CYS-702; CYS-1165; HIS-1424 AND
RP LYS-1841.
RX PubMed=10973259; DOI=10.1038/79063;
RA Seri M., Cusano M., Gangarossa S., Caridi G., Bordo D., Lo Nigro C.,
RA Ghiggeri G.M., Ravazzolo R., Savino M., Del Vecchio M., d'Apolito M.,
RA Iolascon A., Zelante L.L., Savoia A., Balduini C.L., Noris P.,
RA Magrini U., Belletti S., Heath K.E., Babcock M., Glucksman M.J.,
RA Aliprandis E., Bizzaro N., Desnick R.J., Martignetti J.A.;
RT "Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and
RT Sebastian syndromes.";
RL Nat. Genet. 26:103-105(2000).
RN [37]
RP VARIANTS MHA ILE-1155 AND LYS-1841.
RX PubMed=10973260; DOI=10.1038/79069;
RA Kelley M.J., Jawien W., Ortel T.L., Korczak J.F.;
RT "Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-
RT Hegglin anomaly.";
RL Nat. Genet. 26:106-108(2000).
RN [38]
RP VARIANTS MHA/SBS/FTNS/EPS/APSM ASN-373; CYS-702; HIS-702; PRO-1114;
RP ASN-1424; HIS-1424 AND LYS-1841.
RX PubMed=11590545; DOI=10.1086/324267;
RA Heath K.E., Campos-Barros A., Toren A., Rozenfeld-Granot G.,
RA Carlsson L.E., Savige J., Denison J.C., Gregory M.C., White J.G.,
RA Barker D.F., Greinacher A., Epstein C.J., Glucksman M.J.,
RA Martignetti J.A.;
RT "Nonmuscle myosin heavy chain IIA mutations define a spectrum of
RT autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and
RT Fechtner, Sebastian, Epstein, and Alport-like syndromes.";
RL Am. J. Hum. Genet. 69:1033-1045(2001).
RN [39]
RP VARIANTS MHA/FTNS/SBS THR-95; CYS-1165; LEU-1165; 1205-LEU--GLN-1207
RP DEL; HIS-1424; ASN-1424; TYR-1424 AND LYS-1841, AND VARIANT VAL-1626.
RX PubMed=11776386; DOI=10.1007/s100380170007;
RA Kunishima S., Matsushita T., Kojima T., Amemiya N., Choi Y.M.,
RA Hosaka N., Inoue M., Jung Y., Mamiya S., Matsumoto K., Miyajima Y.,
RA Zhang G., Ruan C., Saito K., Song K.S., Yoon H.-J., Kamiya T.,
RA Saito H.;
RT "Identification of six novel MYH9 mutations and genotype-phenotype
RT relationships in autosomal dominant macrothrombocytopenia with
RT leukocyte inclusions.";
RL J. Hum. Genet. 46:722-729(2001).
RN [40]
RP VARIANT EPS HIS-702.
RX PubMed=11935325; DOI=10.1007/s00439-001-0659-1;
RA Seri M., Savino M., Bordo D., Cusano R., Rocca B., Meloni I.,
RA Di Bari F., Koivisto P.A., Bolognesi M., Ghiggeri G.M., Landolfi R.,
RA Balduini C.L., Zelante L., Ravazzolo R., Renieri A., Savoia A.;
RT "Epstein syndrome: another renal disorder with mutations in the
RT nonmuscle myosin heavy chain 9 gene.";
RL Hum. Genet. 110:182-186(2002).
RN [41]
RP VARIANTS FTNS/EPS LEU-96; LEU-1165; ASN-1424 AND LYS-1841, VARIANT
RP TRP-1400, AND TISSUE SPECIFICITY.
RX PubMed=11752022;
RA Arrondel C., Vodovar N., Knebelmann B., Gruenfeld J.-P., Gubler M.-C.,
RA Antignac C., Heidet L.;
RT "Expression of the nonmuscle myosin heavy chain IIA in the human
RT kidney and screening for MYH9 mutations in Epstein and Fechtner
RT syndromes.";
RL J. Am. Soc. Nephrol. 13:65-74(2002).
RN [42]
RP CHARACTERIZATION OF VARIANT ASN-1424.
RX PubMed=12649151; DOI=10.1182/blood-2002-09-2783;
RA Deutsch S., Rideau A., Bochaton-Piallat M.-L., Merla G., Geinoz A.,
RA Gabbiani G., Schwede T., Matthes T., Antonarakis S.E., Beris P.;
RT "Asp1424Asn MYH9 mutation results in an unstable protein responsible
RT for the phenotypes in May-Hegglin anomaly/Fechtner syndrome.";
RL Blood 102:529-534(2003).
RN [43]
RP VARIANT FTNS/SBS CYS-1165, VARIANTS SBS LEU-1165 AND
RP 1205-LEU--GLN-1207 DEL, VARIANTS MHA HIS-1424; ASN-1424; TYR-1424 AND
RP LYS-1841, VARIANT EPS VAL-1816, AND VARIANT FTNS/MHA LYS-1841.
RX PubMed=12533692;
RA Kunishima S., Matsushita T., Kojima T., Sako M., Kimura F., Jo E.-K.,
RA Inoue C., Kamiya T., Saito H.;
RT "Immunofluorescence analysis of neutrophil nonmuscle myosin heavy
RT chain-A in MYH9 disorders: association of subcellular localization
RT with MYH9 mutations.";
RL Lab. Invest. 83:115-122(2003).
RN [44]
RP VARIANT EPS HIS-702, VARIANTS FTNS GLN-910; ILE-1155 AND HIS-1424,
RP VARIANTS MHA/SBS 1066-GLU--ALA-1072 DEL AND ASN-1424, AND VARIANT
RP EPS/FTNS/MHA/SBS CYS-702.
RX PubMed=12792306; DOI=10.1097/00005792-200305000-00006;
RA Seri M., Pecci A., Di Bari F., Cusano R., Savino M., Panza E.,
RA Nigro A., Noris P., Gangarossa S., Rocca B., Gresele P., Bizzaro N.,
RA Malatesta P., Koivisto P.A., Longo I., Musso R., Pecoraro C.,
RA Iolascon A., Magrini U., Rodriguez Soriano J., Renieri A.,
RA Ghiggeri G.M., Ravazzolo R., Balduini C.L., Savoia A.;
RT "MYH9-related disease: may-Hegglin anomaly, Sebastian syndrome,
RT Fechtner syndrome, and Epstein syndrome are not distinct entities but
RT represent a variable expression of a single illness.";
RL Medicine (Baltimore) 82:203-215(2003).
RN [45]
RP VARIANT MPSD ASN-1424.
RX PubMed=12621333; DOI=10.1097/00129492-200303000-00013;
RA Mhatre A.N., Kim Y., Brodie H.A., Lalwani A.K.;
RT "Macrothrombocytopenia and progressive deafness is due to a mutation
RT in MYH9.";
RL Otol. Neurotol. 24:205-209(2003).
RN [46]
RP VARIANT EPS LEU-96.
RX PubMed=16969870; DOI=10.1002/ajmg.a.31454;
RA Utsch B., DiFeo A., Kujat A., Karle S., Schuster V., Lenk H.,
RA Jacobs U., Mueller M., Doetsch J., Rascher W., Reutter H.,
RA Martignetti J.A., Ludwig M., Troebs R.-B.;
RT "Bladder exstrophy and Epstein type congenital macrothrombocytopenia:
RT evidence for a common cause?";
RL Am. J. Med. Genet. A 140:2251-2253(2006).
RN [47]
RP VARIANT [LARGE SCALE ANALYSIS] ASN-810.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [48]
RP POSITION OF MUTATIONS IN MYH9-RELATED DISEASE.
RX PubMed=18059020; DOI=10.1002/humu.20661;
RA Pecci A., Panza E., Pujol-Moix N., Klersy C., Di Bari F., Bozzi V.,
RA Gresele P., Lethagen S., Fabris F., Dufour C., Granata A., Doubek M.,
RA Pecoraro C., Koivisto P.A., Heller P.G., Iolascon A., Alvisi P.,
RA Schwabe D., De Candia E., Rocca B., Russo U., Ramenghi U., Noris P.,
RA Seri M., Balduini C.L., Savoia A.;
RT "Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations
RT predicts the natural history of MYH9-related disease.";
RL Hum. Mutat. 29:409-417(2008).
CC -!- FUNCTION: Cellular myosin that appears to play a role in
CC cytokinesis, cell shape, and specialized functions such as
CC secretion and capping. During cell spreading, plays an important
CC role in cytoskeleton reorganization, focal contacts formation (in
CC the margins but not the central part of spreading cells), and
CC lamellipodial retraction; this function is mechanically
CC antagonized by MYH10.
CC -!- SUBUNIT: Interacts with PDLIM2 (By similarity). Interacts with
CC SLC6A4 (By similarity). Myosin is a hexameric protein that
CC consists of 2 heavy chain subunits (MHC), 2 alkali light chain
CC subunits (MLC) and 2 regulatory light chain subunits (MLC-2).
CC Interacts with RASIP1. Interacts with DDR1 (By similarity).
CC Interacts with SVIL and HTRA3.
CC -!- INTERACTION:
CC P61073:CXCR4; NbExp=5; IntAct=EBI-350338, EBI-489411;
CC P62993:GRB2; NbExp=3; IntAct=EBI-350338, EBI-401755;
CC O00255:MEN1; NbExp=7; IntAct=EBI-350338, EBI-592789;
CC P19338:NCL; NbExp=3; IntAct=EBI-350338, EBI-346967;
CC O46385:SVIL (xeno); NbExp=2; IntAct=EBI-350338, EBI-6995105;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton (By similarity).
CC Cytoplasm, cell cortex (By similarity). Note=Colocalizes with
CC actin filaments at lamellipodia margins and at the leading edge of
CC migrating cells.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P35579-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P35579-2; Sequence=VSP_035409, VSP_035410;
CC -!- TISSUE SPECIFICITY: In the kidney, expressed in the glomeruli.
CC Also expressed in leukocytes.
CC -!- DOMAIN: The rodlike tail sequence is highly repetitive, showing
CC cycles of a 28-residue repeat pattern composed of 4 heptapeptides,
CC characteristic for alpha-helical coiled coils.
CC -!- PTM: ISGylated.
CC -!- DISEASE: May-Hegglin anomaly (MHA) [MIM:155100]: A disorder
CC characterized by thrombocytopenia, giant platelets and Dohle body-
CC like inclusions in peripheral blood leukocytes. appearing as
CC highly parallel paracrystalline bodies. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Sebastian syndrome (SBS) [MIM:605249]: Autosomal dominant
CC macrothrombocytopenia characterized by thrombocytopenia, giant
CC platelets and leukocyte inclusions that are smaller and less
CC organized than in May-Hegglin anomaly. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Fechtner syndrome (FTNS) [MIM:153640]: Autosomal dominant
CC macrothrombocytopenia characterized by thrombocytopenia, giant
CC platelets and leukocyte inclusions that are small and poorly
CC organized. Additionally, FTNS is distinguished by Alport-like
CC clinical features of sensorineural deafness, cataracts and
CC nephritis. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Alport syndrome, with macrothrombocytopenia (APSM)
CC [MIM:153650]: An autosomal dominant disorder characterized by the
CC association of ocular lesions, sensorineural hearing loss and
CC nephritis (Alport syndrome) with platelet defects. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Epstein syndrome (EPS) [MIM:153650]: An autosomal
CC dominant disorder characterized by the association of
CC macrothrombocytopathy, sensorineural hearing loss and nephritis.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Deafness, autosomal dominant, 17 (DFNA17) [MIM:603622]: A
CC form of deafness characterized by progressive high frequency
CC hearing impairment and cochleosaccular degeneration. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Macrothrombocytopenia and progressive sensorineural
CC deafness (MPSD) [MIM:600208]: An autosomal dominant disorder
CC characterized by the association of macrothrombocytopathy and
CC progressive sensorineural hearing loss without renal dysfunction.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Note=Subjects with mutations in the motor domain of MYH9
CC present with severe thrombocytopenia and develop nephritis and
CC deafness before the age of 40 years, while those with mutations in
CC the tail domain have a much lower risk of noncongenital
CC complications and significantly higher platelet counts. The
CC clinical course of patients with mutations in the four most
CC frequently affected residues of MYH9 (responsible for 70% of MYH9-
CC related cases) were evaluated. Mutations at residue 1933 do not
CC induce kidney damage or cataracts and cause deafness only in the
CC elderly, those in position 702 result in severe thrombocytopenia
CC and produce nephritis and deafness at a juvenile age, while
CC alterations at residue 1424 or 1841 result in intermediate
CC clinical pictures.
CC -!- DISEASE: Note=Genetic variations in MYH9 are associated with non-
CC diabetic end stage renal disease (ESRD).
CC -!- SIMILARITY: Contains 1 IQ domain.
CC -!- SIMILARITY: Contains 1 myosin head-like domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAD89954.1; Type=Frameshift; Positions=1890;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MYH9ID481.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MYH9";
CC -----------------------------------------------------------------------
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DR EMBL; CR456526; CAG30412.1; -; mRNA.
DR EMBL; AB191263; BAD52439.1; -; mRNA.
DR EMBL; AL832639; CAD89954.1; ALT_FRAME; mRNA.
DR EMBL; AB290175; BAG06729.1; -; mRNA.
DR EMBL; Z82215; CAB05105.1; -; Genomic_DNA.
DR EMBL; CH471095; EAW60096.1; -; Genomic_DNA.
DR EMBL; M81105; AAA59888.1; -; mRNA.
DR EMBL; AK291609; BAF84298.1; -; mRNA.
DR EMBL; M69180; AAA61765.1; -; mRNA.
DR EMBL; M31013; AAA36349.1; -; mRNA.
DR PIR; A61231; A61231.
DR RefSeq; NP_002464.1; NM_002473.4.
DR UniGene; Hs.474751; -.
DR PDB; 2LNK; NMR; -; C=1897-1935.
DR PDB; 3ZWH; X-ray; 1.94 A; Q=1894-1937.
DR PDB; 4ETO; X-ray; 1.54 A; P=1908-1923.
DR PDBsum; 2LNK; -.
DR PDBsum; 3ZWH; -.
DR PDBsum; 4ETO; -.
DR ProteinModelPortal; P35579; -.
DR SMR; P35579; 7-897, 1894-1935.
DR DIP; DIP-33103N; -.
DR IntAct; P35579; 48.
DR MINT; MINT-7901706; -.
DR STRING; 9606.ENSP00000216181; -.
DR ChEMBL; CHEMBL2189151; -.
DR PhosphoSite; P35579; -.
DR DMDM; 6166599; -.
DR PaxDb; P35579; -.
DR PeptideAtlas; P35579; -.
DR PRIDE; P35579; -.
DR DNASU; 4627; -.
DR Ensembl; ENST00000216181; ENSP00000216181; ENSG00000100345.
DR GeneID; 4627; -.
DR KEGG; hsa:4627; -.
DR UCSC; uc003aph.1; human.
DR CTD; 4627; -.
DR GeneCards; GC22M036677; -.
DR HGNC; HGNC:7579; MYH9.
DR HPA; CAB015386; -.
DR HPA; HPA001644; -.
DR MIM; 153640; phenotype.
DR MIM; 153650; phenotype.
DR MIM; 155100; phenotype.
DR MIM; 160775; gene.
DR MIM; 600208; phenotype.
DR MIM; 603622; phenotype.
DR MIM; 605249; phenotype.
DR neXtProt; NX_P35579; -.
DR Orphanet; 90635; Autosomal dominant nonsyndromic sensorineural deafness type DFNA.
DR Orphanet; 182050; MYH9-related thrombocytopenia.
DR PharmGKB; PA31377; -.
DR eggNOG; COG5022; -.
DR HOGENOM; HOG000173958; -.
DR HOVERGEN; HBG004704; -.
DR InParanoid; P35579; -.
DR KO; K10352; -.
DR OMA; KRENDSI; -.
DR OrthoDB; EOG71CFK3; -.
DR PhylomeDB; P35579; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; MYH9; human.
DR GeneWiki; MYH9; -.
DR GenomeRNAi; 4627; -.
DR NextBio; 17810; -.
DR PMAP-CutDB; P35579; -.
DR PRO; PR:P35579; -.
DR ArrayExpress; P35579; -.
DR Bgee; P35579; -.
DR CleanEx; HS_MYH9; -.
DR Genevestigator; P35579; -.
DR GO; GO:0005826; C:actomyosin contractile ring; IDA:UniProtKB.
DR GO; GO:0005913; C:cell-cell adherens junction; IEA:Ensembl.
DR GO; GO:0032154; C:cleavage furrow; IDA:UniProtKB.
DR GO; GO:0030863; C:cortical cytoskeleton; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0001772; C:immunological synapse; IEA:Ensembl.
DR GO; GO:0016460; C:myosin II complex; IEA:Ensembl.
DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0001726; C:ruffle; IDA:UniProtKB.
DR GO; GO:0005819; C:spindle; IEA:Ensembl.
DR GO; GO:0001725; C:stress fiber; IDA:UniProtKB.
DR GO; GO:0001931; C:uropod; IDA:MGI.
DR GO; GO:0051015; F:actin filament binding; IDA:UniProtKB.
DR GO; GO:0030898; F:actin-dependent ATPase activity; IDA:MGI.
DR GO; GO:0043531; F:ADP binding; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IDA:MGI.
DR GO; GO:0000146; F:microfilament motor activity; IDA:UniProtKB.
DR GO; GO:0043495; F:protein anchor; IMP:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0031532; P:actin cytoskeleton reorganization; IMP:UniProtKB.
DR GO; GO:0030048; P:actin filament-based movement; IDA:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IDA:UniProtKB.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0043534; P:blood vessel endothelial cell migration; IMP:UniProtKB.
DR GO; GO:0016337; P:cell-cell adhesion; IEA:Ensembl.
DR GO; GO:0000910; P:cytokinesis; IMP:UniProtKB.
DR GO; GO:0051295; P:establishment of meiotic spindle localization; IEA:Ensembl.
DR GO; GO:0001768; P:establishment of T cell polarity; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0007229; P:integrin-mediated signaling pathway; NAS:UniProtKB.
DR GO; GO:0050900; P:leukocyte migration; NAS:UniProtKB.
DR GO; GO:0000212; P:meiotic spindle organization; IEA:Ensembl.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:UniProtKB.
DR GO; GO:0030224; P:monocyte differentiation; IEP:UniProtKB.
DR GO; GO:0007520; P:myoblast fusion; IEA:Ensembl.
DR GO; GO:0030220; P:platelet formation; IMP:UniProtKB.
DR GO; GO:0015031; P:protein transport; IMP:UniProtKB.
DR GO; GO:0008360; P:regulation of cell shape; IMP:UniProtKB.
DR GO; GO:0038032; P:termination of G-protein coupled receptor signaling pathway; IEA:InterPro.
DR GO; GO:0032796; P:uropod organization; IEA:Ensembl.
DR Gene3D; 4.10.270.10; -; 1.
DR InterPro; IPR000048; IQ_motif_EF-hand-BS.
DR InterPro; IPR027401; Myosin-like_IQ_dom.
DR InterPro; IPR001609; Myosin_head_motor_dom.
DR InterPro; IPR004009; Myosin_N.
DR InterPro; IPR002928; Myosin_tail.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR016137; Regulat_G_prot_signal_superfam.
DR Pfam; PF00612; IQ; 1.
DR Pfam; PF00063; Myosin_head; 1.
DR Pfam; PF02736; Myosin_N; 1.
DR Pfam; PF01576; Myosin_tail_1; 1.
DR PRINTS; PR00193; MYOSINHEAVY.
DR SMART; SM00015; IQ; 1.
DR SMART; SM00242; MYSc; 1.
DR SUPFAM; SSF48097; SSF48097; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS50096; IQ; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Actin-binding; Alport syndrome;
KW Alternative splicing; ATP-binding; Calmodulin-binding; Cataract;
KW Cell adhesion; Cell shape; Coiled coil; Complete proteome; Cytoplasm;
KW Cytoskeleton; Deafness; Direct protein sequencing; Disease mutation;
KW Motor protein; Myosin; Non-syndromic deafness; Nucleotide-binding;
KW Phosphoprotein; Polymorphism; Reference proteome; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 1960 Myosin-9.
FT /FTId=PRO_0000123416.
FT DOMAIN 2 778 Myosin head-like.
FT DOMAIN 779 808 IQ.
FT NP_BIND 174 181 ATP (Potential).
FT REGION 654 676 Actin-binding.
FT COILED 837 1926 Potential.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 8 8 N6-acetyllysine.
FT MOD_RES 11 11 Phosphotyrosine.
FT MOD_RES 102 102 N6-acetyllysine.
FT MOD_RES 299 299 N6-acetyllysine.
FT MOD_RES 754 754 Phosphotyrosine (By similarity).
FT MOD_RES 1024 1024 N6-acetyllysine.
FT MOD_RES 1357 1357 N6-acetyllysine.
FT MOD_RES 1392 1392 N6-acetyllysine.
FT MOD_RES 1404 1404 N6-acetyllysine.
FT MOD_RES 1410 1410 N6-acetyllysine.
FT MOD_RES 1459 1459 N6-acetyllysine.
FT MOD_RES 1638 1638 N6-acetyllysine.
FT MOD_RES 1714 1714 Phosphoserine.
FT MOD_RES 1943 1943 Phosphoserine.
FT VAR_SEQ 1 136 Missing (in isoform 2).
FT /FTId=VSP_035409.
FT VAR_SEQ 980 1421 Missing (in isoform 2).
FT /FTId=VSP_035410.
FT VARIANT 93 93 N -> K (in MHA).
FT /FTId=VAR_010791.
FT VARIANT 95 95 A -> T (in MHA).
FT /FTId=VAR_018308.
FT VARIANT 96 96 S -> L (in EPS).
FT /FTId=VAR_018309.
FT VARIANT 373 373 K -> N (in MHA and SBS).
FT /FTId=VAR_018310.
FT VARIANT 702 702 R -> C (in APSM, EPS, FTNS, MHA and SBS).
FT /FTId=VAR_010792.
FT VARIANT 702 702 R -> H (in APSM and EPS).
FT /FTId=VAR_018311.
FT VARIANT 705 705 R -> H (in DFNA17).
FT /FTId=VAR_010793.
FT VARIANT 810 810 K -> N (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036006.
FT VARIANT 910 910 K -> Q (in FTNS).
FT /FTId=VAR_044226.
FT VARIANT 967 967 V -> E (in dbSNP:rs16996652).
FT /FTId=VAR_044227.
FT VARIANT 1066 1072 Missing (in MHA and SBS).
FT /FTId=VAR_044228.
FT VARIANT 1114 1114 S -> P (in APSM).
FT /FTId=VAR_018312.
FT VARIANT 1155 1155 T -> I (in MHA and FTNS).
FT /FTId=VAR_010794.
FT VARIANT 1165 1165 R -> C (in FTNS and SBS).
FT /FTId=VAR_010795.
FT VARIANT 1165 1165 R -> L (in FTNS, MHA and SBS).
FT /FTId=VAR_018313.
FT VARIANT 1205 1207 Missing (in SBS).
FT /FTId=VAR_018314.
FT VARIANT 1400 1400 R -> W (in a EPS patient; might
FT contribute to pathogenicity; when
FT associated with L-96; dbSNP:rs76368635).
FT /FTId=VAR_018315.
FT VARIANT 1424 1424 D -> H (in FTNS and MHA).
FT /FTId=VAR_010796.
FT VARIANT 1424 1424 D -> N (in FTNS, MHA, SBS and MPSD;
FT affects protein stability).
FT /FTId=VAR_018316.
FT VARIANT 1424 1424 D -> Y (in MHA).
FT /FTId=VAR_018317.
FT VARIANT 1626 1626 I -> V (in dbSNP:rs2269529).
FT /FTId=VAR_018318.
FT VARIANT 1816 1816 I -> V (in EPS).
FT /FTId=VAR_030385.
FT VARIANT 1841 1841 E -> K (in FTNS, SBS, MHA and EPS).
FT /FTId=VAR_010797.
FT CONFLICT 53 55 EAI -> RGH (in Ref. 9).
FT CONFLICT 660 660 T -> S (in Ref. 9).
FT CONFLICT 869 869 T -> M (in Ref. 11; AAA36349).
FT CONFLICT 931 931 C -> Y (in Ref. 11; AAA36349).
FT CONFLICT 1000 1000 R -> I (in Ref. 8; BAF84298).
FT CONFLICT 1240 1241 KG -> GR (in Ref. 11; AAA36349).
FT CONFLICT 1350 1350 E -> EE (in Ref. 11).
FT CONFLICT 1462 1462 E -> G (in Ref. 1; CAD89954).
FT CONFLICT 1546 1546 D -> G (in Ref. 1; CAD89954).
FT CONFLICT 1764 1764 T -> A (in Ref. 11; AAA36349).
FT CONFLICT 1771 1771 S -> G (in Ref. 11; AAA36349).
FT STRAND 1895 1898
FT HELIX 1899 1903
FT TURN 1904 1906
FT HELIX 1909 1918
FT STRAND 1922 1925
SQ SEQUENCE 1960 AA; 226532 MW; 588F84BB8C106E6F CRC64;
MAQQAADKYL YVDKNFINNP LAQADWAAKK LVWVPSDKSG FEPASLKEEV GEEAIVELVE
NGKKVKVNKD DIQKMNPPKF SKVEDMAELT CLNEASVLHN LKERYYSGLI YTYSGLFCVV
INPYKNLPIY SEEIVEMYKG KKRHEMPPHI YAITDTAYRS MMQDREDQSI LCTGESGAGK
TENTKKVIQY LAYVASSHKS KKDQGELERQ LLQANPILEA FGNAKTVKND NSSRFGKFIR
INFDVNGYIV GANIETYLLE KSRAIRQAKE ERTFHIFYYL LSGAGEHLKT DLLLEPYNKY
RFLSNGHVTI PGQQDKDMFQ ETMEAMRIMG IPEEEQMGLL RVISGVLQLG NIVFKKERNT
DQASMPDNTA AQKVSHLLGI NVTDFTRGIL TPRIKVGRDY VQKAQTKEQA DFAIEALAKA
TYERMFRWLV LRINKALDKT KRQGASFIGI LDIAGFEIFD LNSFEQLCIN YTNEKLQQLF
NHTMFILEQE EYQREGIEWN FIDFGLDLQP CIDLIEKPAG PPGILALLDE ECWFPKATDK
SFVEKVMQEQ GTHPKFQKPK QLKDKADFCI IHYAGKVDYK ADEWLMKNMD PLNDNIATLL
HQSSDKFVSE LWKDVDRIIG LDQVAGMSET ALPGAFKTRK GMFRTVGQLY KEQLAKLMAT
LRNTNPNFVR CIIPNHEKKA GKLDPHLVLD QLRCNGVLEG IRICRQGFPN RVVFQEFRQR
YEILTPNSIP KGFMDGKQAC VLMIKALELD SNLYRIGQSK VFFRAGVLAH LEEERDLKIT
DVIIGFQACC RGYLARKAFA KRQQQLTAMK VLQRNCAAYL KLRNWQWWRL FTKVKPLLQV
SRQEEEMMAK EEELVKVREK QLAAENRLTE METLQSQLMA EKLQLQEQLQ AETELCAEAE
ELRARLTAKK QELEEICHDL EARVEEEEER CQHLQAEKKK MQQNIQELEE QLEEEESARQ
KLQLEKVTTE AKLKKLEEEQ IILEDQNCKL AKEKKLLEDR IAEFTTNLTE EEEKSKSLAK
LKNKHEAMIT DLEERLRREE KQRQELEKTR RKLEGDSTDL SDQIAELQAQ IAELKMQLAK
KEEELQAALA RVEEEAAQKN MALKKIRELE SQISELQEDL ESERASRNKA EKQKRDLGEE
LEALKTELED TLDSTAAQQE LRSKREQEVN ILKKTLEEEA KTHEAQIQEM RQKHSQAVEE
LAEQLEQTKR VKANLEKAKQ TLENERGELA NEVKVLLQGK GDSEHKRKKV EAQLQELQVK
FNEGERVRTE LADKVTKLQV ELDNVTGLLS QSDSKSSKLT KDFSALESQL QDTQELLQEE
NRQKLSLSTK LKQVEDEKNS FREQLEEEEE AKHNLEKQIA TLHAQVADMK KKMEDSVGCL
ETAEEVKRKL QKDLEGLSQR HEEKVAAYDK LEKTKTRLQQ ELDDLLVDLD HQRQSACNLE
KKQKKFDQLL AEEKTISAKY AEERDRAEAE AREKETKALS LARALEEAME QKAELERLNK
QFRTEMEDLM SSKDDVGKSV HELEKSKRAL EQQVEEMKTQ LEELEDELQA TEDAKLRLEV
NLQAMKAQFE RDLQGRDEQS EEKKKQLVRQ VREMEAELED ERKQRSMAVA ARKKLEMDLK
DLEAHIDSAN KNRDEAIKQL RKLQAQMKDC MRELDDTRAS REEILAQAKE NEKKLKSMEA
EMIQLQEELA AAERAKRQAQ QERDELADEI ANSSGKGALA LEEKRRLEAR IAQLEEELEE
EQGNTELIND RLKKANLQID QINTDLNLER SHAQKNENAR QQLERQNKEL KVKLQEMEGT
VKSKYKASIT ALEAKIAQLE EQLDNETKER QAACKQVRRT EKKLKDVLLQ VDDERRNAEQ
YKDQADKAST RLKQLKRQLE EAEEEAQRAN ASRRKLQREL EDATETADAM NREVSSLKNK
LRRGDLPFVV PRRMARKGAG DGSDEEVDGK ADGAEAKPAE
//
ID MYH9_HUMAN Reviewed; 1960 AA.
AC P35579; A8K6E4; O60805; Q60FE2; Q86T83;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Myosin-9;
DE AltName: Full=Cellular myosin heavy chain, type A;
DE AltName: Full=Myosin heavy chain 9;
DE AltName: Full=Myosin heavy chain, non-muscle IIa;
DE AltName: Full=Non-muscle myosin heavy chain A;
DE Short=NMMHC-A;
DE AltName: Full=Non-muscle myosin heavy chain IIa;
DE Short=NMMHC II-a;
DE Short=NMMHC-IIA;
GN Name=MYH9;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=16106752; DOI=10.1093/dnares/12.1.53;
RA Kato S., Ohtoko K., Ohtake H., Kimura T.;
RT "Vector-capping: a simple method for preparing a high-quality full-
RT length cDNA library.";
RL DNA Res. 12:53-62(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Spinal cord;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Yamakawa H., Kikuno R.F., Nagase T., Ohara O.;
RT "Multiplex amplification and cloning of 5'-ends of cDNA by ligase-free
RT recombination: Preparation of full-lemgth cDNA clones encoding motor
RT proteins.";
RL Submitted (JAN-2007) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M.,
RA Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K.,
RA Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J.,
RA Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G.,
RA Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R.,
RA Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E.,
RA Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G.,
RA Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S.,
RA Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A.,
RA Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M.,
RA Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T.,
RA Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J.,
RA Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T.,
RA Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T.,
RA Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L.,
RA Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M.,
RA Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J.,
RA Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S.,
RA Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T.,
RA Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I.,
RA Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H.,
RA Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L.,
RA Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z.,
RA Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P.,
RA Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S.,
RA Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J.,
RA Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T.,
RA Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J.,
RA Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S.,
RA Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E.,
RA Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P.,
RA Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E.,
RA O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X.,
RA Khan A.S., Lane L., Tilahun Y., Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-1337, AND TISSUE SPECIFICITY.
RX PubMed=1912569;
RA Toothaker L.E., Gonzalez D.A., Tung N., Lemons R.S., le Beau M.M.,
RA Arnaout M.A., Clayton L.K., Tenen D.G.;
RT "Cellular myosin heavy chain in human leukocytes: isolation of 5' cDNA
RT clones, characterization of the protein, chromosomal localization, and
RT upregulation during myeloid differentiation.";
RL Blood 78:1826-1833(1991).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-1009.
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-715.
RX PubMed=1860190;
RA Simons M., Wang M., McBride O.W., Kawamoto S., Yamakawa K., Gdula D.,
RA Adelstein R.S., Weir L.;
RT "Human nonmuscle myosin heavy chains are encoded by two genes located
RT on different chromosomes.";
RL Circ. Res. 69:530-539(1991).
RN [10]
RP PROTEIN SEQUENCE OF 2-47; 67-74; 126-139; 187-199; 203-225; 241-261;
RP 290-299; 328-355; 359-387; 408-419; 476-494; 546-555; 581-613;
RP 618-637; 645-651; 657-670; 683-693; 712-718; 721-731; 746-755;
RP 765-775; 802-810; 824-829; 834-842; 861-867; 924-930; 995-1014;
RP 1042-1048; 1052-1075; 1081-1099; 1136-1162; 1166-1191; 1261-1266;
RP 1278-1295; 1302-1322; 1393-1400; 1405-1413; 1418-1433; 1484-1492;
RP 1504-1513; 1519-1525; 1529-1555; 1558-1566; 1606-1612; 1614-1638;
RP 1642-1648; 1662-1669; 1704-1724; 1794-1802; 1807-1828; 1857-1867;
RP 1899-1912; 1923-1932 AND 1951-1960, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RA Bienvenut W.V., Claeys R.;
RL Submitted (AUG-2005) to UniProtKB.
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 714-1960.
RX PubMed=1967836; DOI=10.1073/pnas.87.3.1164;
RA Saez C.G., Myers J.C., Shows T.B., Leinwand L.A.;
RT "Human nonmuscle myosin heavy chain mRNA: generation of diversity
RT through alternative polyadenylylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:1164-1168(1990).
RN [12]
RP INTERACTION WITH SVIL.
RX PubMed=12917436; DOI=10.1074/jbc.M305311200;
RA Chen Y., Takizawa N., Crowley J.L., Oh S.W., Gatto C.L., Kambara T.,
RA Sato O., Li X.-D., Ikebe M., Luna E.J.;
RT "F-actin and myosin II binding domains in supervillin.";
RL J. Biol. Chem. 278:46094-46106(2003).
RN [13]
RP ISGYLATION.
RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132;
RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J.,
RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.;
RT "Proteomic identification of proteins conjugated to ISG15 in mouse and
RT human cells.";
RL Biochem. Biophys. Res. Commun. 336:496-506(2005).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RC TISSUE=Prostate cancer;
RX PubMed=17487921; DOI=10.1002/elps.200600782;
RA Giorgianni F., Zhao Y., Desiderio D.M., Beranova-Giorgianni S.;
RT "Toward a global characterization of the phosphoproteome in prostate
RT cancer cells: identification of phosphoproteins in the LNCaP cell
RT line.";
RL Electrophoresis 28:2027-2034(2007).
RN [17]
RP INTERACTION WITH SVIL.
RX PubMed=17925381; DOI=10.1242/jcs.008219;
RA Takizawa N., Ikebe R., Ikebe M., Luna E.J.;
RT "Supervillin slows cell spreading by facilitating myosin II activation
RT at the cell periphery.";
RL J. Cell Sci. 120:3792-3803(2007).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RC TISSUE=T-cell;
RX PubMed=19367720; DOI=10.1021/pr800500r;
RA Carrascal M., Ovelleiro D., Casas V., Gay M., Abian J.;
RT "Phosphorylation analysis of primary human T lymphocytes using
RT sequential IMAC and titanium oxide enrichment.";
RL J. Proteome Res. 7:5167-5176(2008).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [20]
RP ASSOCIATION WITH END STAGE RENAL DISEASE.
RX PubMed=18794856; DOI=10.1038/ng.226;
RA Kopp J.B., Smith M.W., Nelson G.W., Johnson R.C., Freedman B.I.,
RA Bowden D.W., Oleksyk T., McKenzie L.M., Kajiyama H., Ahuja T.S.,
RA Berns J.S., Briggs W., Cho M.E., Dart R.A., Kimmel P.L., Korbet S.M.,
RA Michel D.M., Mokrzycki M.H., Schelling J.R., Simon E., Trachtman H.,
RA Vlahov D., Winkler C.A.;
RT "MYH9 is a major-effect risk gene for focal segmental
RT glomerulosclerosis.";
RL Nat. Genet. 40:1175-1184(2008).
RN [21]
RP ASSOCIATION WITH END STAGE RENAL DISEASE.
RX PubMed=18794854; DOI=10.1038/ng.232;
RA Kao W.H., Klag M.J., Meoni L.A., Reich D., Berthier-Schaad Y., Li M.,
RA Coresh J., Patterson N., Tandon A., Powe N.R., Fink N.E., Sadler J.H.,
RA Weir M.R., Abboud H.E., Adler S.G., Divers J., Iyengar S.K.,
RA Freedman B.I., Kimmel P.L., Knowler W.C., Kohn O.F., Kramp K.,
RA Leehey D.J., Nicholas S.B., Pahl M.V., Schelling J.R., Sedor J.R.,
RA Thornley-Brown D., Winkler C.A., Smith M.W., Parekh R.S.;
RT "MYH9 is associated with nondiabetic end-stage renal disease in
RT African Americans.";
RL Nat. Genet. 40:1185-1192(2008).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=18318008; DOI=10.1002/pmic.200700884;
RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D.,
RA Zou H., Gu J.;
RT "Large-scale phosphoproteome analysis of human liver tissue by
RT enrichment and fractionation of phosphopeptides with strong anion
RT exchange chromatography.";
RL Proteomics 8:1346-1361(2008).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [25]
RP ASSOCIATION WITH END STAGE RENAL DISEASE.
RX PubMed=19177153; DOI=10.1038/ki.2008.701;
RA Freedman B.I., Hicks P.J., Bostrom M.A., Cunningham M.E., Liu Y.,
RA Divers J., Kopp J.B., Winkler C.A., Nelson G.W., Langefeld C.D.,
RA Bowden D.W.;
RT "Polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9) are
RT strongly associated with end-stage renal disease historically
RT attributed to hypertension in African Americans.";
RL Kidney Int. 75:736-745(2009).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-11 AND SER-1943, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [28]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2; LYS-8; LYS-102; LYS-299;
RP LYS-1024; LYS-1357; LYS-1392; LYS-1404; LYS-1410; LYS-1459 AND
RP LYS-1638, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [29]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=20052411; DOI=10.1371/journal.pone.0008560;
RA Betapudi V.;
RT "Myosin II motor proteins with different functions determine the fate
RT of lamellipodia extension during cell spreading.";
RL PLoS ONE 5:E8560-E8560(2010).
RN [30]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1714 AND SER-1943, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [31]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [32]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1943, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [33]
RP INTERACTION WITH HTRA3.
RX PubMed=22229724; DOI=10.2144/000113798;
RA Singh H., Makino S., Endo Y., Li Y., Stephens A.N., Nie G.;
RT "Application of the wheat-germ cell-free translation system to produce
RT high temperature requirement A3 (HtrA3) proteases.";
RL BioTechniques 52:23-28(2012).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [35]
RP VARIANT DFNA17 HIS-705.
RX PubMed=11023810;
RA Lalwani A.K., Goldstein J.A., Kelley M.J., Luxford W., Castelein C.M.,
RA Mhatre A.N.;
RT "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in
RT nonmuscle myosin MYH9.";
RL Am. J. Hum. Genet. 67:1121-1128(2000).
RN [36]
RP VARIANTS MHA/FTNS/SBS LYS-93; CYS-702; CYS-1165; HIS-1424 AND
RP LYS-1841.
RX PubMed=10973259; DOI=10.1038/79063;
RA Seri M., Cusano M., Gangarossa S., Caridi G., Bordo D., Lo Nigro C.,
RA Ghiggeri G.M., Ravazzolo R., Savino M., Del Vecchio M., d'Apolito M.,
RA Iolascon A., Zelante L.L., Savoia A., Balduini C.L., Noris P.,
RA Magrini U., Belletti S., Heath K.E., Babcock M., Glucksman M.J.,
RA Aliprandis E., Bizzaro N., Desnick R.J., Martignetti J.A.;
RT "Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and
RT Sebastian syndromes.";
RL Nat. Genet. 26:103-105(2000).
RN [37]
RP VARIANTS MHA ILE-1155 AND LYS-1841.
RX PubMed=10973260; DOI=10.1038/79069;
RA Kelley M.J., Jawien W., Ortel T.L., Korczak J.F.;
RT "Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-
RT Hegglin anomaly.";
RL Nat. Genet. 26:106-108(2000).
RN [38]
RP VARIANTS MHA/SBS/FTNS/EPS/APSM ASN-373; CYS-702; HIS-702; PRO-1114;
RP ASN-1424; HIS-1424 AND LYS-1841.
RX PubMed=11590545; DOI=10.1086/324267;
RA Heath K.E., Campos-Barros A., Toren A., Rozenfeld-Granot G.,
RA Carlsson L.E., Savige J., Denison J.C., Gregory M.C., White J.G.,
RA Barker D.F., Greinacher A., Epstein C.J., Glucksman M.J.,
RA Martignetti J.A.;
RT "Nonmuscle myosin heavy chain IIA mutations define a spectrum of
RT autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and
RT Fechtner, Sebastian, Epstein, and Alport-like syndromes.";
RL Am. J. Hum. Genet. 69:1033-1045(2001).
RN [39]
RP VARIANTS MHA/FTNS/SBS THR-95; CYS-1165; LEU-1165; 1205-LEU--GLN-1207
RP DEL; HIS-1424; ASN-1424; TYR-1424 AND LYS-1841, AND VARIANT VAL-1626.
RX PubMed=11776386; DOI=10.1007/s100380170007;
RA Kunishima S., Matsushita T., Kojima T., Amemiya N., Choi Y.M.,
RA Hosaka N., Inoue M., Jung Y., Mamiya S., Matsumoto K., Miyajima Y.,
RA Zhang G., Ruan C., Saito K., Song K.S., Yoon H.-J., Kamiya T.,
RA Saito H.;
RT "Identification of six novel MYH9 mutations and genotype-phenotype
RT relationships in autosomal dominant macrothrombocytopenia with
RT leukocyte inclusions.";
RL J. Hum. Genet. 46:722-729(2001).
RN [40]
RP VARIANT EPS HIS-702.
RX PubMed=11935325; DOI=10.1007/s00439-001-0659-1;
RA Seri M., Savino M., Bordo D., Cusano R., Rocca B., Meloni I.,
RA Di Bari F., Koivisto P.A., Bolognesi M., Ghiggeri G.M., Landolfi R.,
RA Balduini C.L., Zelante L., Ravazzolo R., Renieri A., Savoia A.;
RT "Epstein syndrome: another renal disorder with mutations in the
RT nonmuscle myosin heavy chain 9 gene.";
RL Hum. Genet. 110:182-186(2002).
RN [41]
RP VARIANTS FTNS/EPS LEU-96; LEU-1165; ASN-1424 AND LYS-1841, VARIANT
RP TRP-1400, AND TISSUE SPECIFICITY.
RX PubMed=11752022;
RA Arrondel C., Vodovar N., Knebelmann B., Gruenfeld J.-P., Gubler M.-C.,
RA Antignac C., Heidet L.;
RT "Expression of the nonmuscle myosin heavy chain IIA in the human
RT kidney and screening for MYH9 mutations in Epstein and Fechtner
RT syndromes.";
RL J. Am. Soc. Nephrol. 13:65-74(2002).
RN [42]
RP CHARACTERIZATION OF VARIANT ASN-1424.
RX PubMed=12649151; DOI=10.1182/blood-2002-09-2783;
RA Deutsch S., Rideau A., Bochaton-Piallat M.-L., Merla G., Geinoz A.,
RA Gabbiani G., Schwede T., Matthes T., Antonarakis S.E., Beris P.;
RT "Asp1424Asn MYH9 mutation results in an unstable protein responsible
RT for the phenotypes in May-Hegglin anomaly/Fechtner syndrome.";
RL Blood 102:529-534(2003).
RN [43]
RP VARIANT FTNS/SBS CYS-1165, VARIANTS SBS LEU-1165 AND
RP 1205-LEU--GLN-1207 DEL, VARIANTS MHA HIS-1424; ASN-1424; TYR-1424 AND
RP LYS-1841, VARIANT EPS VAL-1816, AND VARIANT FTNS/MHA LYS-1841.
RX PubMed=12533692;
RA Kunishima S., Matsushita T., Kojima T., Sako M., Kimura F., Jo E.-K.,
RA Inoue C., Kamiya T., Saito H.;
RT "Immunofluorescence analysis of neutrophil nonmuscle myosin heavy
RT chain-A in MYH9 disorders: association of subcellular localization
RT with MYH9 mutations.";
RL Lab. Invest. 83:115-122(2003).
RN [44]
RP VARIANT EPS HIS-702, VARIANTS FTNS GLN-910; ILE-1155 AND HIS-1424,
RP VARIANTS MHA/SBS 1066-GLU--ALA-1072 DEL AND ASN-1424, AND VARIANT
RP EPS/FTNS/MHA/SBS CYS-702.
RX PubMed=12792306; DOI=10.1097/00005792-200305000-00006;
RA Seri M., Pecci A., Di Bari F., Cusano R., Savino M., Panza E.,
RA Nigro A., Noris P., Gangarossa S., Rocca B., Gresele P., Bizzaro N.,
RA Malatesta P., Koivisto P.A., Longo I., Musso R., Pecoraro C.,
RA Iolascon A., Magrini U., Rodriguez Soriano J., Renieri A.,
RA Ghiggeri G.M., Ravazzolo R., Balduini C.L., Savoia A.;
RT "MYH9-related disease: may-Hegglin anomaly, Sebastian syndrome,
RT Fechtner syndrome, and Epstein syndrome are not distinct entities but
RT represent a variable expression of a single illness.";
RL Medicine (Baltimore) 82:203-215(2003).
RN [45]
RP VARIANT MPSD ASN-1424.
RX PubMed=12621333; DOI=10.1097/00129492-200303000-00013;
RA Mhatre A.N., Kim Y., Brodie H.A., Lalwani A.K.;
RT "Macrothrombocytopenia and progressive deafness is due to a mutation
RT in MYH9.";
RL Otol. Neurotol. 24:205-209(2003).
RN [46]
RP VARIANT EPS LEU-96.
RX PubMed=16969870; DOI=10.1002/ajmg.a.31454;
RA Utsch B., DiFeo A., Kujat A., Karle S., Schuster V., Lenk H.,
RA Jacobs U., Mueller M., Doetsch J., Rascher W., Reutter H.,
RA Martignetti J.A., Ludwig M., Troebs R.-B.;
RT "Bladder exstrophy and Epstein type congenital macrothrombocytopenia:
RT evidence for a common cause?";
RL Am. J. Med. Genet. A 140:2251-2253(2006).
RN [47]
RP VARIANT [LARGE SCALE ANALYSIS] ASN-810.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [48]
RP POSITION OF MUTATIONS IN MYH9-RELATED DISEASE.
RX PubMed=18059020; DOI=10.1002/humu.20661;
RA Pecci A., Panza E., Pujol-Moix N., Klersy C., Di Bari F., Bozzi V.,
RA Gresele P., Lethagen S., Fabris F., Dufour C., Granata A., Doubek M.,
RA Pecoraro C., Koivisto P.A., Heller P.G., Iolascon A., Alvisi P.,
RA Schwabe D., De Candia E., Rocca B., Russo U., Ramenghi U., Noris P.,
RA Seri M., Balduini C.L., Savoia A.;
RT "Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations
RT predicts the natural history of MYH9-related disease.";
RL Hum. Mutat. 29:409-417(2008).
CC -!- FUNCTION: Cellular myosin that appears to play a role in
CC cytokinesis, cell shape, and specialized functions such as
CC secretion and capping. During cell spreading, plays an important
CC role in cytoskeleton reorganization, focal contacts formation (in
CC the margins but not the central part of spreading cells), and
CC lamellipodial retraction; this function is mechanically
CC antagonized by MYH10.
CC -!- SUBUNIT: Interacts with PDLIM2 (By similarity). Interacts with
CC SLC6A4 (By similarity). Myosin is a hexameric protein that
CC consists of 2 heavy chain subunits (MHC), 2 alkali light chain
CC subunits (MLC) and 2 regulatory light chain subunits (MLC-2).
CC Interacts with RASIP1. Interacts with DDR1 (By similarity).
CC Interacts with SVIL and HTRA3.
CC -!- INTERACTION:
CC P61073:CXCR4; NbExp=5; IntAct=EBI-350338, EBI-489411;
CC P62993:GRB2; NbExp=3; IntAct=EBI-350338, EBI-401755;
CC O00255:MEN1; NbExp=7; IntAct=EBI-350338, EBI-592789;
CC P19338:NCL; NbExp=3; IntAct=EBI-350338, EBI-346967;
CC O46385:SVIL (xeno); NbExp=2; IntAct=EBI-350338, EBI-6995105;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton (By similarity).
CC Cytoplasm, cell cortex (By similarity). Note=Colocalizes with
CC actin filaments at lamellipodia margins and at the leading edge of
CC migrating cells.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P35579-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P35579-2; Sequence=VSP_035409, VSP_035410;
CC -!- TISSUE SPECIFICITY: In the kidney, expressed in the glomeruli.
CC Also expressed in leukocytes.
CC -!- DOMAIN: The rodlike tail sequence is highly repetitive, showing
CC cycles of a 28-residue repeat pattern composed of 4 heptapeptides,
CC characteristic for alpha-helical coiled coils.
CC -!- PTM: ISGylated.
CC -!- DISEASE: May-Hegglin anomaly (MHA) [MIM:155100]: A disorder
CC characterized by thrombocytopenia, giant platelets and Dohle body-
CC like inclusions in peripheral blood leukocytes. appearing as
CC highly parallel paracrystalline bodies. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Sebastian syndrome (SBS) [MIM:605249]: Autosomal dominant
CC macrothrombocytopenia characterized by thrombocytopenia, giant
CC platelets and leukocyte inclusions that are smaller and less
CC organized than in May-Hegglin anomaly. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Fechtner syndrome (FTNS) [MIM:153640]: Autosomal dominant
CC macrothrombocytopenia characterized by thrombocytopenia, giant
CC platelets and leukocyte inclusions that are small and poorly
CC organized. Additionally, FTNS is distinguished by Alport-like
CC clinical features of sensorineural deafness, cataracts and
CC nephritis. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Alport syndrome, with macrothrombocytopenia (APSM)
CC [MIM:153650]: An autosomal dominant disorder characterized by the
CC association of ocular lesions, sensorineural hearing loss and
CC nephritis (Alport syndrome) with platelet defects. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Epstein syndrome (EPS) [MIM:153650]: An autosomal
CC dominant disorder characterized by the association of
CC macrothrombocytopathy, sensorineural hearing loss and nephritis.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Deafness, autosomal dominant, 17 (DFNA17) [MIM:603622]: A
CC form of deafness characterized by progressive high frequency
CC hearing impairment and cochleosaccular degeneration. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Macrothrombocytopenia and progressive sensorineural
CC deafness (MPSD) [MIM:600208]: An autosomal dominant disorder
CC characterized by the association of macrothrombocytopathy and
CC progressive sensorineural hearing loss without renal dysfunction.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Note=Subjects with mutations in the motor domain of MYH9
CC present with severe thrombocytopenia and develop nephritis and
CC deafness before the age of 40 years, while those with mutations in
CC the tail domain have a much lower risk of noncongenital
CC complications and significantly higher platelet counts. The
CC clinical course of patients with mutations in the four most
CC frequently affected residues of MYH9 (responsible for 70% of MYH9-
CC related cases) were evaluated. Mutations at residue 1933 do not
CC induce kidney damage or cataracts and cause deafness only in the
CC elderly, those in position 702 result in severe thrombocytopenia
CC and produce nephritis and deafness at a juvenile age, while
CC alterations at residue 1424 or 1841 result in intermediate
CC clinical pictures.
CC -!- DISEASE: Note=Genetic variations in MYH9 are associated with non-
CC diabetic end stage renal disease (ESRD).
CC -!- SIMILARITY: Contains 1 IQ domain.
CC -!- SIMILARITY: Contains 1 myosin head-like domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAD89954.1; Type=Frameshift; Positions=1890;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MYH9ID481.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MYH9";
CC -----------------------------------------------------------------------
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DR EMBL; CR456526; CAG30412.1; -; mRNA.
DR EMBL; AB191263; BAD52439.1; -; mRNA.
DR EMBL; AL832639; CAD89954.1; ALT_FRAME; mRNA.
DR EMBL; AB290175; BAG06729.1; -; mRNA.
DR EMBL; Z82215; CAB05105.1; -; Genomic_DNA.
DR EMBL; CH471095; EAW60096.1; -; Genomic_DNA.
DR EMBL; M81105; AAA59888.1; -; mRNA.
DR EMBL; AK291609; BAF84298.1; -; mRNA.
DR EMBL; M69180; AAA61765.1; -; mRNA.
DR EMBL; M31013; AAA36349.1; -; mRNA.
DR PIR; A61231; A61231.
DR RefSeq; NP_002464.1; NM_002473.4.
DR UniGene; Hs.474751; -.
DR PDB; 2LNK; NMR; -; C=1897-1935.
DR PDB; 3ZWH; X-ray; 1.94 A; Q=1894-1937.
DR PDB; 4ETO; X-ray; 1.54 A; P=1908-1923.
DR PDBsum; 2LNK; -.
DR PDBsum; 3ZWH; -.
DR PDBsum; 4ETO; -.
DR ProteinModelPortal; P35579; -.
DR SMR; P35579; 7-897, 1894-1935.
DR DIP; DIP-33103N; -.
DR IntAct; P35579; 48.
DR MINT; MINT-7901706; -.
DR STRING; 9606.ENSP00000216181; -.
DR ChEMBL; CHEMBL2189151; -.
DR PhosphoSite; P35579; -.
DR DMDM; 6166599; -.
DR PaxDb; P35579; -.
DR PeptideAtlas; P35579; -.
DR PRIDE; P35579; -.
DR DNASU; 4627; -.
DR Ensembl; ENST00000216181; ENSP00000216181; ENSG00000100345.
DR GeneID; 4627; -.
DR KEGG; hsa:4627; -.
DR UCSC; uc003aph.1; human.
DR CTD; 4627; -.
DR GeneCards; GC22M036677; -.
DR HGNC; HGNC:7579; MYH9.
DR HPA; CAB015386; -.
DR HPA; HPA001644; -.
DR MIM; 153640; phenotype.
DR MIM; 153650; phenotype.
DR MIM; 155100; phenotype.
DR MIM; 160775; gene.
DR MIM; 600208; phenotype.
DR MIM; 603622; phenotype.
DR MIM; 605249; phenotype.
DR neXtProt; NX_P35579; -.
DR Orphanet; 90635; Autosomal dominant nonsyndromic sensorineural deafness type DFNA.
DR Orphanet; 182050; MYH9-related thrombocytopenia.
DR PharmGKB; PA31377; -.
DR eggNOG; COG5022; -.
DR HOGENOM; HOG000173958; -.
DR HOVERGEN; HBG004704; -.
DR InParanoid; P35579; -.
DR KO; K10352; -.
DR OMA; KRENDSI; -.
DR OrthoDB; EOG71CFK3; -.
DR PhylomeDB; P35579; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; MYH9; human.
DR GeneWiki; MYH9; -.
DR GenomeRNAi; 4627; -.
DR NextBio; 17810; -.
DR PMAP-CutDB; P35579; -.
DR PRO; PR:P35579; -.
DR ArrayExpress; P35579; -.
DR Bgee; P35579; -.
DR CleanEx; HS_MYH9; -.
DR Genevestigator; P35579; -.
DR GO; GO:0005826; C:actomyosin contractile ring; IDA:UniProtKB.
DR GO; GO:0005913; C:cell-cell adherens junction; IEA:Ensembl.
DR GO; GO:0032154; C:cleavage furrow; IDA:UniProtKB.
DR GO; GO:0030863; C:cortical cytoskeleton; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0001772; C:immunological synapse; IEA:Ensembl.
DR GO; GO:0016460; C:myosin II complex; IEA:Ensembl.
DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0001726; C:ruffle; IDA:UniProtKB.
DR GO; GO:0005819; C:spindle; IEA:Ensembl.
DR GO; GO:0001725; C:stress fiber; IDA:UniProtKB.
DR GO; GO:0001931; C:uropod; IDA:MGI.
DR GO; GO:0051015; F:actin filament binding; IDA:UniProtKB.
DR GO; GO:0030898; F:actin-dependent ATPase activity; IDA:MGI.
DR GO; GO:0043531; F:ADP binding; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IDA:MGI.
DR GO; GO:0000146; F:microfilament motor activity; IDA:UniProtKB.
DR GO; GO:0043495; F:protein anchor; IMP:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0031532; P:actin cytoskeleton reorganization; IMP:UniProtKB.
DR GO; GO:0030048; P:actin filament-based movement; IDA:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IDA:UniProtKB.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0043534; P:blood vessel endothelial cell migration; IMP:UniProtKB.
DR GO; GO:0016337; P:cell-cell adhesion; IEA:Ensembl.
DR GO; GO:0000910; P:cytokinesis; IMP:UniProtKB.
DR GO; GO:0051295; P:establishment of meiotic spindle localization; IEA:Ensembl.
DR GO; GO:0001768; P:establishment of T cell polarity; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0007229; P:integrin-mediated signaling pathway; NAS:UniProtKB.
DR GO; GO:0050900; P:leukocyte migration; NAS:UniProtKB.
DR GO; GO:0000212; P:meiotic spindle organization; IEA:Ensembl.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:UniProtKB.
DR GO; GO:0030224; P:monocyte differentiation; IEP:UniProtKB.
DR GO; GO:0007520; P:myoblast fusion; IEA:Ensembl.
DR GO; GO:0030220; P:platelet formation; IMP:UniProtKB.
DR GO; GO:0015031; P:protein transport; IMP:UniProtKB.
DR GO; GO:0008360; P:regulation of cell shape; IMP:UniProtKB.
DR GO; GO:0038032; P:termination of G-protein coupled receptor signaling pathway; IEA:InterPro.
DR GO; GO:0032796; P:uropod organization; IEA:Ensembl.
DR Gene3D; 4.10.270.10; -; 1.
DR InterPro; IPR000048; IQ_motif_EF-hand-BS.
DR InterPro; IPR027401; Myosin-like_IQ_dom.
DR InterPro; IPR001609; Myosin_head_motor_dom.
DR InterPro; IPR004009; Myosin_N.
DR InterPro; IPR002928; Myosin_tail.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR016137; Regulat_G_prot_signal_superfam.
DR Pfam; PF00612; IQ; 1.
DR Pfam; PF00063; Myosin_head; 1.
DR Pfam; PF02736; Myosin_N; 1.
DR Pfam; PF01576; Myosin_tail_1; 1.
DR PRINTS; PR00193; MYOSINHEAVY.
DR SMART; SM00015; IQ; 1.
DR SMART; SM00242; MYSc; 1.
DR SUPFAM; SSF48097; SSF48097; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS50096; IQ; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Actin-binding; Alport syndrome;
KW Alternative splicing; ATP-binding; Calmodulin-binding; Cataract;
KW Cell adhesion; Cell shape; Coiled coil; Complete proteome; Cytoplasm;
KW Cytoskeleton; Deafness; Direct protein sequencing; Disease mutation;
KW Motor protein; Myosin; Non-syndromic deafness; Nucleotide-binding;
KW Phosphoprotein; Polymorphism; Reference proteome; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 1960 Myosin-9.
FT /FTId=PRO_0000123416.
FT DOMAIN 2 778 Myosin head-like.
FT DOMAIN 779 808 IQ.
FT NP_BIND 174 181 ATP (Potential).
FT REGION 654 676 Actin-binding.
FT COILED 837 1926 Potential.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 8 8 N6-acetyllysine.
FT MOD_RES 11 11 Phosphotyrosine.
FT MOD_RES 102 102 N6-acetyllysine.
FT MOD_RES 299 299 N6-acetyllysine.
FT MOD_RES 754 754 Phosphotyrosine (By similarity).
FT MOD_RES 1024 1024 N6-acetyllysine.
FT MOD_RES 1357 1357 N6-acetyllysine.
FT MOD_RES 1392 1392 N6-acetyllysine.
FT MOD_RES 1404 1404 N6-acetyllysine.
FT MOD_RES 1410 1410 N6-acetyllysine.
FT MOD_RES 1459 1459 N6-acetyllysine.
FT MOD_RES 1638 1638 N6-acetyllysine.
FT MOD_RES 1714 1714 Phosphoserine.
FT MOD_RES 1943 1943 Phosphoserine.
FT VAR_SEQ 1 136 Missing (in isoform 2).
FT /FTId=VSP_035409.
FT VAR_SEQ 980 1421 Missing (in isoform 2).
FT /FTId=VSP_035410.
FT VARIANT 93 93 N -> K (in MHA).
FT /FTId=VAR_010791.
FT VARIANT 95 95 A -> T (in MHA).
FT /FTId=VAR_018308.
FT VARIANT 96 96 S -> L (in EPS).
FT /FTId=VAR_018309.
FT VARIANT 373 373 K -> N (in MHA and SBS).
FT /FTId=VAR_018310.
FT VARIANT 702 702 R -> C (in APSM, EPS, FTNS, MHA and SBS).
FT /FTId=VAR_010792.
FT VARIANT 702 702 R -> H (in APSM and EPS).
FT /FTId=VAR_018311.
FT VARIANT 705 705 R -> H (in DFNA17).
FT /FTId=VAR_010793.
FT VARIANT 810 810 K -> N (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036006.
FT VARIANT 910 910 K -> Q (in FTNS).
FT /FTId=VAR_044226.
FT VARIANT 967 967 V -> E (in dbSNP:rs16996652).
FT /FTId=VAR_044227.
FT VARIANT 1066 1072 Missing (in MHA and SBS).
FT /FTId=VAR_044228.
FT VARIANT 1114 1114 S -> P (in APSM).
FT /FTId=VAR_018312.
FT VARIANT 1155 1155 T -> I (in MHA and FTNS).
FT /FTId=VAR_010794.
FT VARIANT 1165 1165 R -> C (in FTNS and SBS).
FT /FTId=VAR_010795.
FT VARIANT 1165 1165 R -> L (in FTNS, MHA and SBS).
FT /FTId=VAR_018313.
FT VARIANT 1205 1207 Missing (in SBS).
FT /FTId=VAR_018314.
FT VARIANT 1400 1400 R -> W (in a EPS patient; might
FT contribute to pathogenicity; when
FT associated with L-96; dbSNP:rs76368635).
FT /FTId=VAR_018315.
FT VARIANT 1424 1424 D -> H (in FTNS and MHA).
FT /FTId=VAR_010796.
FT VARIANT 1424 1424 D -> N (in FTNS, MHA, SBS and MPSD;
FT affects protein stability).
FT /FTId=VAR_018316.
FT VARIANT 1424 1424 D -> Y (in MHA).
FT /FTId=VAR_018317.
FT VARIANT 1626 1626 I -> V (in dbSNP:rs2269529).
FT /FTId=VAR_018318.
FT VARIANT 1816 1816 I -> V (in EPS).
FT /FTId=VAR_030385.
FT VARIANT 1841 1841 E -> K (in FTNS, SBS, MHA and EPS).
FT /FTId=VAR_010797.
FT CONFLICT 53 55 EAI -> RGH (in Ref. 9).
FT CONFLICT 660 660 T -> S (in Ref. 9).
FT CONFLICT 869 869 T -> M (in Ref. 11; AAA36349).
FT CONFLICT 931 931 C -> Y (in Ref. 11; AAA36349).
FT CONFLICT 1000 1000 R -> I (in Ref. 8; BAF84298).
FT CONFLICT 1240 1241 KG -> GR (in Ref. 11; AAA36349).
FT CONFLICT 1350 1350 E -> EE (in Ref. 11).
FT CONFLICT 1462 1462 E -> G (in Ref. 1; CAD89954).
FT CONFLICT 1546 1546 D -> G (in Ref. 1; CAD89954).
FT CONFLICT 1764 1764 T -> A (in Ref. 11; AAA36349).
FT CONFLICT 1771 1771 S -> G (in Ref. 11; AAA36349).
FT STRAND 1895 1898
FT HELIX 1899 1903
FT TURN 1904 1906
FT HELIX 1909 1918
FT STRAND 1922 1925
SQ SEQUENCE 1960 AA; 226532 MW; 588F84BB8C106E6F CRC64;
MAQQAADKYL YVDKNFINNP LAQADWAAKK LVWVPSDKSG FEPASLKEEV GEEAIVELVE
NGKKVKVNKD DIQKMNPPKF SKVEDMAELT CLNEASVLHN LKERYYSGLI YTYSGLFCVV
INPYKNLPIY SEEIVEMYKG KKRHEMPPHI YAITDTAYRS MMQDREDQSI LCTGESGAGK
TENTKKVIQY LAYVASSHKS KKDQGELERQ LLQANPILEA FGNAKTVKND NSSRFGKFIR
INFDVNGYIV GANIETYLLE KSRAIRQAKE ERTFHIFYYL LSGAGEHLKT DLLLEPYNKY
RFLSNGHVTI PGQQDKDMFQ ETMEAMRIMG IPEEEQMGLL RVISGVLQLG NIVFKKERNT
DQASMPDNTA AQKVSHLLGI NVTDFTRGIL TPRIKVGRDY VQKAQTKEQA DFAIEALAKA
TYERMFRWLV LRINKALDKT KRQGASFIGI LDIAGFEIFD LNSFEQLCIN YTNEKLQQLF
NHTMFILEQE EYQREGIEWN FIDFGLDLQP CIDLIEKPAG PPGILALLDE ECWFPKATDK
SFVEKVMQEQ GTHPKFQKPK QLKDKADFCI IHYAGKVDYK ADEWLMKNMD PLNDNIATLL
HQSSDKFVSE LWKDVDRIIG LDQVAGMSET ALPGAFKTRK GMFRTVGQLY KEQLAKLMAT
LRNTNPNFVR CIIPNHEKKA GKLDPHLVLD QLRCNGVLEG IRICRQGFPN RVVFQEFRQR
YEILTPNSIP KGFMDGKQAC VLMIKALELD SNLYRIGQSK VFFRAGVLAH LEEERDLKIT
DVIIGFQACC RGYLARKAFA KRQQQLTAMK VLQRNCAAYL KLRNWQWWRL FTKVKPLLQV
SRQEEEMMAK EEELVKVREK QLAAENRLTE METLQSQLMA EKLQLQEQLQ AETELCAEAE
ELRARLTAKK QELEEICHDL EARVEEEEER CQHLQAEKKK MQQNIQELEE QLEEEESARQ
KLQLEKVTTE AKLKKLEEEQ IILEDQNCKL AKEKKLLEDR IAEFTTNLTE EEEKSKSLAK
LKNKHEAMIT DLEERLRREE KQRQELEKTR RKLEGDSTDL SDQIAELQAQ IAELKMQLAK
KEEELQAALA RVEEEAAQKN MALKKIRELE SQISELQEDL ESERASRNKA EKQKRDLGEE
LEALKTELED TLDSTAAQQE LRSKREQEVN ILKKTLEEEA KTHEAQIQEM RQKHSQAVEE
LAEQLEQTKR VKANLEKAKQ TLENERGELA NEVKVLLQGK GDSEHKRKKV EAQLQELQVK
FNEGERVRTE LADKVTKLQV ELDNVTGLLS QSDSKSSKLT KDFSALESQL QDTQELLQEE
NRQKLSLSTK LKQVEDEKNS FREQLEEEEE AKHNLEKQIA TLHAQVADMK KKMEDSVGCL
ETAEEVKRKL QKDLEGLSQR HEEKVAAYDK LEKTKTRLQQ ELDDLLVDLD HQRQSACNLE
KKQKKFDQLL AEEKTISAKY AEERDRAEAE AREKETKALS LARALEEAME QKAELERLNK
QFRTEMEDLM SSKDDVGKSV HELEKSKRAL EQQVEEMKTQ LEELEDELQA TEDAKLRLEV
NLQAMKAQFE RDLQGRDEQS EEKKKQLVRQ VREMEAELED ERKQRSMAVA ARKKLEMDLK
DLEAHIDSAN KNRDEAIKQL RKLQAQMKDC MRELDDTRAS REEILAQAKE NEKKLKSMEA
EMIQLQEELA AAERAKRQAQ QERDELADEI ANSSGKGALA LEEKRRLEAR IAQLEEELEE
EQGNTELIND RLKKANLQID QINTDLNLER SHAQKNENAR QQLERQNKEL KVKLQEMEGT
VKSKYKASIT ALEAKIAQLE EQLDNETKER QAACKQVRRT EKKLKDVLLQ VDDERRNAEQ
YKDQADKAST RLKQLKRQLE EAEEEAQRAN ASRRKLQREL EDATETADAM NREVSSLKNK
LRRGDLPFVV PRRMARKGAG DGSDEEVDGK ADGAEAKPAE
//
MIM
153640
*RECORD*
*FIELD* NO
153640
*FIELD* TI
#153640 FECHTNER SYNDROME; FTNS
;;MACROTHROMBOCYTOPENIA, NEPHRITIS, DEAFNESS, AND LEUKOCYTE INCLUSIONS;;
read moreALPORT SYNDROME WITH MACROTHROMBOCYTOPENIA, FORMERLY; APSM, FORMERLY
*FIELD* TX
A number sign (#) is used with entry because Fechtner syndrome is caused
by heterozygous mutation in the gene encoding nonmuscle myosin heavy
chain-9 (MYH9; 160775) on chromosome 22q11.
DESCRIPTION
Fechtner syndrome is an autosomal dominant disorder characterized by the
triad of thrombocytopenia, giant platelets, and Dohle body-like
inclusions in peripheral blood leukocytes, with the additional features
of nephritis, hearing loss, and eye abnormalities, mostly cataracts
(Peterson et al., 1985).
There are several other disorders caused by mutation in the MYH9 gene
that share overlapping features with Fechtner syndrome. May-Hegglin
anomaly (155100) is characterized by the triad of thrombocytopenia,
giant platelets, and Dohle body-like inclusions in peripheral blood
leukocytes. Epstein syndrome (153650) has the platelet defect, deafness,
and nephritis, but does not have cataract and lacks leukocyte inclusion
bodies on classic staining of peripheral blood smears. The findings of
nephritis, hearing loss, and occasional cataracts in Fechtner and
Epstein syndromes are reminiscent of Alport syndrome (see 301050).
Sebastian syndrome (605249) is similar to May-Hegglin anomaly, but has a
different ultrastructural appearance of the leukocyte inclusions. Seri
et al. (2003) suggested that these 4 disorders, May-Hegglin, Sebastian,
Epstein, and Fechtner syndromes, are not distinct entities, but rather
represent a single disorder with a continuous clinical spectrum, for
which they proposed the term 'MYH9-related disease.' However, other
disorders, e.g., macrothrombocytopenia and progressive sensorineural
deafness (600208) and a form of nonsyndromic deafness (DFNA17; 603622),
are also caused by mutation in the MYH9 gene.
CLINICAL FEATURES
Peterson et al. (1985) reported a family in which 8 members of 4
generations showed nephritis, deafness, congenital cataracts,
macrothrombocytopenia, and leukocyte inclusions in various combinations.
The authors referred to the disorder as the 'Fechtner syndrome,'
presumably from the surname of the family. The family differed from
others reported, such as families with Epstein syndrome, in that their
hematologic abnormalities included not only macrothrombocytopenia but
also small, pale blue cytoplasmic inclusions in the neutrophils and
eosinophils. Light microscopic appearance of the inclusions resembled
that of toxic Dohle bodies and inclusions of May-Hegglin anomaly, but
their ultrastructural appearance was unique. Deafness was high-tone
sensorineural. Renal disease ranged from microscopic hematuria to
end-stage renal failure necessitating dialysis and kidney
transplantation. All affected adults had cataracts.
Gershoni-Baruch et al. (1988) reported a second family with Fechtner
syndrome; 16 members were affected. The authors noted that since the
hematologic abnormalities are a consistent feature of the syndrome and
seem to be present at birth, they would presumably permit prenatal
diagnosis by detection of the changes in fetal blood samples.
Heynen et al. (1988) described the Fechtner syndrome in a female patient
who had developed multiple ecchymoses from the time she started walking
at the age of 1 year, due to severe thrombocytopenia. Hearing problems
developing at the age of 8 years progressed to almost complete deafness.
The blood smear showed giant platelets the size of granulocytes. The
patient had moderate proteinuria, but there were no abnormalities in the
urinary sediment or in renal function. Heynen et al. (1988) postulated
an abnormality in the cytoskeleton of megakaryocytes such that formation
of the demarcation membrane system and the expulsion of platelets do not
occur normally.
Rocca et al. (1993) reported a 4-generation family in which 10 of 14
individuals had macrothrombocytopenia with leukocyte inclusions. Some,
but not all, affected members had Alport-like symptoms, such as
deafness, nephritis, and cataracts. For example, members aged less than
50 years had clinically silent ocular abnormalities, mainly lens
opacities. These observations were consistent with 'reduced expression
of Alport manifestations,' thus showing similarity to Sebastian
syndrome. Heath et al. (2001) identified a heterozygous mutation in the
MYH9 gene (E1841K; 160775.0002) in the family reported by Rocca et al.
(1993).
MAPPING
In an extended Israeli family with Fechtner syndrome plus impaired liver
functions and hypercholesterolemia in some individuals, Toren et al.
(1999) mapped the disease-causing gene to the long arm of chromosome 22.
Six markers yielded a lod score of more than 3.00. A maximum 2-point lod
score of 7.02 was obtained with the marker D22S283 at a recombination
fraction of 0.0. Recombination analysis placed the disease-causing gene
in a 5.5-Mb interval between markers D22S284 and D22S1167. Toren et al.
(1999) stated that no collagen genes or genes comprising the basement
membrane had been mapped to this region, 22q12.1-q13.2. Toren et al.
(2000) mapped Epstein syndrome (153650) to the same region of chromosome
22q, suggesting that it is allelic to Fechtner syndrome.
MOLECULAR GENETICS
The May-Hegglin/Fechtner Syndrome Consortium (2000) identified 2
different mutations in the MYH9 gene (160775.0005-160775.0006) in
patients with Fechtner syndrome. This same group identified other
mutations in the MYH9 gene in probands from families with May-Hegglin
anomaly and Sebastian syndrome, indicating that these disorders are
allelic.
*FIELD* RF
1. Gershoni-Baruch, R.; Baruch, Y.; Viener, A.; Lichtig, C.: Fechtner
syndrome: clinical and genetic aspects. Am. J. Med. Genet. 31: 357-367,
1988.
2. Heath, K. E.; Campos-Barros, A.; Toren, A.; Rozenfeld-Granot, G.;
Carlsson, L. E.; Savige, J.; Denison, J. C.; Gregory, M. C.; White,
J. G.; Barker, D. F.; Greinacher, A.; Epstein, C. J.; Glucksman, M.
J.; Martignetti, J. A.: Nonmuscle myosin heavy chain IIA mutations
define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin
anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. Am.
J. Hum. Genet. 69: 1033-1045, 2001.
3. Heynen, M. J.; Blockmans, D.; Verwilghen, R. L.; Vermylen, J.:
Congenital macrothrombocytopenia, leucocyte inclusions, deafness and
proteinuria: functional and electron microscopic observations on platelets
and megakaryocytes. Brit. J. Haemat. 70: 441-448, 1988.
4. May-Hegglin/Fechtner Syndrome Consortium: Mutations in MYH9
result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. Nature
Genet. 26: 103-105, 2000.
5. Peterson, L. C.; Rao, K. V.; Crosson, J. T.; White, J. G.: Fechtner
syndrome: a variant of Alport's syndrome with leukocyte inclusions
and macrothrombocytopenia. Blood 65: 397-406, 1985.
6. Rocca, B.; Laghi, F.; Zini, G.; Maggiano, N.; Landolfi, R.: Fechtner
syndrome: report of a third family and literature review. Brit. J.
Haemat. 85: 423-426, 1993.
7. Seri, M.; Pecci, A.; Di Bari, F.; Cusano, R.; Savino, M.; Panza,
E.; Nigro, A.; Noris, P.; Gangarossa, S.; Rocca, B.; Gresele, P.;
Bizzaro, N.; and 13 others: MYH9-related disease: May-Hegglin anomaly,
Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not
distinct entities but represent a variable expression of a single
illness. Medicine 82: 203-215, 2003.
8. Toren, A.; Amariglio, N.; Rozenfeld-Granot, G.; Simon, A. J.; Brok-Simoni,
F.; Pras, E.; Rechavi, G.: Genetic linkage of autosomal-dominant
Alport syndrome with leukocyte inclusions and macrothrombocytopenia
(Fechtner syndrome) to chromosome 22q11-13. Am. J. Hum. Genet. 65:
1711-1717, 1999.
9. Toren, A.; Rozenfeld-Granot, G.; Rocca, B.; Epstein, C. J.; Amariglio,
N.; Laghi, F.; Landolfi, R.; Brok-Simoni, F.; Carlsson, L. E.; Rechavi,
G.; Greinacher, A.: Autosomal-dominant giant platelet syndromes:
a hint of the same genetic defect as in Fechtner syndrome owing to
a similar genetic linkage to chromosome 22q11-13. Blood 96: 3447-3451,
2000.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
High-tone sensorineural deafness (67% of patients);
[Eyes];
Congenital cataracts;
Juvenile glaucoma
GENITOURINARY:
[Kidneys];
Nephritis;
End stage renal disease (20-40 years)(28% of patients)
HEMATOLOGY:
Thrombocytopenia;
Giant platelets;
Leukocyte inclusion bodies (Dohle-like bodies);
Variable bleeding episodes (menorrhagia, easy bruisability, postoperative
hemorrhage)
LABORATORY ABNORMALITIES:
Proteinuria;
Hematuria;
Leukocyte inclusion bodies (EM) - intermediate filaments and ribosome
clusters irregularly dispersed in cytoplasm;
Moderate to severe thrombocytopenia (30-90 x 10(9)/l);
Normal to prolonged bleeding time;
Median mean platelet volume (MPV) 20fl;
Normal platelet aggregation response to epinephrine, arachidonic acid
(AA), adenosine 5'-diphosphate (ADP), collagen, and ristocetin
MISCELLANEOUS:
Allelic to May-Heglin anomaly (155100), Sebastian syndrome (605249),
Epstein syndrome (153650), and deafness, autosomal dominant 17 (603622)
MOLECULAR BASIS:
Caused by mutation in the myosin, heavy chain 9, non-muscle gene (MYH9,
160775.0005)
*FIELD* CN
Kelly A. Przylepa - revised: 3/1/2007
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
wwang: 02/07/2011
joanna: 10/11/2010
terry: 2/12/2009
joanna: 1/15/2008
joanna: 3/1/2007
*FIELD* CN
Cassandra L. Kniffin - updated: 9/22/2010
Victor A. McKusick - updated: 1/5/2001
Victor A. McKusick - updated: 8/29/2000
Victor A. McKusick - updated: 12/28/1999
*FIELD* CD
Victor A. McKusick: 11/4/1988
*FIELD* ED
carol: 09/23/2010
ckniffin: 9/22/2010
mcapotos: 1/17/2001
mcapotos: 1/11/2001
terry: 1/5/2001
alopez: 8/31/2000
terry: 8/29/2000
mgross: 12/29/1999
mgross: 12/28/1999
mimadm: 11/6/1994
carol: 12/13/1993
supermim: 3/16/1992
carol: 3/27/1991
carol: 3/14/1991
supermim: 3/20/1990
*RECORD*
*FIELD* NO
153640
*FIELD* TI
#153640 FECHTNER SYNDROME; FTNS
;;MACROTHROMBOCYTOPENIA, NEPHRITIS, DEAFNESS, AND LEUKOCYTE INCLUSIONS;;
read moreALPORT SYNDROME WITH MACROTHROMBOCYTOPENIA, FORMERLY; APSM, FORMERLY
*FIELD* TX
A number sign (#) is used with entry because Fechtner syndrome is caused
by heterozygous mutation in the gene encoding nonmuscle myosin heavy
chain-9 (MYH9; 160775) on chromosome 22q11.
DESCRIPTION
Fechtner syndrome is an autosomal dominant disorder characterized by the
triad of thrombocytopenia, giant platelets, and Dohle body-like
inclusions in peripheral blood leukocytes, with the additional features
of nephritis, hearing loss, and eye abnormalities, mostly cataracts
(Peterson et al., 1985).
There are several other disorders caused by mutation in the MYH9 gene
that share overlapping features with Fechtner syndrome. May-Hegglin
anomaly (155100) is characterized by the triad of thrombocytopenia,
giant platelets, and Dohle body-like inclusions in peripheral blood
leukocytes. Epstein syndrome (153650) has the platelet defect, deafness,
and nephritis, but does not have cataract and lacks leukocyte inclusion
bodies on classic staining of peripheral blood smears. The findings of
nephritis, hearing loss, and occasional cataracts in Fechtner and
Epstein syndromes are reminiscent of Alport syndrome (see 301050).
Sebastian syndrome (605249) is similar to May-Hegglin anomaly, but has a
different ultrastructural appearance of the leukocyte inclusions. Seri
et al. (2003) suggested that these 4 disorders, May-Hegglin, Sebastian,
Epstein, and Fechtner syndromes, are not distinct entities, but rather
represent a single disorder with a continuous clinical spectrum, for
which they proposed the term 'MYH9-related disease.' However, other
disorders, e.g., macrothrombocytopenia and progressive sensorineural
deafness (600208) and a form of nonsyndromic deafness (DFNA17; 603622),
are also caused by mutation in the MYH9 gene.
CLINICAL FEATURES
Peterson et al. (1985) reported a family in which 8 members of 4
generations showed nephritis, deafness, congenital cataracts,
macrothrombocytopenia, and leukocyte inclusions in various combinations.
The authors referred to the disorder as the 'Fechtner syndrome,'
presumably from the surname of the family. The family differed from
others reported, such as families with Epstein syndrome, in that their
hematologic abnormalities included not only macrothrombocytopenia but
also small, pale blue cytoplasmic inclusions in the neutrophils and
eosinophils. Light microscopic appearance of the inclusions resembled
that of toxic Dohle bodies and inclusions of May-Hegglin anomaly, but
their ultrastructural appearance was unique. Deafness was high-tone
sensorineural. Renal disease ranged from microscopic hematuria to
end-stage renal failure necessitating dialysis and kidney
transplantation. All affected adults had cataracts.
Gershoni-Baruch et al. (1988) reported a second family with Fechtner
syndrome; 16 members were affected. The authors noted that since the
hematologic abnormalities are a consistent feature of the syndrome and
seem to be present at birth, they would presumably permit prenatal
diagnosis by detection of the changes in fetal blood samples.
Heynen et al. (1988) described the Fechtner syndrome in a female patient
who had developed multiple ecchymoses from the time she started walking
at the age of 1 year, due to severe thrombocytopenia. Hearing problems
developing at the age of 8 years progressed to almost complete deafness.
The blood smear showed giant platelets the size of granulocytes. The
patient had moderate proteinuria, but there were no abnormalities in the
urinary sediment or in renal function. Heynen et al. (1988) postulated
an abnormality in the cytoskeleton of megakaryocytes such that formation
of the demarcation membrane system and the expulsion of platelets do not
occur normally.
Rocca et al. (1993) reported a 4-generation family in which 10 of 14
individuals had macrothrombocytopenia with leukocyte inclusions. Some,
but not all, affected members had Alport-like symptoms, such as
deafness, nephritis, and cataracts. For example, members aged less than
50 years had clinically silent ocular abnormalities, mainly lens
opacities. These observations were consistent with 'reduced expression
of Alport manifestations,' thus showing similarity to Sebastian
syndrome. Heath et al. (2001) identified a heterozygous mutation in the
MYH9 gene (E1841K; 160775.0002) in the family reported by Rocca et al.
(1993).
MAPPING
In an extended Israeli family with Fechtner syndrome plus impaired liver
functions and hypercholesterolemia in some individuals, Toren et al.
(1999) mapped the disease-causing gene to the long arm of chromosome 22.
Six markers yielded a lod score of more than 3.00. A maximum 2-point lod
score of 7.02 was obtained with the marker D22S283 at a recombination
fraction of 0.0. Recombination analysis placed the disease-causing gene
in a 5.5-Mb interval between markers D22S284 and D22S1167. Toren et al.
(1999) stated that no collagen genes or genes comprising the basement
membrane had been mapped to this region, 22q12.1-q13.2. Toren et al.
(2000) mapped Epstein syndrome (153650) to the same region of chromosome
22q, suggesting that it is allelic to Fechtner syndrome.
MOLECULAR GENETICS
The May-Hegglin/Fechtner Syndrome Consortium (2000) identified 2
different mutations in the MYH9 gene (160775.0005-160775.0006) in
patients with Fechtner syndrome. This same group identified other
mutations in the MYH9 gene in probands from families with May-Hegglin
anomaly and Sebastian syndrome, indicating that these disorders are
allelic.
*FIELD* RF
1. Gershoni-Baruch, R.; Baruch, Y.; Viener, A.; Lichtig, C.: Fechtner
syndrome: clinical and genetic aspects. Am. J. Med. Genet. 31: 357-367,
1988.
2. Heath, K. E.; Campos-Barros, A.; Toren, A.; Rozenfeld-Granot, G.;
Carlsson, L. E.; Savige, J.; Denison, J. C.; Gregory, M. C.; White,
J. G.; Barker, D. F.; Greinacher, A.; Epstein, C. J.; Glucksman, M.
J.; Martignetti, J. A.: Nonmuscle myosin heavy chain IIA mutations
define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin
anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. Am.
J. Hum. Genet. 69: 1033-1045, 2001.
3. Heynen, M. J.; Blockmans, D.; Verwilghen, R. L.; Vermylen, J.:
Congenital macrothrombocytopenia, leucocyte inclusions, deafness and
proteinuria: functional and electron microscopic observations on platelets
and megakaryocytes. Brit. J. Haemat. 70: 441-448, 1988.
4. May-Hegglin/Fechtner Syndrome Consortium: Mutations in MYH9
result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. Nature
Genet. 26: 103-105, 2000.
5. Peterson, L. C.; Rao, K. V.; Crosson, J. T.; White, J. G.: Fechtner
syndrome: a variant of Alport's syndrome with leukocyte inclusions
and macrothrombocytopenia. Blood 65: 397-406, 1985.
6. Rocca, B.; Laghi, F.; Zini, G.; Maggiano, N.; Landolfi, R.: Fechtner
syndrome: report of a third family and literature review. Brit. J.
Haemat. 85: 423-426, 1993.
7. Seri, M.; Pecci, A.; Di Bari, F.; Cusano, R.; Savino, M.; Panza,
E.; Nigro, A.; Noris, P.; Gangarossa, S.; Rocca, B.; Gresele, P.;
Bizzaro, N.; and 13 others: MYH9-related disease: May-Hegglin anomaly,
Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not
distinct entities but represent a variable expression of a single
illness. Medicine 82: 203-215, 2003.
8. Toren, A.; Amariglio, N.; Rozenfeld-Granot, G.; Simon, A. J.; Brok-Simoni,
F.; Pras, E.; Rechavi, G.: Genetic linkage of autosomal-dominant
Alport syndrome with leukocyte inclusions and macrothrombocytopenia
(Fechtner syndrome) to chromosome 22q11-13. Am. J. Hum. Genet. 65:
1711-1717, 1999.
9. Toren, A.; Rozenfeld-Granot, G.; Rocca, B.; Epstein, C. J.; Amariglio,
N.; Laghi, F.; Landolfi, R.; Brok-Simoni, F.; Carlsson, L. E.; Rechavi,
G.; Greinacher, A.: Autosomal-dominant giant platelet syndromes:
a hint of the same genetic defect as in Fechtner syndrome owing to
a similar genetic linkage to chromosome 22q11-13. Blood 96: 3447-3451,
2000.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
High-tone sensorineural deafness (67% of patients);
[Eyes];
Congenital cataracts;
Juvenile glaucoma
GENITOURINARY:
[Kidneys];
Nephritis;
End stage renal disease (20-40 years)(28% of patients)
HEMATOLOGY:
Thrombocytopenia;
Giant platelets;
Leukocyte inclusion bodies (Dohle-like bodies);
Variable bleeding episodes (menorrhagia, easy bruisability, postoperative
hemorrhage)
LABORATORY ABNORMALITIES:
Proteinuria;
Hematuria;
Leukocyte inclusion bodies (EM) - intermediate filaments and ribosome
clusters irregularly dispersed in cytoplasm;
Moderate to severe thrombocytopenia (30-90 x 10(9)/l);
Normal to prolonged bleeding time;
Median mean platelet volume (MPV) 20fl;
Normal platelet aggregation response to epinephrine, arachidonic acid
(AA), adenosine 5'-diphosphate (ADP), collagen, and ristocetin
MISCELLANEOUS:
Allelic to May-Heglin anomaly (155100), Sebastian syndrome (605249),
Epstein syndrome (153650), and deafness, autosomal dominant 17 (603622)
MOLECULAR BASIS:
Caused by mutation in the myosin, heavy chain 9, non-muscle gene (MYH9,
160775.0005)
*FIELD* CN
Kelly A. Przylepa - revised: 3/1/2007
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
wwang: 02/07/2011
joanna: 10/11/2010
terry: 2/12/2009
joanna: 1/15/2008
joanna: 3/1/2007
*FIELD* CN
Cassandra L. Kniffin - updated: 9/22/2010
Victor A. McKusick - updated: 1/5/2001
Victor A. McKusick - updated: 8/29/2000
Victor A. McKusick - updated: 12/28/1999
*FIELD* CD
Victor A. McKusick: 11/4/1988
*FIELD* ED
carol: 09/23/2010
ckniffin: 9/22/2010
mcapotos: 1/17/2001
mcapotos: 1/11/2001
terry: 1/5/2001
alopez: 8/31/2000
terry: 8/29/2000
mgross: 12/29/1999
mgross: 12/28/1999
mimadm: 11/6/1994
carol: 12/13/1993
supermim: 3/16/1992
carol: 3/27/1991
carol: 3/14/1991
supermim: 3/20/1990
MIM
153650
*RECORD*
*FIELD* NO
153650
*FIELD* TI
#153650 EPSTEIN SYNDROME
;;MACROTHROMBOCYTOPENIA, NEPHRITIS, AND DEAFNESS
*FIELD* TX
read moreA number sign (#) is used with this entry because Epstein syndrome is
caused by heterozygous mutation in the gene encoding the nonmuscle
myosin heavy chain-9 gene (MYH9; 160775) on chromosome 22q11.
DESCRIPTION
Epstein syndrome is an autosomal dominant disorder characterized by
thrombocytopenia, giant platelets, nephritis, and deafness (Epstein et
al., 1972).
There are several other disorders caused by mutation in the MYH9 gene
that share overlapping features with Epstein syndrome. May-Hegglin
anomaly (155100) is characterized by the triad of thrombocytopenia,
giant platelets, and Dohle body-like inclusions in peripheral blood
leukocytes. These leukocyte inclusions are not found on classic staining
of peripheral blood in Epstein syndrome. Fechtner syndrome (153640) has
the platelet defect accompanied by nephritis, hearing loss, and eye
abnormalities, mostly cataracts. The findings of nephritis, hearing
loss, and occasional cataracts in Fechtner and Epstein syndromes are
reminiscent of Alport syndrome (see 301050). Sebastian syndrome (605249)
is similar to May-Hegglin anomaly, but has a different ultrastructural
appearance of the leukocyte inclusions. Seri et al. (2003) suggested
that these 4 disorders, May-Hegglin, Sebastian, Epstein, and Fechtner
syndromes, are not distinct entities, but rather represent a single
disorder with a continuous clinical spectrum, for which they proposed
the term 'MYH9-related disease.' However, other disorders, e.g.,
macrothrombocytopenia and progressive sensorineural deafness (600208)
and a form of nonsyndromic deafness (DFNA17; 603622), are also caused by
mutation in the MYH9 gene.
CLINICAL FEATURES
Epstein et al. (1972) described 2 unrelated families, each with 2
members with macrothrombocytopathia, nephritis, and deafness. In 1
family, a third member, a young child, had the platelet disorder and a
mild hearing loss. Except for the greater severity in females, the renal
disease was indistinguishable from that of X-linked Alport syndrome
(301050). Likewise, the high frequency sensorineural hearing loss was
similar to that of the Alport syndrome. Thrombocytopenia was present
with giant platelets showing abnormal ultrastructure and defective
adherence to glass, and the bleeding time was prolonged. Aggregation of
platelets in response to collagen and epinephrine and release of
phospholipids were all impaired, and the release of nucleotide after
exposure to collagen was abnormally low.
Parsa et al. (1976) reported another kindred with the triad of
hereditary nephritis, deafness, and thrombocytopenia with giant
platelets. Electron microscopic studies of megakaryocytes led the
authors to suggest that the giant platelets may result from a
degenerative process in megakaryocytes leading to nuclear regression and
cytoplasmic fragmentation, rather than from the normal blebbing process.
Giant platelets also occur in the Fechtner syndrome and in association
with the May-Hegglin anomaly.
Using immunocytochemical analysis, Seri et al. (2003) detected an
irregular distribution of myosin in neutrophil cytoplasm of all 22
patients with mutations in the MYH9 gene, including 5 patients with a
diagnosis of Epstein syndrome. Large myosin aggregates appeared as
Dohle-like bodies, whereas the smaller ones were not readily
recognizable on Giemsa-stained peripheral blood smears.
- Clinical Variability
Utsch et al. (2006) reported a newborn girl with Epstein syndrome and a
heterozygous mutation in the MYH9 gene (160775.0012). Although she did
not show deafness or nephritis, she had macrothrombocytopenia and
impaired platelet aggregation response to ADP and epinephrine. Bone
marrow aspirate showed enhanced megakaryocytopoiesis with predominance
of immature and dysplastic megakaryocytes. Erythropoiesis and
granulocytopoiesis were normal. In addition, she had classic exstrophy
of the bladder (600057). Prenatal ultrasound studies showed protrusion
of the abdominal wall and a single umbilical artery. After birth, she
was noted to have diastasis of the symphysis, epispadic open urethral
groove, bifid clitoris and labia minora, an open laying bladder plate,
and duplication of the vagina. The authors noted the young age of the
patient, and suggested that she may develop deafness and/or nephritis in
the future. Utsch et al. (2006) suggested that although MYH9 mutations
had not previously been associated with urogenital malformations, the
mutation may have played a role in the bladder exstrophy in this
patient.
INHERITANCE
In the family with Epstein syndrome described by Epstein et al. (1972),
the inheritance pattern was clearly dominant, although there was no
male-to-male transmission. The fact that females were as severely
affected as males made X-linked dominance unlikely, however.
Furthermore, no male-to-male transmission occurred in the family
reported by Eckstein et al. (1975).
MAPPING
In linkage studies of the original family described by Epstein et al.
(1972), Toren et al. (2000) found a maximum 2-point lod score of 3.41
with marker D22S683 at a recombination fraction of 0.00. Recombination
analysis placed the disease-causing gene in a 3.37-Mb interval between
the markers D22S284 and D22S693. The clinical likeness and similar
interval containing the disease-causing gene suggested that Epstein
syndrome may be due to a defect in the same gene as that in the other
autosomal dominant giant platelet syndromes.
MOLECULAR GENETICS
Heath et al. (2001) found that the original family reported by Epstein
et al. (1972) had a missense mutation in the gene that encodes nonmuscle
myosin heavy chain IIA (MYH9; 160775.0006), which is also the site of
mutations causing other forms of autosomal dominant
macrothrombocytopenia: May-Hegglin anomaly, Fechtner syndrome, and
Sebastian syndrome.
HISTORY
M'Rad et al. (1992) reported studies of 31 families with Alport
syndrome. One family had a severe form of the disease with deafness and
end-stage renal disease (ESRD) at the age of 14 but without ocular signs
of Alport syndrome. M'Rad et al. (1992) considered the disorder to be
X-linked in this family because the mother was less severely affected
than the son. In both mother and son, macrothrombocytopathia and
inclusions resembling Dohle bodies were observed. The segregation of the
only informative marker was consistent with X-linkage.
*FIELD* SA
Bernheim et al. (1976); Hansen et al. (1978); Heynen et al. (1988)
*FIELD* RF
1. Bernheim, J.; Dechavanne, M.; Bryon, P. A.; Lagarde, M.; Colon,
S.; Pozet, N.; Traeger, J.: Thrombocytopenia, macrothrombocytopathia,
nephritis and deafness. Am. J. Med. 61: 145-150, 1976.
2. Eckstein, J. D.; Filip, D. J.; Watts, J. C.: Hereditary thrombocytopenia,
deafness and renal disease. Ann. Intern. Med. 82: 639-645, 1975.
3. Epstein, C. J.; Sahud, M. A.; Piel, C. F.; Goodman, J. R.; Bernfield,
M. R.; Kushner, J. H.; Ablin, A. R.: Hereditary macrothrombocytopathia,
nephritis and deafness. Am. J. Med. 52: 299-310, 1972.
4. Hansen, M. S.; Behnke, O.; Pedersen, N. T.; Videbaek, A.: Megathrombocytopenia
associated with glomerulonephritis, deafness and aortic cystic medianecrosis. Scand.
J. Haemat. 21: 197-205, 1978.
5. Heath, K. E.; Campos-Barros, A.; Toren, A.; Rozenfeld-Granot, G.;
Carlsson, L. E.; Savige, J.; Denison, J. C.; Gregory, M. C.; White,
J. G.; Barker, D. F.; Greinacher, A.; Epstein, C. J.; Glucksman, M.
J.; Martignetti, J. A.: Nonmuscle myosin heavy chain IIA mutations
define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin
anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. Am.
J. Hum. Genet. 69: 1033-1045, 2001.
6. Heynen, M. J.; Blockmans, D.; Verwilghen, R. L.; Vermylen, J.:
Congenital macrothrombocytopenia, leucocyte inclusions, deafness and
proteinuria: functional and electron microscopic observations on platelets
and megakaryocytes. Brit. J. Haemat. 70: 441-448, 1988.
7. M'Rad, R.; Sanak, M.; Deschenes, G.; Zhou, J.; Bonaiti-Pellie,
C.; Holvoet-Vermaut, L.; Heuertz, S.; Gubler, M.-C.; Broyer, M.; Grunfeld,
J.-P.; Tryggvason, K.; Hors-Cayla, M.-C.: Alport syndrome: a genetic
study of 31 families. Hum. Genet. 90: 420-426, 1992.
8. Parsa, K. P.; Lee, D. B. N.; Zamboni, L.; Glassock, R. J.: Hereditary
nephritis, deafness and abnormal thrombopoiesis: study of a new kindred. Am.
J. Med. 60: 665-672, 1976.
9. Seri, M.; Pecci, A.; Di Bari, F.; Cusano, R.; Savino, M.; Panza,
E.; Nigro, A.; Noris, P.; Gangarossa, S.; Rocca, B.; Gresele, P.;
Bizzaro, N.; and 13 others: MYH9-related disease: May-Hegglin anomaly,
Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not
distinct entities but represent a variable expression of a single
illness. Medicine 82: 203-215, 2003.
10. Toren, A.; Rozenfeld-Granot, G.; Rocca, B.; Epstein, C. J.; Amariglio,
N.; Laghi, F.; Landolfi, R.; Brok-Simoni, F.; Carlsson, L. E.; Rechavi,
G.; Greinacher, A.: Autosomal-dominant giant platelet syndromes:
a hint of the same genetic defect as in Fechtner syndrome owing to
a similar genetic linkage to chromosome 22q11-13. Blood 96: 3447-3451,
2000.
11. Utsch, B.; DiFeo, A.; Kujat, A.; Karle, S.; Schuster, V.; Lenk,
H.; Jacobs, U.; Muller, M.; Dotsch, J.; Rascher, W.; Reutter, H.;
Martignetti, J. A.; Ludwig, M.; Trobs, R.-B.: Bladder exstrophy and
Epstein type congenital macrothrombocytopenia: evidence for a common
cause? (Letter) Am. J. Med. Genet. 140A: 2251-2253, 2006.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Deafness, bilateral sensorineural, high frequency (100% of patients);
[Eyes];
Cataract (Alport syndrome with macrothrombocytopenia);
No cataract (Epstein syndrome)
CARDIOVASCULAR:
[Vascular];
Hypertension, moderate, secondary to renal disease
GENITOURINARY:
[Kidneys];
Nephritis;
End stage renal disease (33% of patients);
Hypertension, moderate
HEMATOLOGY:
Mild bleeding episodes (epistaxis, GI bleeding, menorrhagia);
Thrombocytopenia;
Giant platelets;
No leukocyte inclusion bodies on Giemsa staining;
MYH9-positive inclusions on immunohistochemical staining
LABORATORY ABNORMALITIES:
Microscopic hematuria;
Proteinuria;
Severe thrombocytopenia (30-60 x 10(9)/L);
Normal-prolonged bleeding time;
Reduced platelet aggregation response to ADP, collagen, epinephrine
MISCELLANEOUS:
Bleeding episodes occur early in life and may disappear with age
MOLECULAR BASIS:
Caused by mutation in the myosin, heavy polypeptide-9, nonmuscle gene
(MYH9, 160775.0006)
*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Kelly A. Przylepa - revised: 12/24/2007
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
wwang: 10/29/2010
ckniffin: 10/11/2010
joanna: 1/14/2008
joanna: 12/24/2007
alopez: 11/30/2001
*FIELD* CN
Cassandra L. Kniffin - updated: 9/22/2010
Cassandra L. Kniffin - updated: 12/18/2006
Victor A. McKusick - updated: 11/27/2001
Victor A. McKusick - updated: 1/5/2001
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 09/23/2010
ckniffin: 9/22/2010
ckniffin: 5/27/2010
wwang: 12/27/2006
ckniffin: 12/18/2006
carol: 4/16/2004
terry: 5/10/2002
alopez: 11/30/2001
terry: 11/27/2001
carol: 1/18/2001
mcapotos: 1/17/2001
mcapotos: 1/11/2001
terry: 1/5/2001
mimadm: 11/6/1994
terry: 5/10/1994
carol: 4/2/1993
supermim: 3/16/1992
carol: 3/4/1992
carol: 2/17/1992
*RECORD*
*FIELD* NO
153650
*FIELD* TI
#153650 EPSTEIN SYNDROME
;;MACROTHROMBOCYTOPENIA, NEPHRITIS, AND DEAFNESS
*FIELD* TX
read moreA number sign (#) is used with this entry because Epstein syndrome is
caused by heterozygous mutation in the gene encoding the nonmuscle
myosin heavy chain-9 gene (MYH9; 160775) on chromosome 22q11.
DESCRIPTION
Epstein syndrome is an autosomal dominant disorder characterized by
thrombocytopenia, giant platelets, nephritis, and deafness (Epstein et
al., 1972).
There are several other disorders caused by mutation in the MYH9 gene
that share overlapping features with Epstein syndrome. May-Hegglin
anomaly (155100) is characterized by the triad of thrombocytopenia,
giant platelets, and Dohle body-like inclusions in peripheral blood
leukocytes. These leukocyte inclusions are not found on classic staining
of peripheral blood in Epstein syndrome. Fechtner syndrome (153640) has
the platelet defect accompanied by nephritis, hearing loss, and eye
abnormalities, mostly cataracts. The findings of nephritis, hearing
loss, and occasional cataracts in Fechtner and Epstein syndromes are
reminiscent of Alport syndrome (see 301050). Sebastian syndrome (605249)
is similar to May-Hegglin anomaly, but has a different ultrastructural
appearance of the leukocyte inclusions. Seri et al. (2003) suggested
that these 4 disorders, May-Hegglin, Sebastian, Epstein, and Fechtner
syndromes, are not distinct entities, but rather represent a single
disorder with a continuous clinical spectrum, for which they proposed
the term 'MYH9-related disease.' However, other disorders, e.g.,
macrothrombocytopenia and progressive sensorineural deafness (600208)
and a form of nonsyndromic deafness (DFNA17; 603622), are also caused by
mutation in the MYH9 gene.
CLINICAL FEATURES
Epstein et al. (1972) described 2 unrelated families, each with 2
members with macrothrombocytopathia, nephritis, and deafness. In 1
family, a third member, a young child, had the platelet disorder and a
mild hearing loss. Except for the greater severity in females, the renal
disease was indistinguishable from that of X-linked Alport syndrome
(301050). Likewise, the high frequency sensorineural hearing loss was
similar to that of the Alport syndrome. Thrombocytopenia was present
with giant platelets showing abnormal ultrastructure and defective
adherence to glass, and the bleeding time was prolonged. Aggregation of
platelets in response to collagen and epinephrine and release of
phospholipids were all impaired, and the release of nucleotide after
exposure to collagen was abnormally low.
Parsa et al. (1976) reported another kindred with the triad of
hereditary nephritis, deafness, and thrombocytopenia with giant
platelets. Electron microscopic studies of megakaryocytes led the
authors to suggest that the giant platelets may result from a
degenerative process in megakaryocytes leading to nuclear regression and
cytoplasmic fragmentation, rather than from the normal blebbing process.
Giant platelets also occur in the Fechtner syndrome and in association
with the May-Hegglin anomaly.
Using immunocytochemical analysis, Seri et al. (2003) detected an
irregular distribution of myosin in neutrophil cytoplasm of all 22
patients with mutations in the MYH9 gene, including 5 patients with a
diagnosis of Epstein syndrome. Large myosin aggregates appeared as
Dohle-like bodies, whereas the smaller ones were not readily
recognizable on Giemsa-stained peripheral blood smears.
- Clinical Variability
Utsch et al. (2006) reported a newborn girl with Epstein syndrome and a
heterozygous mutation in the MYH9 gene (160775.0012). Although she did
not show deafness or nephritis, she had macrothrombocytopenia and
impaired platelet aggregation response to ADP and epinephrine. Bone
marrow aspirate showed enhanced megakaryocytopoiesis with predominance
of immature and dysplastic megakaryocytes. Erythropoiesis and
granulocytopoiesis were normal. In addition, she had classic exstrophy
of the bladder (600057). Prenatal ultrasound studies showed protrusion
of the abdominal wall and a single umbilical artery. After birth, she
was noted to have diastasis of the symphysis, epispadic open urethral
groove, bifid clitoris and labia minora, an open laying bladder plate,
and duplication of the vagina. The authors noted the young age of the
patient, and suggested that she may develop deafness and/or nephritis in
the future. Utsch et al. (2006) suggested that although MYH9 mutations
had not previously been associated with urogenital malformations, the
mutation may have played a role in the bladder exstrophy in this
patient.
INHERITANCE
In the family with Epstein syndrome described by Epstein et al. (1972),
the inheritance pattern was clearly dominant, although there was no
male-to-male transmission. The fact that females were as severely
affected as males made X-linked dominance unlikely, however.
Furthermore, no male-to-male transmission occurred in the family
reported by Eckstein et al. (1975).
MAPPING
In linkage studies of the original family described by Epstein et al.
(1972), Toren et al. (2000) found a maximum 2-point lod score of 3.41
with marker D22S683 at a recombination fraction of 0.00. Recombination
analysis placed the disease-causing gene in a 3.37-Mb interval between
the markers D22S284 and D22S693. The clinical likeness and similar
interval containing the disease-causing gene suggested that Epstein
syndrome may be due to a defect in the same gene as that in the other
autosomal dominant giant platelet syndromes.
MOLECULAR GENETICS
Heath et al. (2001) found that the original family reported by Epstein
et al. (1972) had a missense mutation in the gene that encodes nonmuscle
myosin heavy chain IIA (MYH9; 160775.0006), which is also the site of
mutations causing other forms of autosomal dominant
macrothrombocytopenia: May-Hegglin anomaly, Fechtner syndrome, and
Sebastian syndrome.
HISTORY
M'Rad et al. (1992) reported studies of 31 families with Alport
syndrome. One family had a severe form of the disease with deafness and
end-stage renal disease (ESRD) at the age of 14 but without ocular signs
of Alport syndrome. M'Rad et al. (1992) considered the disorder to be
X-linked in this family because the mother was less severely affected
than the son. In both mother and son, macrothrombocytopathia and
inclusions resembling Dohle bodies were observed. The segregation of the
only informative marker was consistent with X-linkage.
*FIELD* SA
Bernheim et al. (1976); Hansen et al. (1978); Heynen et al. (1988)
*FIELD* RF
1. Bernheim, J.; Dechavanne, M.; Bryon, P. A.; Lagarde, M.; Colon,
S.; Pozet, N.; Traeger, J.: Thrombocytopenia, macrothrombocytopathia,
nephritis and deafness. Am. J. Med. 61: 145-150, 1976.
2. Eckstein, J. D.; Filip, D. J.; Watts, J. C.: Hereditary thrombocytopenia,
deafness and renal disease. Ann. Intern. Med. 82: 639-645, 1975.
3. Epstein, C. J.; Sahud, M. A.; Piel, C. F.; Goodman, J. R.; Bernfield,
M. R.; Kushner, J. H.; Ablin, A. R.: Hereditary macrothrombocytopathia,
nephritis and deafness. Am. J. Med. 52: 299-310, 1972.
4. Hansen, M. S.; Behnke, O.; Pedersen, N. T.; Videbaek, A.: Megathrombocytopenia
associated with glomerulonephritis, deafness and aortic cystic medianecrosis. Scand.
J. Haemat. 21: 197-205, 1978.
5. Heath, K. E.; Campos-Barros, A.; Toren, A.; Rozenfeld-Granot, G.;
Carlsson, L. E.; Savige, J.; Denison, J. C.; Gregory, M. C.; White,
J. G.; Barker, D. F.; Greinacher, A.; Epstein, C. J.; Glucksman, M.
J.; Martignetti, J. A.: Nonmuscle myosin heavy chain IIA mutations
define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin
anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. Am.
J. Hum. Genet. 69: 1033-1045, 2001.
6. Heynen, M. J.; Blockmans, D.; Verwilghen, R. L.; Vermylen, J.:
Congenital macrothrombocytopenia, leucocyte inclusions, deafness and
proteinuria: functional and electron microscopic observations on platelets
and megakaryocytes. Brit. J. Haemat. 70: 441-448, 1988.
7. M'Rad, R.; Sanak, M.; Deschenes, G.; Zhou, J.; Bonaiti-Pellie,
C.; Holvoet-Vermaut, L.; Heuertz, S.; Gubler, M.-C.; Broyer, M.; Grunfeld,
J.-P.; Tryggvason, K.; Hors-Cayla, M.-C.: Alport syndrome: a genetic
study of 31 families. Hum. Genet. 90: 420-426, 1992.
8. Parsa, K. P.; Lee, D. B. N.; Zamboni, L.; Glassock, R. J.: Hereditary
nephritis, deafness and abnormal thrombopoiesis: study of a new kindred. Am.
J. Med. 60: 665-672, 1976.
9. Seri, M.; Pecci, A.; Di Bari, F.; Cusano, R.; Savino, M.; Panza,
E.; Nigro, A.; Noris, P.; Gangarossa, S.; Rocca, B.; Gresele, P.;
Bizzaro, N.; and 13 others: MYH9-related disease: May-Hegglin anomaly,
Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not
distinct entities but represent a variable expression of a single
illness. Medicine 82: 203-215, 2003.
10. Toren, A.; Rozenfeld-Granot, G.; Rocca, B.; Epstein, C. J.; Amariglio,
N.; Laghi, F.; Landolfi, R.; Brok-Simoni, F.; Carlsson, L. E.; Rechavi,
G.; Greinacher, A.: Autosomal-dominant giant platelet syndromes:
a hint of the same genetic defect as in Fechtner syndrome owing to
a similar genetic linkage to chromosome 22q11-13. Blood 96: 3447-3451,
2000.
11. Utsch, B.; DiFeo, A.; Kujat, A.; Karle, S.; Schuster, V.; Lenk,
H.; Jacobs, U.; Muller, M.; Dotsch, J.; Rascher, W.; Reutter, H.;
Martignetti, J. A.; Ludwig, M.; Trobs, R.-B.: Bladder exstrophy and
Epstein type congenital macrothrombocytopenia: evidence for a common
cause? (Letter) Am. J. Med. Genet. 140A: 2251-2253, 2006.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Deafness, bilateral sensorineural, high frequency (100% of patients);
[Eyes];
Cataract (Alport syndrome with macrothrombocytopenia);
No cataract (Epstein syndrome)
CARDIOVASCULAR:
[Vascular];
Hypertension, moderate, secondary to renal disease
GENITOURINARY:
[Kidneys];
Nephritis;
End stage renal disease (33% of patients);
Hypertension, moderate
HEMATOLOGY:
Mild bleeding episodes (epistaxis, GI bleeding, menorrhagia);
Thrombocytopenia;
Giant platelets;
No leukocyte inclusion bodies on Giemsa staining;
MYH9-positive inclusions on immunohistochemical staining
LABORATORY ABNORMALITIES:
Microscopic hematuria;
Proteinuria;
Severe thrombocytopenia (30-60 x 10(9)/L);
Normal-prolonged bleeding time;
Reduced platelet aggregation response to ADP, collagen, epinephrine
MISCELLANEOUS:
Bleeding episodes occur early in life and may disappear with age
MOLECULAR BASIS:
Caused by mutation in the myosin, heavy polypeptide-9, nonmuscle gene
(MYH9, 160775.0006)
*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Kelly A. Przylepa - revised: 12/24/2007
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
wwang: 10/29/2010
ckniffin: 10/11/2010
joanna: 1/14/2008
joanna: 12/24/2007
alopez: 11/30/2001
*FIELD* CN
Cassandra L. Kniffin - updated: 9/22/2010
Cassandra L. Kniffin - updated: 12/18/2006
Victor A. McKusick - updated: 11/27/2001
Victor A. McKusick - updated: 1/5/2001
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 09/23/2010
ckniffin: 9/22/2010
ckniffin: 5/27/2010
wwang: 12/27/2006
ckniffin: 12/18/2006
carol: 4/16/2004
terry: 5/10/2002
alopez: 11/30/2001
terry: 11/27/2001
carol: 1/18/2001
mcapotos: 1/17/2001
mcapotos: 1/11/2001
terry: 1/5/2001
mimadm: 11/6/1994
terry: 5/10/1994
carol: 4/2/1993
supermim: 3/16/1992
carol: 3/4/1992
carol: 2/17/1992
MIM
155100
*RECORD*
*FIELD* NO
155100
*FIELD* TI
#155100 MAY-HEGGLIN ANOMALY; MHA
;;BLEEDING DISORDER, PLATELET-TYPE, 6; BDPLT6;;
DOHLE LEUKOCYTE INCLUSIONS WITH GIANT PLATELETS;;
read moreMACROTHROMBOCYTOPENIA WITH LEUKOCYTE INCLUSIONS
*FIELD* TX
A number sign (#) is used with this entry because the May-Hegglin
anomaly (MHA) is caused by mutation in the gene encoding nonmuscle
myosin heavy chain-9 (MYH9; 160775) on chromosome 22q11.2.
DESCRIPTION
May-Hegglin anomaly is an autosomal dominant disorder characterized by
the triad of thrombocytopenia, giant platelets, and Dohle body-like
inclusions in peripheral blood leukocytes. About 25 to 50% of affected
individuals have mild to moderate episodic bleeding (summary by Kelley
et al., 2000).
There are several other disorders caused by mutation in the MYH9 gene
that share overlapping features with May-Hegglin anomaly. Fechtner
syndrome (153640) has the platelet defect accompanied by nephritis,
hearing loss, and eye abnormalities, mostly cataracts. Epstein syndrome
(153650) has the platelet defect, deafness, and nephritis, but does not
have cataract and lacks leukocyte inclusion bodies on classic staining
of peripheral blood smears. The findings of nephritis, hearing loss, and
occasional cataracts in Fechtner and Epstein syndromes are reminiscent
of Alport syndrome (301050). Sebastian syndrome (605249) is the most
similar to May-Hegglin anomaly, but has a different ultrastructural
appearance of the leukocyte inclusions. In MHA, the inclusions are
composed of clusters of ribosomes oriented along parallel
microfilaments, whereas in Sebastian syndrome, the leukocyte inclusions
are composed of highly dispersed filaments and few ribosomes. Seri et
al. (2003) suggested that these 4 disorders, May-Hegglin, Fechtner,
Sebastian, and Epstein syndromes, are not distinct entities, but rather
represent a single disorder with a continuous clinical spectrum, for
which they proposed the term 'MYH9-related disease.'
CLINICAL FEATURES
May (1909) described inclusion bodies in granulocytes from the
peripheral blood of an asymptomatic 24-year-old woman. Hegglin (1945)
observed the triad of thrombocytopenia, giant platelets, and inclusion
bodies in the leukocytes in 2 generations of a family. The leukocyte
inclusions consisted of cytoplasmic RNA-containing inclusions, so-called
Dohle bodies, which can also be seen transiently during acute
infections.
Oski et al. (1962) observed the anomaly in a mother and her 2 children.
Of 24 reported cases, 9 had thrombocytopenia. On the basis of electron
microscopic studies, Jenis et al. (1971) suggested that the inclusions
represented paracrystalline arrays of depolymerized ribosomes.
Jenis et al. (1971) suggested a hypothetical model for the development
of the May-Hegglin inclusion based on ultrastructural studies of marrow
precursors containing the inclusions. They suggested that the filaments
represent completely unfolded, i.e., depolymerized, ribosomes. Similar
basophilic inclusions occurred in the Fechtner syndrome.
Fujita et al. (1990) described the May-Hegglin anomaly in a 39-year-old
male and his son and daughter. All 3 also had spastic paraplegia, which
began in the offspring at about age 12 and in the father at about age
20. Renal function was normal.
In a patient with end-stage renal failure being prepared for renal
transplant and in his healthy brother, Nel et al. (1992) found the
May-Hegglin anomaly. They concluded that there was no relation to the
renal failure. Almost all neutrophils contained at least one inclusion
body. These bodies were larger than toxic Dohle bodies found in
septicemia, stained better, and were not accompanied by toxic
granulation in the cytoplasm. Most of the inclusions were spindle shaped
and occurred in any location in the cell cytoplasm as compared with the
smaller, more irregular or rounded Dohle bodies, which tended to have a
peripheral location in the cell. On electron microscopy, the bodies were
shown to have parallel filaments oriented in the long axis of the
inclusion.
Greinacher et al. (1992) described 2 families with May-Hegglin anomaly,
one with 4 and the other with 3 affected persons. Platelet counts were
markedly reduced and were correctly determined only in the counting
chamber. Bleeding time and platelet aggregation were normal, but
platelet nucleotide concentrations (ATP and ADP) were elevated. Giant
platelets and spindle-shaped inclusion bodies were found in the
granulocytes, which functioned normally. Both families were ascertained
through a child who was found to have thrombocytopenia during acute
infection. Misdiagnosis in such cases can lead to mismanagement,
including the use of dangerous therapy.
- Clinical Variability
Seri et al. (2003) found sensorineural hearing loss for high tones in 9
(82%) of 11 patients initially diagnosed as having May-Hegglin anomaly
or Sebastian syndrome. Three patients with May-Hegglin anomaly or
Sebastian syndrome were found to have cataracts. In addition,
microscopic hematuria or proteinuria was found in 4 patients with
May-Hegglin anomaly and 2 with Sebastian syndrome. These findings
emphasized the phenotypic overlap among MYH9-related disorders.
MAPPING
In a Japanese family with May-Hegglin anomaly, Kunishima et al. (1999)
performed a genomewide linkage study using highly polymorphic short
tandem repeat markers. Linkage was found with chromosome 22q12.3-q13.2,
with a maximum 2-point lod score of 4.52 at a recombination fraction of
0.00 for markers D22S1142 and D22S277. Haplotype analysis mapped a
critical region for the disease locus to a 13.6-cM region, between
D22S280 and D22S272. The relative proximity of the GP1BB gene (138720)
on 22q11.2, as well as its involvement in autosomal dominant isolated
giant platelet disease (see BSS: 231200) (Kunishima et al., 1997),
suggested a possible involvement of GP1BB in MHA. However, sequence
analysis in 2 patients showed no abnormality in the GP1BB gene.
Martignetti et al. (2000) confirmed the assignment of the MHA locus to
22q12.3-q13.1, and determined that the physical size of the MHA region
is 0.7 Mb.
In a genomewide linkage screen in 3 families with MHA, Kelley et al.
(2000) found a maximum lod score of 3.91 at a recombination fraction of
0.076 for marker D22S683. Within the largest family, the maximum lod
score was 5.36 at theta = 0.00 at marker D22S445. Fine mapping of
recombination events using 8 adjacent markers indicated that the minimal
disease region in this largest family alone is in a region of
approximately 26 cM from D22S683 to the telomere. The maximum lod score
for the 3 families combined was 5.84 at theta = 0.00 for marker IL2RB
(146710), which maps to 22q11.2-q13.
MOLECULAR GENETICS
The May-Hegglin/Fechtner Syndrome Consortium (2000) identified 6 MYH9
mutations in 7 unrelated probands with one or another of the 3 autosomal
dominant giant platelet disorders: May-Hegglin anomaly, Fechtner
syndrome, and Sebastian syndrome. Kelley et al. (2000) likewise
identified mutations in the MYH9 gene in patients with May-Hegglin
anomaly. In 5 of 10 families, they found an E1841K mutation
(160775.0002) that the May-Hegglin/Fechtner Syndrome Consortium (2000)
found in 2 families. In 4 of 10 families, they found an R1922X mutation
(160775.0001) that the May-Hegglin/Fechtner Syndrome Consortium (2000)
found in 1 family. In the remaining family of the 10 studied, they found
a T1155I mutation (160775.0007).
*FIELD* SA
Cabrera et al. (1981); Godwin and Ginsburg (1974); Jordan and Larsen
(1965)
*FIELD* RF
1. Cabrera, J. R.; Fontan, G.; Lorente, F.; Regidor, C.; Fernandez,
M. N.: Defective neutrophil mobility in the May-Hegglin anomaly. Brit.
J. Haemat. 47: 337-343, 1981.
2. Fujita, Y.; Fujii, T.; Nishio, A.; Tuboi, K.; Tsuji, K.; Nakamura,
M.: Familial case of May-Hegglin anomaly associated with familial
spastic paraplegia. Am. J. Hemat. 35: 219-221, 1990.
3. Godwin, H. A.; Ginsburg, A. D.: May-Hegglin anomaly: a defect
in megakaryocyte. Brit. J. Haemat. 26: 117-128, 1974.
4. Greinacher, A.; Bux, J.; Kiefel, V.; White, J. G.; Mueller-Eckhardt,
C.: May-Hegglin anomaly: a rare cause of thrombocytopenia. Europ.
J. Pediat. 151: 668-671, 1992.
5. Hegglin, R.: Gleichzeitige konstitutionelle Veranderungen an Neutrophilen
und Thrombocyten. Helv. Med. Acta 12: 439-440, 1945.
6. Jenis, E. H.; Takeuchi, A.; Dillon, D. E.; Ruymann, F. B.; Rivkin,
S.: The May-Hegglin anomaly: ultrastructure of the granulocyte inclusion. Am.
J. Clin. Path. 55: 187-196, 1971.
7. Jordan, S. W.; Larsen, W. E.: Ultrastructural studies of the May-Hegglin
anomaly. Blood 25: 921-932, 1965.
8. Kelley, M. J.; Jawien, W.; Lin, A.; Hoffmeister, K.; Pugh, E. W.;
Doheny, K. F.; Korczak, J. F.: Autosomal dominant macrothrombocytopenia
with leukocyte inclusions (May-Hegglin anomaly) is linked to chromosome
22q12-13. Hum. Genet. 106: 557-564, 2000.
9. Kelley, M. J.; Jawien, W.; Ortel, T. L.; Korczak, J. F.: Mutation
of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin
anomaly. Nature Genet. 26: 106-108, 2000.
10. Kunishima, S.; Kojima, T.; Tanaka, T.; Kamiya, T.; Ozawa, K.;
Nakamura, Y.; Saito, H.: Mapping of a gene for May-Hegglin anomaly
to chromosome 22q. Hum. Genet. 105: 379-383, 1999.
11. Kunishima, S.; Lopez, J. A.; Kobayashi, S.; Imai, N.; Kamiya,
T.; Saito, H.; Naoe, T.: Missense mutations of the glycoprotein (GP)
Ib-beta gene impairing the GPIb alpha/beta disulfide linkage in a
family with giant platelet disorder. Blood 89: 2404-2412, 1997.
12. Martignetti, J. A.; Heath, K. E.; Harris, J.; Bizzaro, N.; Savoia,
A.; Balduini, C. L.; Desnick, R. J.: The gene for May-Hegglin anomaly
localizes to a less than 1-Mb region on chromosome 22q12.3-13.1. Am.
J. Hum. Genet. 66: 1449-1454, 2000.
13. May, R.: Leukozyteneinschlusse. Dtsch. Arch. Klin. Med. 96:
1-6, 1909.
14. May-Hegglin/Fechtner Syndrome Consortium: Mutations in MYH9
result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. Nature
Genet. 26: 103-105, 2000.
15. Nel, N.; van Rensburg, B. W. J.; du Plessis, L.; Potgieter, C.
D.; Stevens, K.: Coincidental finding of May-Hegglin anomaly in a
patient with end-stage renal failure. Am. J. Hemat. 40: 216-221,
1992.
16. Oski, F. A.; Naiman, J. L.; Allen, D. M.; Diamond, L. K.: Leukocytic
inclusions--Dohle bodies--associated with platelet abnormality (the
May-Hegglin anomaly): report of a family and review of the literature. Blood 20:
657-667, 1962.
17. Seri, M.; Pecci, A.; Di Bari, F.; Cusano, R.; Savino, M.; Panza,
E.; Nigro, A.; Noris, P.; Gangarossa, S.; Rocca, B.; Gresele, P.;
Bizzaro, N.; and 13 others: MYH9-related disease: May-Hegglin anomaly,
Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not
distinct entities but represent a variable expression of a single
illness. Medicine 82: 203-215, 2003.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Myocardial infarction (secondary to coronary artery thrombosis)
GENITOURINARY:
[Kidneys];
No kidney disease
HEMATOLOGY:
Mild-significant bleeding episodes (epistaxis, easy bruisability,
postoperative hemorrhage, menorrhagia);
Thrombocytopenia;
Giant platelets;
Sky-blue leukocyte inclusion bodies (Dohle-like bodies) that contain
clusters of ribosomes oriented along parallel microfilaments
LABORATORY ABNORMALITIES:
Thrombocytopenia, mild-moderate (60-100 x 10(9)/L);
Prolonged bleeding time;
Median mean platelet volume (MPV) 12.5fL;
Normal platelet aggregation response to epinephrine, ADP, collagen,
and ristocetin
MISCELLANEOUS:
Most common inherited giant platelet disorder
MOLECULAR BASIS:
Caused by mutation in the myosin, heavy polypeptide-9, nonmuscle gene
(MYH9, 160775.0001)
*FIELD* CN
Kelly A. Przylepa - revised: 12/24/2007
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 01/14/2008
joanna: 12/24/2007
*FIELD* CN
Cassandra L. Kniffin - updated: 9/22/2010
Victor A. McKusick - updated: 4/3/2001
Victor A. McKusick - updated: 8/29/2000
Victor A. McKusick - updated: 6/13/2000
Victor A. McKusick - updated: 4/13/2000
Victor A. McKusick - updated: 12/6/1999
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 09/12/2011
ckniffin: 9/8/2011
carol: 9/23/2010
ckniffin: 9/22/2010
carol: 3/29/2005
cwells: 11/7/2003
cwells: 4/6/2001
cwells: 4/4/2001
mcapotos: 4/3/2001
alopez: 8/31/2000
terry: 8/29/2000
mcapotos: 7/20/2000
terry: 6/13/2000
carol: 4/20/2000
terry: 4/13/2000
yemi: 2/18/2000
mgross: 12/8/1999
terry: 12/6/1999
mimadm: 11/6/1994
carol: 3/26/1993
carol: 1/28/1993
carol: 8/28/1992
supermim: 3/16/1992
carol: 1/8/1991
*RECORD*
*FIELD* NO
155100
*FIELD* TI
#155100 MAY-HEGGLIN ANOMALY; MHA
;;BLEEDING DISORDER, PLATELET-TYPE, 6; BDPLT6;;
DOHLE LEUKOCYTE INCLUSIONS WITH GIANT PLATELETS;;
read moreMACROTHROMBOCYTOPENIA WITH LEUKOCYTE INCLUSIONS
*FIELD* TX
A number sign (#) is used with this entry because the May-Hegglin
anomaly (MHA) is caused by mutation in the gene encoding nonmuscle
myosin heavy chain-9 (MYH9; 160775) on chromosome 22q11.2.
DESCRIPTION
May-Hegglin anomaly is an autosomal dominant disorder characterized by
the triad of thrombocytopenia, giant platelets, and Dohle body-like
inclusions in peripheral blood leukocytes. About 25 to 50% of affected
individuals have mild to moderate episodic bleeding (summary by Kelley
et al., 2000).
There are several other disorders caused by mutation in the MYH9 gene
that share overlapping features with May-Hegglin anomaly. Fechtner
syndrome (153640) has the platelet defect accompanied by nephritis,
hearing loss, and eye abnormalities, mostly cataracts. Epstein syndrome
(153650) has the platelet defect, deafness, and nephritis, but does not
have cataract and lacks leukocyte inclusion bodies on classic staining
of peripheral blood smears. The findings of nephritis, hearing loss, and
occasional cataracts in Fechtner and Epstein syndromes are reminiscent
of Alport syndrome (301050). Sebastian syndrome (605249) is the most
similar to May-Hegglin anomaly, but has a different ultrastructural
appearance of the leukocyte inclusions. In MHA, the inclusions are
composed of clusters of ribosomes oriented along parallel
microfilaments, whereas in Sebastian syndrome, the leukocyte inclusions
are composed of highly dispersed filaments and few ribosomes. Seri et
al. (2003) suggested that these 4 disorders, May-Hegglin, Fechtner,
Sebastian, and Epstein syndromes, are not distinct entities, but rather
represent a single disorder with a continuous clinical spectrum, for
which they proposed the term 'MYH9-related disease.'
CLINICAL FEATURES
May (1909) described inclusion bodies in granulocytes from the
peripheral blood of an asymptomatic 24-year-old woman. Hegglin (1945)
observed the triad of thrombocytopenia, giant platelets, and inclusion
bodies in the leukocytes in 2 generations of a family. The leukocyte
inclusions consisted of cytoplasmic RNA-containing inclusions, so-called
Dohle bodies, which can also be seen transiently during acute
infections.
Oski et al. (1962) observed the anomaly in a mother and her 2 children.
Of 24 reported cases, 9 had thrombocytopenia. On the basis of electron
microscopic studies, Jenis et al. (1971) suggested that the inclusions
represented paracrystalline arrays of depolymerized ribosomes.
Jenis et al. (1971) suggested a hypothetical model for the development
of the May-Hegglin inclusion based on ultrastructural studies of marrow
precursors containing the inclusions. They suggested that the filaments
represent completely unfolded, i.e., depolymerized, ribosomes. Similar
basophilic inclusions occurred in the Fechtner syndrome.
Fujita et al. (1990) described the May-Hegglin anomaly in a 39-year-old
male and his son and daughter. All 3 also had spastic paraplegia, which
began in the offspring at about age 12 and in the father at about age
20. Renal function was normal.
In a patient with end-stage renal failure being prepared for renal
transplant and in his healthy brother, Nel et al. (1992) found the
May-Hegglin anomaly. They concluded that there was no relation to the
renal failure. Almost all neutrophils contained at least one inclusion
body. These bodies were larger than toxic Dohle bodies found in
septicemia, stained better, and were not accompanied by toxic
granulation in the cytoplasm. Most of the inclusions were spindle shaped
and occurred in any location in the cell cytoplasm as compared with the
smaller, more irregular or rounded Dohle bodies, which tended to have a
peripheral location in the cell. On electron microscopy, the bodies were
shown to have parallel filaments oriented in the long axis of the
inclusion.
Greinacher et al. (1992) described 2 families with May-Hegglin anomaly,
one with 4 and the other with 3 affected persons. Platelet counts were
markedly reduced and were correctly determined only in the counting
chamber. Bleeding time and platelet aggregation were normal, but
platelet nucleotide concentrations (ATP and ADP) were elevated. Giant
platelets and spindle-shaped inclusion bodies were found in the
granulocytes, which functioned normally. Both families were ascertained
through a child who was found to have thrombocytopenia during acute
infection. Misdiagnosis in such cases can lead to mismanagement,
including the use of dangerous therapy.
- Clinical Variability
Seri et al. (2003) found sensorineural hearing loss for high tones in 9
(82%) of 11 patients initially diagnosed as having May-Hegglin anomaly
or Sebastian syndrome. Three patients with May-Hegglin anomaly or
Sebastian syndrome were found to have cataracts. In addition,
microscopic hematuria or proteinuria was found in 4 patients with
May-Hegglin anomaly and 2 with Sebastian syndrome. These findings
emphasized the phenotypic overlap among MYH9-related disorders.
MAPPING
In a Japanese family with May-Hegglin anomaly, Kunishima et al. (1999)
performed a genomewide linkage study using highly polymorphic short
tandem repeat markers. Linkage was found with chromosome 22q12.3-q13.2,
with a maximum 2-point lod score of 4.52 at a recombination fraction of
0.00 for markers D22S1142 and D22S277. Haplotype analysis mapped a
critical region for the disease locus to a 13.6-cM region, between
D22S280 and D22S272. The relative proximity of the GP1BB gene (138720)
on 22q11.2, as well as its involvement in autosomal dominant isolated
giant platelet disease (see BSS: 231200) (Kunishima et al., 1997),
suggested a possible involvement of GP1BB in MHA. However, sequence
analysis in 2 patients showed no abnormality in the GP1BB gene.
Martignetti et al. (2000) confirmed the assignment of the MHA locus to
22q12.3-q13.1, and determined that the physical size of the MHA region
is 0.7 Mb.
In a genomewide linkage screen in 3 families with MHA, Kelley et al.
(2000) found a maximum lod score of 3.91 at a recombination fraction of
0.076 for marker D22S683. Within the largest family, the maximum lod
score was 5.36 at theta = 0.00 at marker D22S445. Fine mapping of
recombination events using 8 adjacent markers indicated that the minimal
disease region in this largest family alone is in a region of
approximately 26 cM from D22S683 to the telomere. The maximum lod score
for the 3 families combined was 5.84 at theta = 0.00 for marker IL2RB
(146710), which maps to 22q11.2-q13.
MOLECULAR GENETICS
The May-Hegglin/Fechtner Syndrome Consortium (2000) identified 6 MYH9
mutations in 7 unrelated probands with one or another of the 3 autosomal
dominant giant platelet disorders: May-Hegglin anomaly, Fechtner
syndrome, and Sebastian syndrome. Kelley et al. (2000) likewise
identified mutations in the MYH9 gene in patients with May-Hegglin
anomaly. In 5 of 10 families, they found an E1841K mutation
(160775.0002) that the May-Hegglin/Fechtner Syndrome Consortium (2000)
found in 2 families. In 4 of 10 families, they found an R1922X mutation
(160775.0001) that the May-Hegglin/Fechtner Syndrome Consortium (2000)
found in 1 family. In the remaining family of the 10 studied, they found
a T1155I mutation (160775.0007).
*FIELD* SA
Cabrera et al. (1981); Godwin and Ginsburg (1974); Jordan and Larsen
(1965)
*FIELD* RF
1. Cabrera, J. R.; Fontan, G.; Lorente, F.; Regidor, C.; Fernandez,
M. N.: Defective neutrophil mobility in the May-Hegglin anomaly. Brit.
J. Haemat. 47: 337-343, 1981.
2. Fujita, Y.; Fujii, T.; Nishio, A.; Tuboi, K.; Tsuji, K.; Nakamura,
M.: Familial case of May-Hegglin anomaly associated with familial
spastic paraplegia. Am. J. Hemat. 35: 219-221, 1990.
3. Godwin, H. A.; Ginsburg, A. D.: May-Hegglin anomaly: a defect
in megakaryocyte. Brit. J. Haemat. 26: 117-128, 1974.
4. Greinacher, A.; Bux, J.; Kiefel, V.; White, J. G.; Mueller-Eckhardt,
C.: May-Hegglin anomaly: a rare cause of thrombocytopenia. Europ.
J. Pediat. 151: 668-671, 1992.
5. Hegglin, R.: Gleichzeitige konstitutionelle Veranderungen an Neutrophilen
und Thrombocyten. Helv. Med. Acta 12: 439-440, 1945.
6. Jenis, E. H.; Takeuchi, A.; Dillon, D. E.; Ruymann, F. B.; Rivkin,
S.: The May-Hegglin anomaly: ultrastructure of the granulocyte inclusion. Am.
J. Clin. Path. 55: 187-196, 1971.
7. Jordan, S. W.; Larsen, W. E.: Ultrastructural studies of the May-Hegglin
anomaly. Blood 25: 921-932, 1965.
8. Kelley, M. J.; Jawien, W.; Lin, A.; Hoffmeister, K.; Pugh, E. W.;
Doheny, K. F.; Korczak, J. F.: Autosomal dominant macrothrombocytopenia
with leukocyte inclusions (May-Hegglin anomaly) is linked to chromosome
22q12-13. Hum. Genet. 106: 557-564, 2000.
9. Kelley, M. J.; Jawien, W.; Ortel, T. L.; Korczak, J. F.: Mutation
of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin
anomaly. Nature Genet. 26: 106-108, 2000.
10. Kunishima, S.; Kojima, T.; Tanaka, T.; Kamiya, T.; Ozawa, K.;
Nakamura, Y.; Saito, H.: Mapping of a gene for May-Hegglin anomaly
to chromosome 22q. Hum. Genet. 105: 379-383, 1999.
11. Kunishima, S.; Lopez, J. A.; Kobayashi, S.; Imai, N.; Kamiya,
T.; Saito, H.; Naoe, T.: Missense mutations of the glycoprotein (GP)
Ib-beta gene impairing the GPIb alpha/beta disulfide linkage in a
family with giant platelet disorder. Blood 89: 2404-2412, 1997.
12. Martignetti, J. A.; Heath, K. E.; Harris, J.; Bizzaro, N.; Savoia,
A.; Balduini, C. L.; Desnick, R. J.: The gene for May-Hegglin anomaly
localizes to a less than 1-Mb region on chromosome 22q12.3-13.1. Am.
J. Hum. Genet. 66: 1449-1454, 2000.
13. May, R.: Leukozyteneinschlusse. Dtsch. Arch. Klin. Med. 96:
1-6, 1909.
14. May-Hegglin/Fechtner Syndrome Consortium: Mutations in MYH9
result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. Nature
Genet. 26: 103-105, 2000.
15. Nel, N.; van Rensburg, B. W. J.; du Plessis, L.; Potgieter, C.
D.; Stevens, K.: Coincidental finding of May-Hegglin anomaly in a
patient with end-stage renal failure. Am. J. Hemat. 40: 216-221,
1992.
16. Oski, F. A.; Naiman, J. L.; Allen, D. M.; Diamond, L. K.: Leukocytic
inclusions--Dohle bodies--associated with platelet abnormality (the
May-Hegglin anomaly): report of a family and review of the literature. Blood 20:
657-667, 1962.
17. Seri, M.; Pecci, A.; Di Bari, F.; Cusano, R.; Savino, M.; Panza,
E.; Nigro, A.; Noris, P.; Gangarossa, S.; Rocca, B.; Gresele, P.;
Bizzaro, N.; and 13 others: MYH9-related disease: May-Hegglin anomaly,
Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not
distinct entities but represent a variable expression of a single
illness. Medicine 82: 203-215, 2003.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Myocardial infarction (secondary to coronary artery thrombosis)
GENITOURINARY:
[Kidneys];
No kidney disease
HEMATOLOGY:
Mild-significant bleeding episodes (epistaxis, easy bruisability,
postoperative hemorrhage, menorrhagia);
Thrombocytopenia;
Giant platelets;
Sky-blue leukocyte inclusion bodies (Dohle-like bodies) that contain
clusters of ribosomes oriented along parallel microfilaments
LABORATORY ABNORMALITIES:
Thrombocytopenia, mild-moderate (60-100 x 10(9)/L);
Prolonged bleeding time;
Median mean platelet volume (MPV) 12.5fL;
Normal platelet aggregation response to epinephrine, ADP, collagen,
and ristocetin
MISCELLANEOUS:
Most common inherited giant platelet disorder
MOLECULAR BASIS:
Caused by mutation in the myosin, heavy polypeptide-9, nonmuscle gene
(MYH9, 160775.0001)
*FIELD* CN
Kelly A. Przylepa - revised: 12/24/2007
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 01/14/2008
joanna: 12/24/2007
*FIELD* CN
Cassandra L. Kniffin - updated: 9/22/2010
Victor A. McKusick - updated: 4/3/2001
Victor A. McKusick - updated: 8/29/2000
Victor A. McKusick - updated: 6/13/2000
Victor A. McKusick - updated: 4/13/2000
Victor A. McKusick - updated: 12/6/1999
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 09/12/2011
ckniffin: 9/8/2011
carol: 9/23/2010
ckniffin: 9/22/2010
carol: 3/29/2005
cwells: 11/7/2003
cwells: 4/6/2001
cwells: 4/4/2001
mcapotos: 4/3/2001
alopez: 8/31/2000
terry: 8/29/2000
mcapotos: 7/20/2000
terry: 6/13/2000
carol: 4/20/2000
terry: 4/13/2000
yemi: 2/18/2000
mgross: 12/8/1999
terry: 12/6/1999
mimadm: 11/6/1994
carol: 3/26/1993
carol: 1/28/1993
carol: 8/28/1992
supermim: 3/16/1992
carol: 1/8/1991
MIM
160775
*RECORD*
*FIELD* NO
160775
*FIELD* TI
*160775 MYOSIN, HEAVY CHAIN 9, NONMUSCLE; MYH9
;;CELLULAR MYOSIN HEAVY CHAIN, TYPE A;;
read moreMYOSIN, HEAVY CHAIN, NONMUSCLE, TYPE A; NMMHCA;;
NONMUSCLE MYOSIN IIA;;
NMHC IIA
*FIELD* TX
CLONING
Saez et al. (1990) provided a molecular genetic characterization of a
human nonmuscle myosin heavy chain expressed in fibroblasts, endothelial
cells, and macrophages. The deduced 1,247-amino acid was weakly
homologous (33%) to sarcomeric MHC, but about 72% identical to smooth
muscle MHC. In contrast to vertebrate sarcomeric MHCs, which generate
diversity through the expression of members of a multigene family, an
alternative polyadenylation site is used in the nonmuscle MHC gene to
generate multiple transcripts that encode the same protein.
D'Apolito et al. (2002) cloned mouse Myh9. The deduced 1,960-amino acid
protein shares 98% identity with human MYH9. Northern blot analysis
detected abundant Myh9 expression in mouse liver, spleen, lung, and
kidney, but not in skeletal muscle or testis.
GENE FUNCTION
Toothaker et al. (1991) observed that antisera raised against the
peptide made from the predicted amino acid sequence specifically reacted
with a 224-kD polypeptide in leukocyte cell lines, and the protein was
upregulated during the induction of monocytic and granulocytic
differentiation in these cells. The cellular myosin heavy chain may be
the major contractile protein responsible for movement in myeloid cell
lines because no mRNA for sarcomeric myosin heavy chains is detected in
these cells.
By screening mouse T-cell cDNA for myosin family members, followed by
Western blot analysis, Jacobelli et al. (2004) found that Myh9 was the
only class II nonmuscle myosin readily and highly detectable. Time-lapse
fluorescence microscopy demonstrated that, during T-cell crawling, Myh9
expression was enriched in the uropod. After encounter with antigen on
antigen-presenting cells (APCs), Myh9 redistributed to the T-cell-APC
interface upon formation of the immunologic synapse. Further imaging and
siRNA analysis showed that Myh9 was required for T-cell uropodal
morphology, but not for synapse formation. TCR-induced phosphorylation
of Myh9 in its multimerization domain indicated that inactivation of the
myosin motor may be a key step in the T-cell 'stop' response during
antigen recognition.
Chung and Kawamoto (2004) identified an intronic region that they
designated 32kb-150, located 32 kb downstream of the transcription start
sites in the human NMHCA gene, as a transcriptional regulatory region.
Among IRF proteins tested, only IRF2 (147576) bound to the
interferon-stimulated response element (ISRE) within 32kb-150 in vitro
and in HeLa cells and mouse fibroblasts. IRF2 acted as a transcriptional
activator in a reporter gene assay. The phorbol ester TPA, which
triggers differentiation of human promyelocytic HL-60 cells into
macrophages, upregulated expression of both NMHCA and IRF2. Chung and
Kawamoto (2004) concluded that IRF2 contributes to transcriptional
activation of the NMHCA gene via 32kb-150 during TPA-induced
differentiation of HL-60 cells.
Wilson et al. (2010) showed that nonmuscle myosin II has a direct role
in actin network disassembly in crawling cells. In fish keratocytes
undergoing motility, myosin II is concentrated in regions at the rear
with high rates of network disassembly. Activation of myosin II by ATP
in detergent-extracted cytoskeletons resulted in rear-localized
disassembly of the actin network. Inhibition of myosin II activity and
stabilization of actin filaments synergistically impeded cell motility,
suggesting the existence of 2 disassembly pathways, one of which
requires myosin II activity. Wilson et al. (2010) concluded that their
results established the importance of myosin II as an enzyme for actin
network disassembly, and proposed that gradual formation and
reorganization of an actomyosin network provides an intrinsic
destruction timer, enabling long-range coordination of actin network
treadmilling in motile cells.
Arii et al. (2010) showed that nonmuscle myosin heavy chain IIA
(NMHC-IIA), a subunit of nonmuscle myosin IIA (NM-IIA), functions as a
herpes simplex virus-1 (HSV-1) entry receptor by interacting with
glycoprotein B. A cell line that is relatively resistant to HSV-1
infection became highly susceptible to infection by this virus when
NMHC-IIA was overexpressed. Antibody to NMHC-IIA blocked HSV-1 infection
in naturally permissive target cells. Furthermore, knockdown of NMHC-IIA
in the permissive cells inhibited HSV-1 infection as well as cell-cell
fusion when glycoproteins B, D, H, and L were coexpressed. Cell surface
expression of NMHC-IIA was markedly and rapidly induced during the
initiation of HSV-1 entry. NMHC-IIA is ubiquitously expressed in various
human tissues and cell types and, therefore, is implicated as a
functional glycoprotein B receptor that mediates broad HSV-1 infectivity
both in vitro and in vivo.
Using immunofluorescence microscopy, Western blot analysis, and
knockdown strategies with human lung fibroblasts, Hanisch et al. (2011)
showed that Salmonella entered nonphagocytic cells by manipulating 2
machineries of actin-based motility in the host: actin polymerization
through the ARP2/3 complex (604221), and actomyosin-mediated
contractility in a myosin IIA- and myosin IIB-dependent manner. Hanisch
et al. (2011) concluded that Salmonella entry can be effected
independently of membrane ruffling.
GENE STRUCTURE
D'Apolito et al. (2002) determined that the mouse Myh9 gene, like human
MYH9, contains 41 exons.
MAPPING
By Southern analysis of a panel of human-mouse somatic cell hybrids,
Saez et al. (1990) demonstrated that the nonmuscle MHC gene is located
on chromosome 22 and is therefore unlinked to the 2 sarcomeric MHC
clusters on chromosomes 14 and 17. A cell line containing a
translocation involving chromosome 22 allowed a regional assignment to
22pter-q13. Toothaker et al. (1991) mapped the gene to 22q12.3-q13.1 by
Southern analysis of human/rodent somatic cell hybrids and by in situ
hybridization. Simons et al. (1991) likewise mapped a nonmuscle myosin
heavy chain gene, which they designated NMMHCA, to 22q11.2. A second
nonmuscle myosin heavy chain, which they designated NMMHC-B (160776),
was found to be encoded by a gene on 17q13. Both were 7.5 kb long. In
the amino-terminal one-third (amino acids 58-718), they were 89%
identical at the amino acid level and 74% identical at the nucleotide
level. Muscle myosin heavy chain genes are located on 17p.
D'Apolito et al. (2002) mapped the mouse Myh9 gene to a region of
chromosome 15 that shares homology of synteny with human chromosome
22q12.3-q13.1.
- Association with Kidney Disease in African Americans
In independent genomewide admixture scans to map susceptibility loci for
kidney disease in African Americans, Kopp et al. (2008) and Kao et al.
(2008) identified variation at the MYH9 locus as a major factor for the
increased risk of nondiabetic kidney disease in this population (FSGS4;
612551).
MOLECULAR GENETICS
The autosomal dominant giant-platelet disorders May-Hegglin anomaly
(155100), Fechtner syndrome (153640), and Sebastian syndrome (605249)
share the triad of thrombocytopenia, large platelets, and characteristic
leukocyte inclusions called Dohle-like bodies. May-Hegglin anomaly and
Sebastian syndrome can be differentiated by subtle ultrastructural
leukocyte inclusion features, whereas Fechtner syndrome is distinguished
by the additional clinical features of sensorineural deafness,
cataracts, and nephritis resembling Alport syndrome (see 104200). The
similarities between these platelet disorders and refinement of the
disease loci for May-Hegglin anomaly and Fechtner syndrome to an
overlapping region of 480 kb on chromosome 22 suggested that all 3
disorders may be allelic. Among the identified candidate genes was MYH9,
which is expressed in platelets and upregulated during granulocyte
differentiation. The May-Hegglin/Fechtner Syndrome Consortium (2000)
identified 6 MYH9 mutations (1 nonsense and 5 missense) in 7 unrelated
probands from families with these 3 disorders. On the basis of molecular
modeling, 2 mutations affecting the myosin head were predicted to impose
electrostatic and conformational changes, whereas the truncating
mutation deleted the unique carboxy-terminal tailpiece. The remaining
missense mutations, all affecting highly conserved coiled-coil domain
positions, imparted destabilizing electrostatic and polar changes. Thus,
the findings demonstrated that mutations in MYH9 result in 3
phenotypically distinct megakaryocyte/platelet/leukocyte syndromes and
are important in the pathogenesis of sensorineural deafness, cataracts,
and nephritis.
Kelley et al. (2000) also screened MYH9 as a candidate gene for
mutations in 10 families with May-Hegglin anomaly. In each family, they
identified 1 of 3 sequence variants within either the alpha-helical
coiled-coil or the tailpiece domain that cosegregated with disease
status.
Kunishima et al. (2001) found mutations in NMMHCA in 6 of 7 Japanese
families with macrothrombocytopenia with leukocyte inclusions: 3
missense mutations, 1 nonsense mutation, and a 1-bp deletion resulting
in a premature termination. Immunofluorescence studies showed that
NMMHCA distribution in neutrophils mimics the inclusion bodies. These
results provided evidence for the involvement of an abnormal form of
NMMHCA in the creation of leukocyte inclusions and also in platelet
morphogenesis.
The May-Hegglin/Fechtner Syndrome Consortium (2000) speculated that
mutations in MYH9 may also have a role in 2 other autosomal dominant
disorders: a form of nonsyndromic deafness characterized by progressive
hearing impairment and cochleosaccular degeneration (DFNA17; 603622) and
Epstein syndrome (153650). Epstein syndrome is clinically identical to
FTNS, although Dohle-like bodies had not been described.
Lalwani et al. (2000) demonstrated a missense mutation (160775.0008) in
the MYH9 gene in affected members of a kindred with DFNA17.
Heath et al. (2001) examined the spectrum of mutations and the
genotype/phenotype and structure-function relationships in a large
cohort (n = 27) of individuals with May-Hegglin anomaly, Fechtner
syndrome (some cases of which were called Alport-like syndrome with
macrothrombocytopenia), or Sebastian syndrome. They demonstrated that
MYH9 mutations also result in Epstein syndrome.
Heath et al. (2001) found that R702C (160775.0006) and R702H
(160775.0009) mutations were associated only with Fechtner syndrome
(some cases designated as Alport-like syndrome with
macrothrombocytopenia) or Epstein syndrome, thus defining a region of
the MYHIIA protein critical in the combined pathogenesis of
macrothrombocytopenia, nephritis, and deafness.
In the proband of the family with macrothrombocytopenia and progressive
sensorineural deafness (600208) reported by Brodie et al. (1992), Mhatre
et al. (2003) identified a missense mutation in the MYH9 gene
(160775.0010). The same mutation had been reported in patients with
May-Hegglin anomaly, Fechtner syndrome, and Sebastian syndrome.
To elucidate the spectrum of MYH9 mutations responsible for the group of
disorders under the general designation autosomal dominant
macrothrombocytopenia with leukocyte inclusions, Kunishima et al. (2001)
examined the MYH9 gene in an additional 11 families and 3 sporadic
patients with the disorders from Japan, Korea, and China. All 14
patients had heterozygous MYH9 mutations, including 3 known mutations:
R1933X (160775.0001), R1165C (160775.0003), and E1841K (160775.0002).
Six novel mutations (3 missense and 3 deletion) were also found. Two
patients had Alport manifestations including deafness, nephritis, and
cataract and had R1165C and E1841K mutations, respectively. However,
taken together with 3 previous reports, the data did not show clear
phenotype-genotype relationships.
Hu et al. (2002) noted that 2 disease-causing mutations, N93K
(160775.0004) and R702C (160775.0006), lie within close proximity in the
3-dimensional structure of the head domain of MYH9. They coexpressed
recombinant fragments of MYH9 along with the appropriate light chains to
create 2-headed meromyosin-like molecules bearing these mutations. The
R702C mutant displayed 25% of the maximal MgATPase activity of wildtype
heavy meromyosin and moved actin filaments at half the wildtype rate in
an in vitro motility assay. Heavy meromyosin containing the N93K
mutation had only 4% of the maximal MgATPase activity and did not
translocate actin filaments. The characteristics of this mutation were
consistent with an inability to fully adopt the 'on' conformation. The
N93K mutation was also associated with a tendency for the myosin to
aggregate, which may explain the leukocyte inclusions associated with
this mutation in humans.
Kunishima et al. (2005) identified a mutation (160775.0011) in a
1-year-old boy with May-Hegglin anomaly resulting from somatic mosaicism
in the father.
Based on an analysis of 19 families with MYH9 mutations, Seri et al.
(2003) suggested that 4 disorders, May-Hegglin, Fechtner, Sebastian, and
Epstein syndromes, are not distinct entities, but rather represent a
single disorder with a continuous clinical spectrum, for which they
proposed the term 'MYH9-related disease.' However, other disorders,
e.g., macrothrombocytopenia and progressive sensorineural deafness and
DFNA17, are also caused by mutation in the MYH9 gene.
By immunofluorescence analysis using a polyclonal antibody against human
platelet MYH9, Kunishima et al. (2003) detected abnormal subcellular
localization of MYH9 in neutrophils from all 21 patients with MYH9
mutations examined, including a patient with Epstein syndrome.
Comparison with May-Grunwald-Giemsa staining revealed that the antibody
always coexisted with the neutrophil inclusion bodies, providing proof
that MYH9 is associated with such bodies. In some cases, neutrophil
inclusions were not detected on conventional May-Grunwald-Giemsa-stained
blood smears, but immunofluorescence analysis found the abnormal MYH9
localization. Kunishima et al. (2003) proposed that the mutant MYH9
protein dimerizes with the wildtype protein to form inclusions,
consistent with a dominant-negative effect.
GENOTYPE/PHENOTYPE CORRELATIONS
Pecci et al. (2005) investigated 11 patients from 6 pedigrees with
different MYH9 mutations (see, e.g., 160775.0001-160775.0005). NMHC IIA
levels were measured in platelets and granulocytes isolated from
peripheral blood and in megakaryocytes cultured from circulating
progenitors. All patients studied had a 50% reduction of NMHC IIA
expression in platelets and megakaryocytes. In subjects with the R1933X
(160775.0001) and E1945X mutations, the whole NMHC IIA of platelets and
megakaryocytes was wildtype. No NMHC IIA inclusions were observed at any
time of megakaryocyte maturation. In granulocytes, the extent of NMHC
IIA reduction in patients with respect to control cells was
significantly greater than that measured in platelets and
megakaryocytes; wildtype protein was sequestered within most of the NMHC
IIA inclusions. Taken together these results indicate that
haploinsufficiency of NMHC IIA in megakaryocytic lineage is the
mechanism of macrothrombocytopenia consequent to MYH9 mutations, whereas
in granulocytes a dominant-negative effect of the mutant allele appeared
to be involved in the formation of inclusion bodies.
In a study of 108 patients from 50 unrelated pedigrees with MYH9
mutations, Pecci et al. (2008) found that 68% of families carried
mutations in 1 of 4 residues: 702 in the motor domain (12 families) and
residues 1424, 1841, and 1933 in the tail domain (9, 7, and 6 pedigrees,
respectively). All subjects with mutations in the motor domain of MYH9
developed severe thrombocytopenia, nephritis, and deafness before the
age of 40 years. Patients with mutations at residue 1424 or 1841 had a
much lower risk of these complications, significantly higher platelet
counts, and an intermediate clinical picture. Patients with mutations at
residue 1933 did not develop kidney damage or cataracts but did develop
deafness late in life.
ANIMAL MODEL
Matsushita et al. (2004) found that homozygous deletion of Myh9 in mice
was embryonic lethal. In contrast, Myh9 +/- mice were viable and fertile
without gross anatomic, hematologic, or nephrologic abnormalities.
However, auditory brainstem responses indicated that 2 of 6 Myh9 +/-
mice had hearing loss. Parker et al. (2006) also found that homozygous
mutations in Myh9 are embryonic lethal in mice. In contrast to the
findings of Matsushita et al. (2004), Parker et al. (2006) did not
observe hearing loss in Myh9 heterozygous adult mice, despite
haploinsufficiency for Myh9 in the mutant mouse inner ear. In addition,
aged Myh9 heterozygous mice did not show signs of cochleosaccular
degeneration common in DFNA17. Parker et al. (2006) used a public
gene-targeted embryonic stem cell bank resource to generate the mice.
*FIELD* AV
.0001
MAY-HEGGLIN ANOMALY
FECHTNER SYNDROME, INCLUDED;;
SEBASTIAN SYNDROME, INCLUDED
MYH9, ARG1933TER
In a family used in linkage studies to define the May-Hegglin anomaly
(155100) critical region on chromosome 22 (Martignetti et al., 2000),
the May-Hegglin/Fechtner Syndrome Consortium (2000) found that affected
individuals had a nonsense mutation in codon 1933 of the MYH9 gene,
predicting the replacement of an arginine by a stop codon (arg1933 to
ter; R1933X) and deletion of the last 28 amino acids.
Kelley et al. (2000) found the arg1933-to-ter mutation in 4 of 10
families they studied. It was caused by a 5797C-T transition in exon 40.
Heath et al. (2001) identified a heterozygous R1933X mutation in
affected members of a family described as having Fechtner syndrome
(153640), although deafness and cataract were not present. Another
family with the R1933X mutation was described as having May-Hegglin
anomaly and Sebastian syndrome (605249).
.0002
MAY-HEGGLIN ANOMALY
FECHTNER SYNDROME, INCLUDED
MYH9, GLU1841LYS
In 2 unrelated families with May-Hegglin anomaly (155100), the
May-Hegglin/Fechtner Syndrome Consortium (2000) found that affected
individuals had the same missense mutation, glu1841 to lys (E1841K),
within the coiled-coil domain of the MYH9 protein. The missense mutation
was caused by a G-to-A transition at nucleotide 5521 in exon 38. Neither
family history nor haplotype analysis suggested common ancestry.
Kelley et al. (2000) found the E1841K mutation in 5 of 10 families
studied and commented that it occurs at a conserved site in the rod
domain.
Heath et al. (2001) identified a heterozygous E1841K mutation in 2
unrelated families with Fechtner syndrome (153640). One of the families
had been reported by Rocca et al. (1993).
.0003
SEBASTIAN SYNDROME
MYH9, ARG1165CYS
In a family with Sebastian syndrome (605249), the May-Hegglin/Fechtner
Syndrome Consortium (2000) found that affected individuals had a
missense mutation in codon 1165 (arg1165 to cys; R1165C) of the MYH9
gene, caused by a C-to-T transition at nucleotide 3493.
.0004
MAY-HEGGLIN ANOMALY
MYH9, ASN93LYS
In a family with May-Hegglin anomaly (155100), the May-Hegglin/Fechtner
Syndrome Consortium (2000) found that the proband had a missense
mutation, asn93 to lys (N93K), within the globular head domain of the
MYH9 gene. The mutation resulted from a C-to-G transversion at
nucleotide 279.
.0005
FECHTNER SYNDROME
MYH9, ASP1424HIS
In a family with Fechtner syndrome (153640) that had been used to define
the critical FTNS mapping region (Cusano et al., 2000), the
May-Hegglin/Fechtner Syndrome Consortium (2000) found that all affected
individuals had a missense mutation in codon 1424 (asp1424 to his;
D1424H) within the coiled-coil domain of the MYH9 protein. The mutation
resulted from a G-to-C transversion at nucleotide 4270.
.0006
FECHTNER SYNDROME
EPSTEIN SYNDROME, INCLUDED;;
SEBASTIAN SYNDROME, INCLUDED;;
MAY-HEGGLIN ANOMALY, INCLUDED
MYH9, ARG702CYS
The May-Hegglin/Fechtner Syndrome Consortium (2000) found that a
sporadic case of Fechtner syndrome (153640) (Moxey-Mims et al., 1999)
had a missense mutation in codon 702 (arg702 to cys; R702C) of the MYH9
protein, altering the globular head domain. The mutation, which resulted
from a C-to-T transition at nucleotide 2104, was not present in either
ascertained parent.
In the original family with Epstein syndrome (153650), family F,
described by Epstein et al. (1972), Heath et al. (2001) found a
transition in exon 16 of the MYH9 gene converting codon 702 from CGT
(arg) to TGT (cys). Heath et al. (2001) found that the R702C mutation
was one of the most frequent, being found in 6 of the 20 families in
which they identified a specific mutation. All of the families
represented Fechtner syndrome. There was no mention of leukocyte
inclusions in the original work-up of this family. For logistic reasons
it had been impossible more recently to get a blood sample for checking
(Epstein, 2002).
Seri et al. (2003) identified a heterozygous R702C mutation in a patient
with sporadic Fechtner syndrome, 2 unrelated patients with sporadic
Epstein syndrome, a patient with sporadic May-Hegglin anomaly (155100),
and in affected members of a family with May-Hegglin anomaly and
Sebastian syndrome (605249). Seri et al. (2003) concluded that these
disorders are not distinct entities, but rather represent a single
disease with a continuous clinical spectrum. The common abnormality is
macrothrombocytopenia and abnormal distribution of MYH9 within
leukocytes, even in those without classic Dohle bodies.
.0007
MAY-HEGGLIN ANOMALY
FECHTNER SYNDROME, INCLUDED
MYH9, THR1155ILE
Kelley et al. (2000) observed a family in which mother and daughter had
May-Hegglin anomaly (155100) caused by a thr1155-to-ile (T1155I)
mutation in the MYH9 gene resulting from a C-to-T transition at
nucleotide 3464. The mutation was not present in the mother's parents,
thus representing a new mutation. Kelley et al. (2000) commented that
the T1155I mutation occurs at a conserved site in the rod domain.
In 2 affected individuals from a family with autosomal dominant Fechtner
syndrome (153640), Seri et al. (2003) identified a heterozygous T1155I
mutation. Seri et al. (2003) concluded that May-Hegglin anomaly and
Fechtner syndrome are not distinct entities, but rather represent a
single disease with a continuous clinical spectrum. The common
abnormality is macrothrombocytopenia and abnormal distribution of MYH9
within leukocytes, even in those without classic Dohle bodies.
.0008
DEAFNESS, AUTOSOMAL DOMINANT 17
MYH9, ARG705HIS
In affected members of a 5-generation family with autosomal dominant
deafness characterized by progressive hearing impairment and
cochleosaccular degeneration (DFNA17; 603622) previously described by
Lalwani et al. (1997), Lalwani et al. (2000) found a G-to-A transition
at nucleotide 2114 in the MYH9 gene. This missense mutation changed
codon 705 from an invariant arginine to a histidine within a highly
conserved SH1 linker region. Previous studies had shown that
modification of amino acid residues within the SH1 helix causes
dysfunction of the ATPase activity of the motor domain in myosin II.
Hildebrand et al. (2006) reported a 5-generation Australian family of
Anglo Celtic origin with nonsyndromic DFNA17 due to a heterozygous R705H
mutation. The self-reported age of onset ranged from 6 years to the
mid-twenties. The hearing loss became severe to profound by the second
to third decades, although there was some intrafamilial variability.
Five affected individuals received cochlear implants with excellent
results. Hildebrand et al. (2006) noted the contrast between the results
of cochlear implant in this family and the poor results reported in 1
patient from the family of Lalwani et al. (2000). Hildebrand et al.
(2006) speculated that early intervention plays an important role in the
therapeutic response.
.0009
FECHTNER SYNDROME
EPSTEIN SYNDROME, INCLUDED
MYH9, ARG702HIS
In a European family living in the United States with Fechtner syndrome
(formerly Alport-like syndrome with macrothrombocytopenia) (153650),
Heath et al. (2001) found a transition converting codon 702 from CGT
(arg) to CAT (his). The globular head domain of the MYHIIA protein was
affected.
Seri et al. (2002) identified the same R702H mutation in affected
members of 2 families, 1 Finnish and 1 Italian, with the phenotype they
labeled Epstein syndrome. Seri et al. (2002) suggested that the R702C
(160775.0006) mutation is associated with Fechtner syndrome, in which
inclusion bodies are found in the leukocytes. Such bodies are said to be
absent in Epstein syndrome, and Seri et al. (2002) suggested, on the
basis of predictions from molecular modeling of the x-ray
crystallographic structure of chick smooth muscle myosin, that the
mutated thiol-reactive group of R702C might lead to intermolecular
disulfide bridges, with the consequent formation of inclusions typical
of Fechtner syndrome. On the contrary, the R702H mutation, they
suggested, does not allow the protein to aggregate and thus to generate
'Dohle-like' bodies. It should be pointed out, however, that the kindred
originally described by Epstein et al. (1972) naturally carried the
R702C mutation.
In the Finnish family reported by Seri et al. (2002), a 22-year-old man
and his son were affected. The father had had recurrent nose bleeding
from the age of 2 years. The Italian family had 6 affected members in 4
sibships in 3 generations. The proposita was a 35-year-old woman who had
been known to be thrombocytopenic, with mild bleeding diathesis, from
the age of 7 years. Hearing loss was selective for high tones. No renal
problem was mentioned. Her father had, however, required hemodialysis
from the age of 28 years and died at the age of 44 years from end-stage
kidney failure.
.0010
MAY-HEGGLIN ANOMALY
FECHTNER SYNDROME, INCLUDED;;
MACROTHROMBOCYTOPENIA AND PROGRESSIVE SENSORINEURAL DEAFNESS, INCLUDED;;
SEBASTIAN SYNDROME, INCLUDED
MYH9, ASP1424ASN
Deutsch et al. (2003) studied a Swiss family and an American family with
the May-Hegglin anomaly (155100)/Fechtner syndrome (153640) and found an
asp1424-to-asn (D1424N) mutation in the MYH9 gene. Affected members in
both families presented with severe thrombocytopenia, as well as
characteristic giant platelets and Dohle-like inclusion bodies on blood
smear examination. In the Swiss family, 2 affected sisters developed
bilateral cataracts at a young age, whereas the third sister and her son
had high-tone sensorineural deafness. Two individuals with
thrombocytopenia showed no extrahematologic symptoms. None showed signs
of nephritis. In the American family, 4 individuals suffered from
sensorineural deafness, but no cataracts or nephritis were observed.
Haplotype analysis indicated that in this family the mutation was a de
novo event in 1 individual. The same mutation had been previously
described in a pedigree of Japanese origin and in 2 pedigrees of
American origin, most likely as a result of independent mutation events
(Heath et al., 2001; Kunishima et al., 2001). Deutsch et al. (2003)
demonstrated that the phenotypes result from a highly unstable MYH9
protein. No abnormalities in protein localization or mRNA stability were
observed. They hypothesized that haploinsufficiency of MYH9 results in a
failure to properly reorganize the cytoskeleton in megakaryocytes as
required for efficient platelet production.
In the proband of the family with macrothrombocytopenia and progressive
sensorineural deafness (600208) reported by Brodie et al. (1992), Mhatre
et al. (2003) identified a heterozygous 4270G-A transition in exon 30 of
the MYH9 gene, resulting in the D1424N substitution in the highly
conserved coiled-coil region of the protein.
Seri et al. (2003) identified a heterozygous D1424N mutation in a
patient described as having May-Hegglin anomaly and Sebastian syndrome
(605249). The authors suggested that the 2 disorders are not separate
entities, but rather represent the same disease with a continuous
clinical spectrum.
.0011
MAY-HEGGLIN ANOMALY
MYH9, 1-BP DEL, 5818G
Kunishima et al. (2005) found a 1-bp deletion, 5818delG, in the MYH9
gene as the cause of May-Hegglin anomaly (155100) in a 1-year-old boy.
The deletion resulted in frameshift and premature termination. Kunishima
et al. (2005) found that the father was a somatic mosaic for this
mutation. The father had normal platelet counts; however, both
normal-sized and giant platelets were observed on his peripheral blood
smears. In addition, 14% of neutrophils contained inclusion bodies, and
the rest showed a normal morphology. Quantitative fluorescent PCR
analysis showed that only 6% of DNA from peripheral blood leukocytes
harbored the mutation. The mutation was demonstrated in a similar
frequency in different tissues, buccal mucosa cells, and hair bulb
cells, implying that the mutation had occurred during gastrulation.
Kunishima et al. (2005) concluded that mosaicism may account for some de
novo mutations in MYH9 disorders.
.0012
EPSTEIN SYNDROME
MYH9, SER96LEU
In affected individuals from 2 unrelated families with Epstein syndrome
(153650), Arrondel et al. (2002) identified a heterozygous 287C-T
transition in the MYH9 gene, resulting in a ser96-to-leu (S96L)
substitution predicted to disturb the helical region of the protein.
Utsch et al. (2006) identified a de novo heterozygous S96L mutation in
an infant girl with features of Epstein syndrome, including
macrothrombocytopenia and impaired platelet function but no evidence of
hearing loss or nephritis. She also had exstrophy of the bladder
(600057). Utsch et al. (2006) noted that although MYH9 mutations had not
previously been associated with urogenital malformations, the mutation
may have played a role in the bladder exstrophy in this patient.
By immunofluorescent studies of leukocytes derived from a patient with
the S96L mutation, Kunishima et al. (2003) detected abnormal subcellular
localization of MYH9, showing a speckled pattern or small dots.
Neutrophil inclusions had not been found on conventional Giemsa
staining.
.0013
MAY-HEGGLIN ANOMALY
SEBASTIAN SYNDROME, INCLUDED
MYH9, 21-BP DEL
In a patient described as having May-Hegglin anomaly (155100) and
Sebastian syndrome (605249), Seri et al. (2003) identified a
heterozygous 21-bp deletion in the MYH9 gene, resulting in an in-frame
deletion of 7 amino acids (E1066-A1072) in the rod domain. De Rocco et
al. (2009) identified the reciprocal in-frame duplication in another
family (160775.0014). Detailed sequence analysis of this region revealed
a 16-nucleotide repeat that was likely responsible for unequal
crossing-over.
.0014
MAY-HEGGLIN ANOMALY
MYH9, 21-BP DUP
In 3 affected members of a family with May-Hegglin anomaly (155100), De
Rocco et al. (2009) identified a heterozygous 21-bp duplication in exon
24 of the MYH9 gene, resulting in an in-frame duplication of 7 amino
acids (E1066-A1072) in the rod domain. All patients had congenital
macrothrombocytopenia and Dohle-like inclusion bodies in neutrophils,
consistent with May-Hegglin anomaly, and 1 patient also had congenital
cataracts, which is part of the phenotypic spectrum of MYH9-related
disorders. Seri et al. (2003) identified the reciprocal in-frame
deletion in another patient (160775.0013). Detailed sequence analysis of
this region revealed a 16-nucleotide repeat that was likely responsible
for unequal crossing-over.
.0015
MACROTHROMBOCYTOPENIA AND PROGRESSIVE SENSORINEURAL DEAFNESS
MYH9, 18-BP DEL, NT228
In a 45-year-old Japanese man with macrothrombocytopenia and
sensorineural deafness (600208), Kunishima et al. (2005) identified a
heterozygous 18-bp deletion (228_245del) in exon 1 of the MYH9 gene,
resulting in an in-frame deletion of 6 amino acids (asn76 to ser81) in a
helix segment adjacent to the SH1 helix. The mutation affected the
N-terminal head domain. The patient had no evidence of renal dysfunction
or cataract. Leukocyte morphology on conventional Giemsa staining was
ambiguous, but immunofluorescent staining showed abnormal subcellular
localization of MYH9. The MYH9-positive structures showed a thread-like
appearance, not punctuated or granular as often described in other
MYH9-related disorders.
*FIELD* RF
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16. Kao, W. H. L.; Klag, M. J.; Meoni, L. A.; Reich, D.; Berthier-Schaad,
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17. Kelley, M. J.; Jawien, W.; Ortel, T. L.; Korczak, J. F.: Mutation
of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin
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18. Kopp, J. B.; Smith, M. W.; Nelson, G. W.; Johnson, R. C.; Freedman,
B. I.; Bowden, D. W.; Oleksyk, T.; McKenzie, L. M.; Kajiyama, H.;
Ahuja, T. S.; Berns, J. S.; Briggs, W.; and 10 others: MYH9 is
a major-effect risk gene for focal segmental glomerulosclerosis. Nature
Genet. 40: 1175-1184, 2008.
19. Kunishima, S.; Kojima, T.; Matsushita, T.; Tanaka, T.; Tsurusawa,
M.; Furukawa, Y.; Nakamura, Y.; Okamura, T.; Amemiya, N.; Nakayama,
T.; Kamiya, T.; Saito, H.: Mutations in the NMMHC-A gene cause autosomal
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20. Kunishima, S.; Matsushita, T.; Kojima, T.; Amemiya, N.; Choi,
Y. M.; Hosaka, N.; Inoue, M.; Jung, Y.; Mamiya, S.; Matsumoto, K.;
Miyajima, Y.; Zhang, G.; Ruan, C.; Saito, K.; Song, K. S.; Yoon, H.-J.;
Kamiya, T.; Saito, H.: Identification of six novel MYH9 mutations
and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia
with leukocyte inclusions. J. Hum. Genet. 46: 722-729, 2001.
21. Kunishima, S.; Matsushita, T.; Kojima, T.; Sako, M.; Kimura, F.;
Jo, E.-K.; Inoue, C.; Kamiya, T.; Saito, H.: Immunofluorescence analysis
of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association
of subcellular localization with MYH9 mutations. Lab. Invest. 83:
115-122, 2003.
22. Kunishima, S.; Matsushita, T.; Shiratsuchi, M.; Ikuta, T.; Nishimura,
J.; Hamaguchi, M.; Naoe, T.; Saito, H.: Detection of unique neutrophil
non-muscle myosin heavy chain-A localization by immunofluorescence
analysis in MYH9 disorder presented with macrothrombocytopenia without
leukocyte inclusions and deafness. Europ. J. Haematol. 74: 1-5,
2005.
23. Kunishima, S.; Matsushita, T.; Yoshihara, T.; Nakase, Y.; Yokoi,
K.; Hamaguchi, M.; Saito, H.: First description of somatic mosaicism
in MYH9 disorders. Brit. J. Haemat. 128: 360-365, 2005.
24. Lalwani, A. K.; Goldstein, J. A.; Kelley, M. J.; Luxford, W.;
Castelein, C. M.; Mhatre, A. N.: Human nonsyndromic hereditary deafness
DFNA17 is due to a mutation in nonmuscle myosin MYH9. Am. J. Hum.
Genet. 67: 1121-1128, 2000.
25. Lalwani, A. K.; Linthicum, F. H.; Wilcox, E. R.; Moore, J. K.;
Walters, F. C.; San Agustin, T. B.; Mislinski, J.; Miller, M. R.;
Sinninger, Y.; Attaie, A.; Luxford, W. M.: A five-generation family
with late-onset progressive hereditary hearing impairment due to cochleosaccular
degeneration. Audiol. Neurootol. 2: 139-154, 1997.
26. Martignetti, J. A.; Heath, K. E.; Harris, J.; Bizzaro, N.; Savoia,
A.; Balduini, C. L.; Desnick, R. J.: The gene for May-Hegglin anomaly
localizes to a less than 1-Mb region on chromosome 22q12.3-13.1. Am.
J. Hum. Genet. 66: 1449-1454, 2000.
27. Matsushita, T.; Hayashi, H.; Kunishima, S.; Hayashi, M.; Ikejiri,
M.; Takeshita, K.; Yuzawa, Y.; Adachi, T.; Hirashima, K.; Sone, M.;
Yamamoto, K.; Takagi, A.; Katsumi, A.; Kawai, K.; Nezu, T.; Takahashi,
M.; Nakashima, T.; Naoe, T.; Kojima, T.; Saito, H.: Targeted disruption
of mouse ortholog of the human MYH9 responsible for macrothrombocytopenia
with different organ involvement: hematological, nephrological, and
otological studies of heterozygous KO mice. Biochem. Biophys. Res.
Commun. 325: 1163-1171, 2004.
28. May-Hegglin/Fechtner Syndrome Consortium: Mutations in MYH9
result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. Nature
Genet. 26: 103-105, 2000.
29. Mhatre, A. N.; Kim, Y.; Brodie, H. A.; Lalwani, A. K.: Macrothrombocytopenia
and progressive deafness is due to a mutation in MYH9. Otol. Neurootol. 24:
205-209, 2003.
30. Moxey-Mims, M. M.; Young, G.; Silverman, A.; Selby, D. M.; White,
J. G.; Kher, K. K.: End-stage renal disease in two pediatric patients
with Fechtner syndrome. Pediat. Nephrol. 13: 782-786, 1999.
31. Parker, L. L.; Gao, J.; Zuo, J.: Absence of hearing loss in a
mouse model for DFNA17 and MYH9-related disease: the use of public
gene-targeted ES cell resources. Brain Res. 1091: 235-242, 2006.
32. Pecci, A.; Canobbio, I.; Balduini, A.; Stefanini, L.; Cisterna,
B.; Marseglia, C.; Noris, P.; Savoia, A.; Balduini, C. L.; Torti,
M.: Pathogenetic mechanisms of hematological abnormalities of patients
with MYH9 mutations. Hum. Molec. Genet. 14: 3169-3178, 2005.
33. Pecci, A.; Panza, E.; Pujol-Moix, N.; Klersy, C.; Di Bari, F.;
Bozzi, V.; Gresele, P.; Lethagen, S.; Fabris, F.; Dufour, C.; Granata,
A.; Doubek, M.; and 14 others: Position of nonmuscle myosin heavy
chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related
disease. Hum. Mutat. 29: 409-417, 2008.
34. Rocca, B.; Laghi, F.; Zini, G.; Maggiano, N.; Landolfi, R.: Fechtner
syndrome: report of a third family and literature review. Brit. J.
Haemat. 85: 423-426, 1993.
35. Saez, C. G.; Myers, J. C.; Shows, T. B.; Leinwand, L. A.: Human
nonmuscle myosin heavy chain mRNA: generation of diversity through
alternative polyadenylation. Proc. Nat. Acad. Sci. 87: 1164-1168,
1990.
36. Seri, M.; Pecci, A.; Di Bari, F.; Cusano, R.; Savino, M.; Panza,
E.; Nigro, A.; Noris, P.; Gangarossa, S.; Rocca, B.; Gresele, P.;
Bizzaro, N.; and 13 others: MYH9-related disease: May-Hegglin anomaly,
Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not
distinct entities but represent a variable expression of a single
illness. Medicine 82: 203-215, 2003.
37. Seri, M.; Savino, M.; Bordo, D.; Cusano, R.; Rocca, B.; Meloni,
I.; Di Bari, F.; Koivisto, P. A.; Bolognesi, M.; Ghiggeri, G. M.;
Landolfi, R.; Balduini, C. L.; Zelante, L.; Ravazzolo, R.; Renieri,
A.; Savoia, A.: Epstein syndrome: another renal disorder with mutations
in the nonmuscle myosin heavy chain 9 gene. Hum. Genet. 110: 182-186,
2002.
38. Simons, M.; Wang, M.; McBride, O. W.; Kawamoto, S.; Yamakawa,
K.; Gdula, D.; Adelstein, R. S.; Weir, L.: Human nonmuscle myosin
heavy chains are encoded by two genes located on different chromosomes. Circulation
Res. 69: 530-539, 1991.
39. Toothaker, L. E.; Gonzalez, D. A.; Tung, N.; Lemons, R. S.; Le
Beau, M. M.; Arnaout, M. A.; Clayton, L. K.; Tenen, D. G.: Cellular
myosin heavy chain in human leukocytes: isolation of 5-prime cDNA
clones, characterization of the protein, chromosomal localization,
and upregulation during myeloid differentiation. Blood 78: 1826-1833,
1991.
40. Utsch, B.; DiFeo, A.; Kujat, A.; Karle, S.; Schuster, V.; Lenk,
H.; Jacobs, U.; Muller, M.; Dotsch, J.; Rascher, W.; Reutter, H.;
Martignetti, J. A.; Ludwig, M.; Trobs, R.-B.: Bladder exstrophy and
Epstein type congenital macrothrombocytopenia: evidence for a common
cause? (Letter) Am. J. Med. Genet. 140A: 2251-2253, 2006.
41. Wilson, C. A.; Tsuchida, M. A.; Allen, G. M.; Barnhart, E. L.;
Applegate, K. T.; Yam, P. T.; Ji, L.; Keren, K.; Danuser, G.; Theriot,
J. A.: Myosin II contributes to cell-scale actin network treadmilling
through network disassembly. Nature 465: 373-377, 2010.
*FIELD* CN
Paul J. Converse - updated: 3/1/2012
Ada Hamosh - updated: 11/11/2010
Cassandra L. Kniffin - updated: 10/11/2010
Cassandra L. Kniffin - updated: 9/22/2010
Ada Hamosh - updated: 6/7/2010
George E. Tiller - updated: 7/21/2009
Ada Hamosh - updated: 1/16/2009
Cassandra L. Kniffin - updated: 6/26/2008
Cassandra L. Kniffin - updated: 12/18/2006
Patricia A. Hartz - updated: 2/9/2006
Victor A. McKusick - updated: 3/21/2005
Paul J. Converse - updated: 4/9/2004
Victor A. McKusick - updated: 10/15/2003
Patricia A. Hartz - updated: 1/16/2003
Victor A. McKusick - updated: 5/10/2002
Victor A. McKusick - updated: 3/6/2002
Victor A. McKusick - updated: 3/4/2002
Victor A. McKusick - updated: 11/27/2001
Victor A. McKusick - updated: 4/3/2001
Victor A. McKusick - updated: 11/21/2000
Victor A. McKusick - updated: 8/29/2000
*FIELD* CD
Victor A. McKusick: 3/1/1990
*FIELD* ED
mgross: 03/02/2012
terry: 3/1/2012
alopez: 12/6/2011
terry: 12/1/2011
alopez: 11/15/2010
terry: 11/11/2010
alopez: 11/3/2010
wwang: 10/29/2010
ckniffin: 10/11/2010
carol: 9/23/2010
ckniffin: 9/22/2010
alopez: 6/7/2010
wwang: 8/7/2009
terry: 7/21/2009
alopez: 3/12/2009
alopez: 1/23/2009
alopez: 1/22/2009
terry: 1/16/2009
terry: 12/2/2008
wwang: 7/2/2008
ckniffin: 6/26/2008
terry: 9/17/2007
carol: 2/23/2007
wwang: 12/27/2006
ckniffin: 12/18/2006
carol: 5/22/2006
mgross: 3/10/2006
mgross: 3/9/2006
terry: 2/9/2006
wwang: 3/23/2005
terry: 3/21/2005
alopez: 5/3/2004
mgross: 4/9/2004
terry: 11/11/2003
cwells: 10/15/2003
cwells: 1/22/2003
terry: 1/16/2003
cwells: 5/29/2002
terry: 5/10/2002
terry: 3/25/2002
alopez: 3/19/2002
terry: 3/6/2002
terry: 3/4/2002
alopez: 11/30/2001
terry: 11/27/2001
cwells: 4/6/2001
cwells: 4/4/2001
mcapotos: 4/3/2001
mcapotos: 2/2/2001
mcapotos: 12/11/2000
mcapotos: 11/29/2000
terry: 11/21/2000
alopez: 8/31/2000
terry: 8/29/2000
alopez: 4/30/1999
mimadm: 4/14/1994
carol: 12/14/1992
carol: 12/7/1992
supermim: 3/16/1992
carol: 11/13/1991
carol: 11/6/1991
*RECORD*
*FIELD* NO
160775
*FIELD* TI
*160775 MYOSIN, HEAVY CHAIN 9, NONMUSCLE; MYH9
;;CELLULAR MYOSIN HEAVY CHAIN, TYPE A;;
read moreMYOSIN, HEAVY CHAIN, NONMUSCLE, TYPE A; NMMHCA;;
NONMUSCLE MYOSIN IIA;;
NMHC IIA
*FIELD* TX
CLONING
Saez et al. (1990) provided a molecular genetic characterization of a
human nonmuscle myosin heavy chain expressed in fibroblasts, endothelial
cells, and macrophages. The deduced 1,247-amino acid was weakly
homologous (33%) to sarcomeric MHC, but about 72% identical to smooth
muscle MHC. In contrast to vertebrate sarcomeric MHCs, which generate
diversity through the expression of members of a multigene family, an
alternative polyadenylation site is used in the nonmuscle MHC gene to
generate multiple transcripts that encode the same protein.
D'Apolito et al. (2002) cloned mouse Myh9. The deduced 1,960-amino acid
protein shares 98% identity with human MYH9. Northern blot analysis
detected abundant Myh9 expression in mouse liver, spleen, lung, and
kidney, but not in skeletal muscle or testis.
GENE FUNCTION
Toothaker et al. (1991) observed that antisera raised against the
peptide made from the predicted amino acid sequence specifically reacted
with a 224-kD polypeptide in leukocyte cell lines, and the protein was
upregulated during the induction of monocytic and granulocytic
differentiation in these cells. The cellular myosin heavy chain may be
the major contractile protein responsible for movement in myeloid cell
lines because no mRNA for sarcomeric myosin heavy chains is detected in
these cells.
By screening mouse T-cell cDNA for myosin family members, followed by
Western blot analysis, Jacobelli et al. (2004) found that Myh9 was the
only class II nonmuscle myosin readily and highly detectable. Time-lapse
fluorescence microscopy demonstrated that, during T-cell crawling, Myh9
expression was enriched in the uropod. After encounter with antigen on
antigen-presenting cells (APCs), Myh9 redistributed to the T-cell-APC
interface upon formation of the immunologic synapse. Further imaging and
siRNA analysis showed that Myh9 was required for T-cell uropodal
morphology, but not for synapse formation. TCR-induced phosphorylation
of Myh9 in its multimerization domain indicated that inactivation of the
myosin motor may be a key step in the T-cell 'stop' response during
antigen recognition.
Chung and Kawamoto (2004) identified an intronic region that they
designated 32kb-150, located 32 kb downstream of the transcription start
sites in the human NMHCA gene, as a transcriptional regulatory region.
Among IRF proteins tested, only IRF2 (147576) bound to the
interferon-stimulated response element (ISRE) within 32kb-150 in vitro
and in HeLa cells and mouse fibroblasts. IRF2 acted as a transcriptional
activator in a reporter gene assay. The phorbol ester TPA, which
triggers differentiation of human promyelocytic HL-60 cells into
macrophages, upregulated expression of both NMHCA and IRF2. Chung and
Kawamoto (2004) concluded that IRF2 contributes to transcriptional
activation of the NMHCA gene via 32kb-150 during TPA-induced
differentiation of HL-60 cells.
Wilson et al. (2010) showed that nonmuscle myosin II has a direct role
in actin network disassembly in crawling cells. In fish keratocytes
undergoing motility, myosin II is concentrated in regions at the rear
with high rates of network disassembly. Activation of myosin II by ATP
in detergent-extracted cytoskeletons resulted in rear-localized
disassembly of the actin network. Inhibition of myosin II activity and
stabilization of actin filaments synergistically impeded cell motility,
suggesting the existence of 2 disassembly pathways, one of which
requires myosin II activity. Wilson et al. (2010) concluded that their
results established the importance of myosin II as an enzyme for actin
network disassembly, and proposed that gradual formation and
reorganization of an actomyosin network provides an intrinsic
destruction timer, enabling long-range coordination of actin network
treadmilling in motile cells.
Arii et al. (2010) showed that nonmuscle myosin heavy chain IIA
(NMHC-IIA), a subunit of nonmuscle myosin IIA (NM-IIA), functions as a
herpes simplex virus-1 (HSV-1) entry receptor by interacting with
glycoprotein B. A cell line that is relatively resistant to HSV-1
infection became highly susceptible to infection by this virus when
NMHC-IIA was overexpressed. Antibody to NMHC-IIA blocked HSV-1 infection
in naturally permissive target cells. Furthermore, knockdown of NMHC-IIA
in the permissive cells inhibited HSV-1 infection as well as cell-cell
fusion when glycoproteins B, D, H, and L were coexpressed. Cell surface
expression of NMHC-IIA was markedly and rapidly induced during the
initiation of HSV-1 entry. NMHC-IIA is ubiquitously expressed in various
human tissues and cell types and, therefore, is implicated as a
functional glycoprotein B receptor that mediates broad HSV-1 infectivity
both in vitro and in vivo.
Using immunofluorescence microscopy, Western blot analysis, and
knockdown strategies with human lung fibroblasts, Hanisch et al. (2011)
showed that Salmonella entered nonphagocytic cells by manipulating 2
machineries of actin-based motility in the host: actin polymerization
through the ARP2/3 complex (604221), and actomyosin-mediated
contractility in a myosin IIA- and myosin IIB-dependent manner. Hanisch
et al. (2011) concluded that Salmonella entry can be effected
independently of membrane ruffling.
GENE STRUCTURE
D'Apolito et al. (2002) determined that the mouse Myh9 gene, like human
MYH9, contains 41 exons.
MAPPING
By Southern analysis of a panel of human-mouse somatic cell hybrids,
Saez et al. (1990) demonstrated that the nonmuscle MHC gene is located
on chromosome 22 and is therefore unlinked to the 2 sarcomeric MHC
clusters on chromosomes 14 and 17. A cell line containing a
translocation involving chromosome 22 allowed a regional assignment to
22pter-q13. Toothaker et al. (1991) mapped the gene to 22q12.3-q13.1 by
Southern analysis of human/rodent somatic cell hybrids and by in situ
hybridization. Simons et al. (1991) likewise mapped a nonmuscle myosin
heavy chain gene, which they designated NMMHCA, to 22q11.2. A second
nonmuscle myosin heavy chain, which they designated NMMHC-B (160776),
was found to be encoded by a gene on 17q13. Both were 7.5 kb long. In
the amino-terminal one-third (amino acids 58-718), they were 89%
identical at the amino acid level and 74% identical at the nucleotide
level. Muscle myosin heavy chain genes are located on 17p.
D'Apolito et al. (2002) mapped the mouse Myh9 gene to a region of
chromosome 15 that shares homology of synteny with human chromosome
22q12.3-q13.1.
- Association with Kidney Disease in African Americans
In independent genomewide admixture scans to map susceptibility loci for
kidney disease in African Americans, Kopp et al. (2008) and Kao et al.
(2008) identified variation at the MYH9 locus as a major factor for the
increased risk of nondiabetic kidney disease in this population (FSGS4;
612551).
MOLECULAR GENETICS
The autosomal dominant giant-platelet disorders May-Hegglin anomaly
(155100), Fechtner syndrome (153640), and Sebastian syndrome (605249)
share the triad of thrombocytopenia, large platelets, and characteristic
leukocyte inclusions called Dohle-like bodies. May-Hegglin anomaly and
Sebastian syndrome can be differentiated by subtle ultrastructural
leukocyte inclusion features, whereas Fechtner syndrome is distinguished
by the additional clinical features of sensorineural deafness,
cataracts, and nephritis resembling Alport syndrome (see 104200). The
similarities between these platelet disorders and refinement of the
disease loci for May-Hegglin anomaly and Fechtner syndrome to an
overlapping region of 480 kb on chromosome 22 suggested that all 3
disorders may be allelic. Among the identified candidate genes was MYH9,
which is expressed in platelets and upregulated during granulocyte
differentiation. The May-Hegglin/Fechtner Syndrome Consortium (2000)
identified 6 MYH9 mutations (1 nonsense and 5 missense) in 7 unrelated
probands from families with these 3 disorders. On the basis of molecular
modeling, 2 mutations affecting the myosin head were predicted to impose
electrostatic and conformational changes, whereas the truncating
mutation deleted the unique carboxy-terminal tailpiece. The remaining
missense mutations, all affecting highly conserved coiled-coil domain
positions, imparted destabilizing electrostatic and polar changes. Thus,
the findings demonstrated that mutations in MYH9 result in 3
phenotypically distinct megakaryocyte/platelet/leukocyte syndromes and
are important in the pathogenesis of sensorineural deafness, cataracts,
and nephritis.
Kelley et al. (2000) also screened MYH9 as a candidate gene for
mutations in 10 families with May-Hegglin anomaly. In each family, they
identified 1 of 3 sequence variants within either the alpha-helical
coiled-coil or the tailpiece domain that cosegregated with disease
status.
Kunishima et al. (2001) found mutations in NMMHCA in 6 of 7 Japanese
families with macrothrombocytopenia with leukocyte inclusions: 3
missense mutations, 1 nonsense mutation, and a 1-bp deletion resulting
in a premature termination. Immunofluorescence studies showed that
NMMHCA distribution in neutrophils mimics the inclusion bodies. These
results provided evidence for the involvement of an abnormal form of
NMMHCA in the creation of leukocyte inclusions and also in platelet
morphogenesis.
The May-Hegglin/Fechtner Syndrome Consortium (2000) speculated that
mutations in MYH9 may also have a role in 2 other autosomal dominant
disorders: a form of nonsyndromic deafness characterized by progressive
hearing impairment and cochleosaccular degeneration (DFNA17; 603622) and
Epstein syndrome (153650). Epstein syndrome is clinically identical to
FTNS, although Dohle-like bodies had not been described.
Lalwani et al. (2000) demonstrated a missense mutation (160775.0008) in
the MYH9 gene in affected members of a kindred with DFNA17.
Heath et al. (2001) examined the spectrum of mutations and the
genotype/phenotype and structure-function relationships in a large
cohort (n = 27) of individuals with May-Hegglin anomaly, Fechtner
syndrome (some cases of which were called Alport-like syndrome with
macrothrombocytopenia), or Sebastian syndrome. They demonstrated that
MYH9 mutations also result in Epstein syndrome.
Heath et al. (2001) found that R702C (160775.0006) and R702H
(160775.0009) mutations were associated only with Fechtner syndrome
(some cases designated as Alport-like syndrome with
macrothrombocytopenia) or Epstein syndrome, thus defining a region of
the MYHIIA protein critical in the combined pathogenesis of
macrothrombocytopenia, nephritis, and deafness.
In the proband of the family with macrothrombocytopenia and progressive
sensorineural deafness (600208) reported by Brodie et al. (1992), Mhatre
et al. (2003) identified a missense mutation in the MYH9 gene
(160775.0010). The same mutation had been reported in patients with
May-Hegglin anomaly, Fechtner syndrome, and Sebastian syndrome.
To elucidate the spectrum of MYH9 mutations responsible for the group of
disorders under the general designation autosomal dominant
macrothrombocytopenia with leukocyte inclusions, Kunishima et al. (2001)
examined the MYH9 gene in an additional 11 families and 3 sporadic
patients with the disorders from Japan, Korea, and China. All 14
patients had heterozygous MYH9 mutations, including 3 known mutations:
R1933X (160775.0001), R1165C (160775.0003), and E1841K (160775.0002).
Six novel mutations (3 missense and 3 deletion) were also found. Two
patients had Alport manifestations including deafness, nephritis, and
cataract and had R1165C and E1841K mutations, respectively. However,
taken together with 3 previous reports, the data did not show clear
phenotype-genotype relationships.
Hu et al. (2002) noted that 2 disease-causing mutations, N93K
(160775.0004) and R702C (160775.0006), lie within close proximity in the
3-dimensional structure of the head domain of MYH9. They coexpressed
recombinant fragments of MYH9 along with the appropriate light chains to
create 2-headed meromyosin-like molecules bearing these mutations. The
R702C mutant displayed 25% of the maximal MgATPase activity of wildtype
heavy meromyosin and moved actin filaments at half the wildtype rate in
an in vitro motility assay. Heavy meromyosin containing the N93K
mutation had only 4% of the maximal MgATPase activity and did not
translocate actin filaments. The characteristics of this mutation were
consistent with an inability to fully adopt the 'on' conformation. The
N93K mutation was also associated with a tendency for the myosin to
aggregate, which may explain the leukocyte inclusions associated with
this mutation in humans.
Kunishima et al. (2005) identified a mutation (160775.0011) in a
1-year-old boy with May-Hegglin anomaly resulting from somatic mosaicism
in the father.
Based on an analysis of 19 families with MYH9 mutations, Seri et al.
(2003) suggested that 4 disorders, May-Hegglin, Fechtner, Sebastian, and
Epstein syndromes, are not distinct entities, but rather represent a
single disorder with a continuous clinical spectrum, for which they
proposed the term 'MYH9-related disease.' However, other disorders,
e.g., macrothrombocytopenia and progressive sensorineural deafness and
DFNA17, are also caused by mutation in the MYH9 gene.
By immunofluorescence analysis using a polyclonal antibody against human
platelet MYH9, Kunishima et al. (2003) detected abnormal subcellular
localization of MYH9 in neutrophils from all 21 patients with MYH9
mutations examined, including a patient with Epstein syndrome.
Comparison with May-Grunwald-Giemsa staining revealed that the antibody
always coexisted with the neutrophil inclusion bodies, providing proof
that MYH9 is associated with such bodies. In some cases, neutrophil
inclusions were not detected on conventional May-Grunwald-Giemsa-stained
blood smears, but immunofluorescence analysis found the abnormal MYH9
localization. Kunishima et al. (2003) proposed that the mutant MYH9
protein dimerizes with the wildtype protein to form inclusions,
consistent with a dominant-negative effect.
GENOTYPE/PHENOTYPE CORRELATIONS
Pecci et al. (2005) investigated 11 patients from 6 pedigrees with
different MYH9 mutations (see, e.g., 160775.0001-160775.0005). NMHC IIA
levels were measured in platelets and granulocytes isolated from
peripheral blood and in megakaryocytes cultured from circulating
progenitors. All patients studied had a 50% reduction of NMHC IIA
expression in platelets and megakaryocytes. In subjects with the R1933X
(160775.0001) and E1945X mutations, the whole NMHC IIA of platelets and
megakaryocytes was wildtype. No NMHC IIA inclusions were observed at any
time of megakaryocyte maturation. In granulocytes, the extent of NMHC
IIA reduction in patients with respect to control cells was
significantly greater than that measured in platelets and
megakaryocytes; wildtype protein was sequestered within most of the NMHC
IIA inclusions. Taken together these results indicate that
haploinsufficiency of NMHC IIA in megakaryocytic lineage is the
mechanism of macrothrombocytopenia consequent to MYH9 mutations, whereas
in granulocytes a dominant-negative effect of the mutant allele appeared
to be involved in the formation of inclusion bodies.
In a study of 108 patients from 50 unrelated pedigrees with MYH9
mutations, Pecci et al. (2008) found that 68% of families carried
mutations in 1 of 4 residues: 702 in the motor domain (12 families) and
residues 1424, 1841, and 1933 in the tail domain (9, 7, and 6 pedigrees,
respectively). All subjects with mutations in the motor domain of MYH9
developed severe thrombocytopenia, nephritis, and deafness before the
age of 40 years. Patients with mutations at residue 1424 or 1841 had a
much lower risk of these complications, significantly higher platelet
counts, and an intermediate clinical picture. Patients with mutations at
residue 1933 did not develop kidney damage or cataracts but did develop
deafness late in life.
ANIMAL MODEL
Matsushita et al. (2004) found that homozygous deletion of Myh9 in mice
was embryonic lethal. In contrast, Myh9 +/- mice were viable and fertile
without gross anatomic, hematologic, or nephrologic abnormalities.
However, auditory brainstem responses indicated that 2 of 6 Myh9 +/-
mice had hearing loss. Parker et al. (2006) also found that homozygous
mutations in Myh9 are embryonic lethal in mice. In contrast to the
findings of Matsushita et al. (2004), Parker et al. (2006) did not
observe hearing loss in Myh9 heterozygous adult mice, despite
haploinsufficiency for Myh9 in the mutant mouse inner ear. In addition,
aged Myh9 heterozygous mice did not show signs of cochleosaccular
degeneration common in DFNA17. Parker et al. (2006) used a public
gene-targeted embryonic stem cell bank resource to generate the mice.
*FIELD* AV
.0001
MAY-HEGGLIN ANOMALY
FECHTNER SYNDROME, INCLUDED;;
SEBASTIAN SYNDROME, INCLUDED
MYH9, ARG1933TER
In a family used in linkage studies to define the May-Hegglin anomaly
(155100) critical region on chromosome 22 (Martignetti et al., 2000),
the May-Hegglin/Fechtner Syndrome Consortium (2000) found that affected
individuals had a nonsense mutation in codon 1933 of the MYH9 gene,
predicting the replacement of an arginine by a stop codon (arg1933 to
ter; R1933X) and deletion of the last 28 amino acids.
Kelley et al. (2000) found the arg1933-to-ter mutation in 4 of 10
families they studied. It was caused by a 5797C-T transition in exon 40.
Heath et al. (2001) identified a heterozygous R1933X mutation in
affected members of a family described as having Fechtner syndrome
(153640), although deafness and cataract were not present. Another
family with the R1933X mutation was described as having May-Hegglin
anomaly and Sebastian syndrome (605249).
.0002
MAY-HEGGLIN ANOMALY
FECHTNER SYNDROME, INCLUDED
MYH9, GLU1841LYS
In 2 unrelated families with May-Hegglin anomaly (155100), the
May-Hegglin/Fechtner Syndrome Consortium (2000) found that affected
individuals had the same missense mutation, glu1841 to lys (E1841K),
within the coiled-coil domain of the MYH9 protein. The missense mutation
was caused by a G-to-A transition at nucleotide 5521 in exon 38. Neither
family history nor haplotype analysis suggested common ancestry.
Kelley et al. (2000) found the E1841K mutation in 5 of 10 families
studied and commented that it occurs at a conserved site in the rod
domain.
Heath et al. (2001) identified a heterozygous E1841K mutation in 2
unrelated families with Fechtner syndrome (153640). One of the families
had been reported by Rocca et al. (1993).
.0003
SEBASTIAN SYNDROME
MYH9, ARG1165CYS
In a family with Sebastian syndrome (605249), the May-Hegglin/Fechtner
Syndrome Consortium (2000) found that affected individuals had a
missense mutation in codon 1165 (arg1165 to cys; R1165C) of the MYH9
gene, caused by a C-to-T transition at nucleotide 3493.
.0004
MAY-HEGGLIN ANOMALY
MYH9, ASN93LYS
In a family with May-Hegglin anomaly (155100), the May-Hegglin/Fechtner
Syndrome Consortium (2000) found that the proband had a missense
mutation, asn93 to lys (N93K), within the globular head domain of the
MYH9 gene. The mutation resulted from a C-to-G transversion at
nucleotide 279.
.0005
FECHTNER SYNDROME
MYH9, ASP1424HIS
In a family with Fechtner syndrome (153640) that had been used to define
the critical FTNS mapping region (Cusano et al., 2000), the
May-Hegglin/Fechtner Syndrome Consortium (2000) found that all affected
individuals had a missense mutation in codon 1424 (asp1424 to his;
D1424H) within the coiled-coil domain of the MYH9 protein. The mutation
resulted from a G-to-C transversion at nucleotide 4270.
.0006
FECHTNER SYNDROME
EPSTEIN SYNDROME, INCLUDED;;
SEBASTIAN SYNDROME, INCLUDED;;
MAY-HEGGLIN ANOMALY, INCLUDED
MYH9, ARG702CYS
The May-Hegglin/Fechtner Syndrome Consortium (2000) found that a
sporadic case of Fechtner syndrome (153640) (Moxey-Mims et al., 1999)
had a missense mutation in codon 702 (arg702 to cys; R702C) of the MYH9
protein, altering the globular head domain. The mutation, which resulted
from a C-to-T transition at nucleotide 2104, was not present in either
ascertained parent.
In the original family with Epstein syndrome (153650), family F,
described by Epstein et al. (1972), Heath et al. (2001) found a
transition in exon 16 of the MYH9 gene converting codon 702 from CGT
(arg) to TGT (cys). Heath et al. (2001) found that the R702C mutation
was one of the most frequent, being found in 6 of the 20 families in
which they identified a specific mutation. All of the families
represented Fechtner syndrome. There was no mention of leukocyte
inclusions in the original work-up of this family. For logistic reasons
it had been impossible more recently to get a blood sample for checking
(Epstein, 2002).
Seri et al. (2003) identified a heterozygous R702C mutation in a patient
with sporadic Fechtner syndrome, 2 unrelated patients with sporadic
Epstein syndrome, a patient with sporadic May-Hegglin anomaly (155100),
and in affected members of a family with May-Hegglin anomaly and
Sebastian syndrome (605249). Seri et al. (2003) concluded that these
disorders are not distinct entities, but rather represent a single
disease with a continuous clinical spectrum. The common abnormality is
macrothrombocytopenia and abnormal distribution of MYH9 within
leukocytes, even in those without classic Dohle bodies.
.0007
MAY-HEGGLIN ANOMALY
FECHTNER SYNDROME, INCLUDED
MYH9, THR1155ILE
Kelley et al. (2000) observed a family in which mother and daughter had
May-Hegglin anomaly (155100) caused by a thr1155-to-ile (T1155I)
mutation in the MYH9 gene resulting from a C-to-T transition at
nucleotide 3464. The mutation was not present in the mother's parents,
thus representing a new mutation. Kelley et al. (2000) commented that
the T1155I mutation occurs at a conserved site in the rod domain.
In 2 affected individuals from a family with autosomal dominant Fechtner
syndrome (153640), Seri et al. (2003) identified a heterozygous T1155I
mutation. Seri et al. (2003) concluded that May-Hegglin anomaly and
Fechtner syndrome are not distinct entities, but rather represent a
single disease with a continuous clinical spectrum. The common
abnormality is macrothrombocytopenia and abnormal distribution of MYH9
within leukocytes, even in those without classic Dohle bodies.
.0008
DEAFNESS, AUTOSOMAL DOMINANT 17
MYH9, ARG705HIS
In affected members of a 5-generation family with autosomal dominant
deafness characterized by progressive hearing impairment and
cochleosaccular degeneration (DFNA17; 603622) previously described by
Lalwani et al. (1997), Lalwani et al. (2000) found a G-to-A transition
at nucleotide 2114 in the MYH9 gene. This missense mutation changed
codon 705 from an invariant arginine to a histidine within a highly
conserved SH1 linker region. Previous studies had shown that
modification of amino acid residues within the SH1 helix causes
dysfunction of the ATPase activity of the motor domain in myosin II.
Hildebrand et al. (2006) reported a 5-generation Australian family of
Anglo Celtic origin with nonsyndromic DFNA17 due to a heterozygous R705H
mutation. The self-reported age of onset ranged from 6 years to the
mid-twenties. The hearing loss became severe to profound by the second
to third decades, although there was some intrafamilial variability.
Five affected individuals received cochlear implants with excellent
results. Hildebrand et al. (2006) noted the contrast between the results
of cochlear implant in this family and the poor results reported in 1
patient from the family of Lalwani et al. (2000). Hildebrand et al.
(2006) speculated that early intervention plays an important role in the
therapeutic response.
.0009
FECHTNER SYNDROME
EPSTEIN SYNDROME, INCLUDED
MYH9, ARG702HIS
In a European family living in the United States with Fechtner syndrome
(formerly Alport-like syndrome with macrothrombocytopenia) (153650),
Heath et al. (2001) found a transition converting codon 702 from CGT
(arg) to CAT (his). The globular head domain of the MYHIIA protein was
affected.
Seri et al. (2002) identified the same R702H mutation in affected
members of 2 families, 1 Finnish and 1 Italian, with the phenotype they
labeled Epstein syndrome. Seri et al. (2002) suggested that the R702C
(160775.0006) mutation is associated with Fechtner syndrome, in which
inclusion bodies are found in the leukocytes. Such bodies are said to be
absent in Epstein syndrome, and Seri et al. (2002) suggested, on the
basis of predictions from molecular modeling of the x-ray
crystallographic structure of chick smooth muscle myosin, that the
mutated thiol-reactive group of R702C might lead to intermolecular
disulfide bridges, with the consequent formation of inclusions typical
of Fechtner syndrome. On the contrary, the R702H mutation, they
suggested, does not allow the protein to aggregate and thus to generate
'Dohle-like' bodies. It should be pointed out, however, that the kindred
originally described by Epstein et al. (1972) naturally carried the
R702C mutation.
In the Finnish family reported by Seri et al. (2002), a 22-year-old man
and his son were affected. The father had had recurrent nose bleeding
from the age of 2 years. The Italian family had 6 affected members in 4
sibships in 3 generations. The proposita was a 35-year-old woman who had
been known to be thrombocytopenic, with mild bleeding diathesis, from
the age of 7 years. Hearing loss was selective for high tones. No renal
problem was mentioned. Her father had, however, required hemodialysis
from the age of 28 years and died at the age of 44 years from end-stage
kidney failure.
.0010
MAY-HEGGLIN ANOMALY
FECHTNER SYNDROME, INCLUDED;;
MACROTHROMBOCYTOPENIA AND PROGRESSIVE SENSORINEURAL DEAFNESS, INCLUDED;;
SEBASTIAN SYNDROME, INCLUDED
MYH9, ASP1424ASN
Deutsch et al. (2003) studied a Swiss family and an American family with
the May-Hegglin anomaly (155100)/Fechtner syndrome (153640) and found an
asp1424-to-asn (D1424N) mutation in the MYH9 gene. Affected members in
both families presented with severe thrombocytopenia, as well as
characteristic giant platelets and Dohle-like inclusion bodies on blood
smear examination. In the Swiss family, 2 affected sisters developed
bilateral cataracts at a young age, whereas the third sister and her son
had high-tone sensorineural deafness. Two individuals with
thrombocytopenia showed no extrahematologic symptoms. None showed signs
of nephritis. In the American family, 4 individuals suffered from
sensorineural deafness, but no cataracts or nephritis were observed.
Haplotype analysis indicated that in this family the mutation was a de
novo event in 1 individual. The same mutation had been previously
described in a pedigree of Japanese origin and in 2 pedigrees of
American origin, most likely as a result of independent mutation events
(Heath et al., 2001; Kunishima et al., 2001). Deutsch et al. (2003)
demonstrated that the phenotypes result from a highly unstable MYH9
protein. No abnormalities in protein localization or mRNA stability were
observed. They hypothesized that haploinsufficiency of MYH9 results in a
failure to properly reorganize the cytoskeleton in megakaryocytes as
required for efficient platelet production.
In the proband of the family with macrothrombocytopenia and progressive
sensorineural deafness (600208) reported by Brodie et al. (1992), Mhatre
et al. (2003) identified a heterozygous 4270G-A transition in exon 30 of
the MYH9 gene, resulting in the D1424N substitution in the highly
conserved coiled-coil region of the protein.
Seri et al. (2003) identified a heterozygous D1424N mutation in a
patient described as having May-Hegglin anomaly and Sebastian syndrome
(605249). The authors suggested that the 2 disorders are not separate
entities, but rather represent the same disease with a continuous
clinical spectrum.
.0011
MAY-HEGGLIN ANOMALY
MYH9, 1-BP DEL, 5818G
Kunishima et al. (2005) found a 1-bp deletion, 5818delG, in the MYH9
gene as the cause of May-Hegglin anomaly (155100) in a 1-year-old boy.
The deletion resulted in frameshift and premature termination. Kunishima
et al. (2005) found that the father was a somatic mosaic for this
mutation. The father had normal platelet counts; however, both
normal-sized and giant platelets were observed on his peripheral blood
smears. In addition, 14% of neutrophils contained inclusion bodies, and
the rest showed a normal morphology. Quantitative fluorescent PCR
analysis showed that only 6% of DNA from peripheral blood leukocytes
harbored the mutation. The mutation was demonstrated in a similar
frequency in different tissues, buccal mucosa cells, and hair bulb
cells, implying that the mutation had occurred during gastrulation.
Kunishima et al. (2005) concluded that mosaicism may account for some de
novo mutations in MYH9 disorders.
.0012
EPSTEIN SYNDROME
MYH9, SER96LEU
In affected individuals from 2 unrelated families with Epstein syndrome
(153650), Arrondel et al. (2002) identified a heterozygous 287C-T
transition in the MYH9 gene, resulting in a ser96-to-leu (S96L)
substitution predicted to disturb the helical region of the protein.
Utsch et al. (2006) identified a de novo heterozygous S96L mutation in
an infant girl with features of Epstein syndrome, including
macrothrombocytopenia and impaired platelet function but no evidence of
hearing loss or nephritis. She also had exstrophy of the bladder
(600057). Utsch et al. (2006) noted that although MYH9 mutations had not
previously been associated with urogenital malformations, the mutation
may have played a role in the bladder exstrophy in this patient.
By immunofluorescent studies of leukocytes derived from a patient with
the S96L mutation, Kunishima et al. (2003) detected abnormal subcellular
localization of MYH9, showing a speckled pattern or small dots.
Neutrophil inclusions had not been found on conventional Giemsa
staining.
.0013
MAY-HEGGLIN ANOMALY
SEBASTIAN SYNDROME, INCLUDED
MYH9, 21-BP DEL
In a patient described as having May-Hegglin anomaly (155100) and
Sebastian syndrome (605249), Seri et al. (2003) identified a
heterozygous 21-bp deletion in the MYH9 gene, resulting in an in-frame
deletion of 7 amino acids (E1066-A1072) in the rod domain. De Rocco et
al. (2009) identified the reciprocal in-frame duplication in another
family (160775.0014). Detailed sequence analysis of this region revealed
a 16-nucleotide repeat that was likely responsible for unequal
crossing-over.
.0014
MAY-HEGGLIN ANOMALY
MYH9, 21-BP DUP
In 3 affected members of a family with May-Hegglin anomaly (155100), De
Rocco et al. (2009) identified a heterozygous 21-bp duplication in exon
24 of the MYH9 gene, resulting in an in-frame duplication of 7 amino
acids (E1066-A1072) in the rod domain. All patients had congenital
macrothrombocytopenia and Dohle-like inclusion bodies in neutrophils,
consistent with May-Hegglin anomaly, and 1 patient also had congenital
cataracts, which is part of the phenotypic spectrum of MYH9-related
disorders. Seri et al. (2003) identified the reciprocal in-frame
deletion in another patient (160775.0013). Detailed sequence analysis of
this region revealed a 16-nucleotide repeat that was likely responsible
for unequal crossing-over.
.0015
MACROTHROMBOCYTOPENIA AND PROGRESSIVE SENSORINEURAL DEAFNESS
MYH9, 18-BP DEL, NT228
In a 45-year-old Japanese man with macrothrombocytopenia and
sensorineural deafness (600208), Kunishima et al. (2005) identified a
heterozygous 18-bp deletion (228_245del) in exon 1 of the MYH9 gene,
resulting in an in-frame deletion of 6 amino acids (asn76 to ser81) in a
helix segment adjacent to the SH1 helix. The mutation affected the
N-terminal head domain. The patient had no evidence of renal dysfunction
or cataract. Leukocyte morphology on conventional Giemsa staining was
ambiguous, but immunofluorescent staining showed abnormal subcellular
localization of MYH9. The MYH9-positive structures showed a thread-like
appearance, not punctuated or granular as often described in other
MYH9-related disorders.
*FIELD* RF
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5. Cusano, R.; Gangarossa, S.; Forabosco, P.; Caridi, G.; Ghiggeri,
G. M.; Russo, G.; Iolascon, A.; Ravazzolo, R.; Seri, M.: Localisation
of the gene responsible for Fechtner syndrome in a region less than
600 Kb on 22q11-q13. Europ. J. Hum. Genet. 8: 895-899, 2000.
6. D'Apolito, M.; Guarnieri, V.; Boncristiano, M.; Zelante, L.; Savoia,
A.: Cloning of the murine non-muscle myosin heavy chain IIA gene
ortholog of human MYH9 responsible for May-Hegglin, Sebastian, Fechtner,
and Epstein syndromes. Gene 286: 215-222, 2002.
7. De Rocco, D.; Pujol-Moix, N.; Pecci, A.; Faletra, F.; Bozzi, V.;
Balduini, C. L.; Savoia, A.: Identification of the first duplication
in MYH9-related disease: a hot spot for unequal crossing-over within
exon 24 of the MYH9 gene. Europ. J. Med. Genet. 52: 191-194, 2009.
8. Deutsch, S.; Rideau, A.; Bochaton-Piallat, M. L.; Merla, G.; Geinoz,
A.; Gabbiani, G.; Schwede, T.; Matthes, T.; Antonarakis, S. E.; Beris,
P.: Asp1424Asn MYH9 mutation results in an unstable protein responsible
for the phenotypes in May-Hegglin anomaly/Fechtner syndrome. Blood 102:
529-534, 2003.
9. Epstein, C. J.: Personal Communication. San Francisco, Ca.
4/16/2002.
10. Epstein, C. J.; Sahud, M. A.; Piel, C. F.; Goodman, J. R.; Bernfield,
M. R.; Kushner, J. H.; Ablin, A. R.: Hereditary macrothrombocytopathia,
nephritis and deafness. Am. J. Med. 52: 299-310, 1972.
11. Hanisch, J.; Kolm, R.; Wozniczka, M.; Bumann, D.; Rottner, K.;
Stradal, T. E. B.: Activation of a RhoA/myosin II-dependent but Arp2/3
complex-independent pathway facilitates Salmonella invasion. Cell
Host Microbe 9: 273-285, 2011.
12. Heath, K. E.; Campos-Barros, A.; Toren, A.; Rozenfeld-Granot,
G.; Carlsson, L. E.; Savige, J.; Denison, J. C.; Gregory, M. C.; White,
J. G.; Barker, D. F.; Greinacher, A.; Epstein, C. J.; Glucksman, M.
J.; Martignetti, J. A.: Nonmuscle myosin heavy chain IIA mutations
define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin
anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. Am.
J. Hum. Genet. 69: 1033-1045, 2001.
13. Hildebrand, M. S.; de Silva, M. G.; Gardner, R. J. M.; Rose, E.;
de Graaf, C. A.; Bahlo, M.; Dahl, H.-H. M.: Cochlear implants for
DFNA17 deafness. Laryngoscope 116: 2211-2215, 2006.
14. Hu, A.; Wang, F.; Sellers, J. R.: Mutations in human nonmuscle
myosin IIA found in patients with May-Hegglin anomaly and Fechtner
syndrome result in impaired enzymatic function. J. Biol. Chem. 277:
46512-46517, 2002.
15. Jacobelli, J.; Chmura, S. A.; Buxton, D. B.; Davis, M. M.; Krummel,
M. F.: A single class II myosin modulates T cell motility and stopping,
but not synapse formation. Nature Immun. 5: 531-538, 2004.
16. Kao, W. H. L.; Klag, M. J.; Meoni, L. A.; Reich, D.; Berthier-Schaad,
Y.; Li, M.; Coresh, J.; Patterson, N.; Tandon, A.; Powe, N. R.; Fink,
N. E.; Sadler, J. H.; and 19 others: MYH9 is associated with nondiabetic
end-stage renal disease in African Americans. Nature Genet. 40:
1185-1192, 2008.
17. Kelley, M. J.; Jawien, W.; Ortel, T. L.; Korczak, J. F.: Mutation
of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin
anomaly. Nature Genet. 26: 106-108, 2000.
18. Kopp, J. B.; Smith, M. W.; Nelson, G. W.; Johnson, R. C.; Freedman,
B. I.; Bowden, D. W.; Oleksyk, T.; McKenzie, L. M.; Kajiyama, H.;
Ahuja, T. S.; Berns, J. S.; Briggs, W.; and 10 others: MYH9 is
a major-effect risk gene for focal segmental glomerulosclerosis. Nature
Genet. 40: 1175-1184, 2008.
19. Kunishima, S.; Kojima, T.; Matsushita, T.; Tanaka, T.; Tsurusawa,
M.; Furukawa, Y.; Nakamura, Y.; Okamura, T.; Amemiya, N.; Nakayama,
T.; Kamiya, T.; Saito, H.: Mutations in the NMMHC-A gene cause autosomal
dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin
anomaly/Sebastian syndrome). Blood 97: 1147-1149, 2001.
20. Kunishima, S.; Matsushita, T.; Kojima, T.; Amemiya, N.; Choi,
Y. M.; Hosaka, N.; Inoue, M.; Jung, Y.; Mamiya, S.; Matsumoto, K.;
Miyajima, Y.; Zhang, G.; Ruan, C.; Saito, K.; Song, K. S.; Yoon, H.-J.;
Kamiya, T.; Saito, H.: Identification of six novel MYH9 mutations
and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia
with leukocyte inclusions. J. Hum. Genet. 46: 722-729, 2001.
21. Kunishima, S.; Matsushita, T.; Kojima, T.; Sako, M.; Kimura, F.;
Jo, E.-K.; Inoue, C.; Kamiya, T.; Saito, H.: Immunofluorescence analysis
of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association
of subcellular localization with MYH9 mutations. Lab. Invest. 83:
115-122, 2003.
22. Kunishima, S.; Matsushita, T.; Shiratsuchi, M.; Ikuta, T.; Nishimura,
J.; Hamaguchi, M.; Naoe, T.; Saito, H.: Detection of unique neutrophil
non-muscle myosin heavy chain-A localization by immunofluorescence
analysis in MYH9 disorder presented with macrothrombocytopenia without
leukocyte inclusions and deafness. Europ. J. Haematol. 74: 1-5,
2005.
23. Kunishima, S.; Matsushita, T.; Yoshihara, T.; Nakase, Y.; Yokoi,
K.; Hamaguchi, M.; Saito, H.: First description of somatic mosaicism
in MYH9 disorders. Brit. J. Haemat. 128: 360-365, 2005.
24. Lalwani, A. K.; Goldstein, J. A.; Kelley, M. J.; Luxford, W.;
Castelein, C. M.; Mhatre, A. N.: Human nonsyndromic hereditary deafness
DFNA17 is due to a mutation in nonmuscle myosin MYH9. Am. J. Hum.
Genet. 67: 1121-1128, 2000.
25. Lalwani, A. K.; Linthicum, F. H.; Wilcox, E. R.; Moore, J. K.;
Walters, F. C.; San Agustin, T. B.; Mislinski, J.; Miller, M. R.;
Sinninger, Y.; Attaie, A.; Luxford, W. M.: A five-generation family
with late-onset progressive hereditary hearing impairment due to cochleosaccular
degeneration. Audiol. Neurootol. 2: 139-154, 1997.
26. Martignetti, J. A.; Heath, K. E.; Harris, J.; Bizzaro, N.; Savoia,
A.; Balduini, C. L.; Desnick, R. J.: The gene for May-Hegglin anomaly
localizes to a less than 1-Mb region on chromosome 22q12.3-13.1. Am.
J. Hum. Genet. 66: 1449-1454, 2000.
27. Matsushita, T.; Hayashi, H.; Kunishima, S.; Hayashi, M.; Ikejiri,
M.; Takeshita, K.; Yuzawa, Y.; Adachi, T.; Hirashima, K.; Sone, M.;
Yamamoto, K.; Takagi, A.; Katsumi, A.; Kawai, K.; Nezu, T.; Takahashi,
M.; Nakashima, T.; Naoe, T.; Kojima, T.; Saito, H.: Targeted disruption
of mouse ortholog of the human MYH9 responsible for macrothrombocytopenia
with different organ involvement: hematological, nephrological, and
otological studies of heterozygous KO mice. Biochem. Biophys. Res.
Commun. 325: 1163-1171, 2004.
28. May-Hegglin/Fechtner Syndrome Consortium: Mutations in MYH9
result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. Nature
Genet. 26: 103-105, 2000.
29. Mhatre, A. N.; Kim, Y.; Brodie, H. A.; Lalwani, A. K.: Macrothrombocytopenia
and progressive deafness is due to a mutation in MYH9. Otol. Neurootol. 24:
205-209, 2003.
30. Moxey-Mims, M. M.; Young, G.; Silverman, A.; Selby, D. M.; White,
J. G.; Kher, K. K.: End-stage renal disease in two pediatric patients
with Fechtner syndrome. Pediat. Nephrol. 13: 782-786, 1999.
31. Parker, L. L.; Gao, J.; Zuo, J.: Absence of hearing loss in a
mouse model for DFNA17 and MYH9-related disease: the use of public
gene-targeted ES cell resources. Brain Res. 1091: 235-242, 2006.
32. Pecci, A.; Canobbio, I.; Balduini, A.; Stefanini, L.; Cisterna,
B.; Marseglia, C.; Noris, P.; Savoia, A.; Balduini, C. L.; Torti,
M.: Pathogenetic mechanisms of hematological abnormalities of patients
with MYH9 mutations. Hum. Molec. Genet. 14: 3169-3178, 2005.
33. Pecci, A.; Panza, E.; Pujol-Moix, N.; Klersy, C.; Di Bari, F.;
Bozzi, V.; Gresele, P.; Lethagen, S.; Fabris, F.; Dufour, C.; Granata,
A.; Doubek, M.; and 14 others: Position of nonmuscle myosin heavy
chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related
disease. Hum. Mutat. 29: 409-417, 2008.
34. Rocca, B.; Laghi, F.; Zini, G.; Maggiano, N.; Landolfi, R.: Fechtner
syndrome: report of a third family and literature review. Brit. J.
Haemat. 85: 423-426, 1993.
35. Saez, C. G.; Myers, J. C.; Shows, T. B.; Leinwand, L. A.: Human
nonmuscle myosin heavy chain mRNA: generation of diversity through
alternative polyadenylation. Proc. Nat. Acad. Sci. 87: 1164-1168,
1990.
36. Seri, M.; Pecci, A.; Di Bari, F.; Cusano, R.; Savino, M.; Panza,
E.; Nigro, A.; Noris, P.; Gangarossa, S.; Rocca, B.; Gresele, P.;
Bizzaro, N.; and 13 others: MYH9-related disease: May-Hegglin anomaly,
Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not
distinct entities but represent a variable expression of a single
illness. Medicine 82: 203-215, 2003.
37. Seri, M.; Savino, M.; Bordo, D.; Cusano, R.; Rocca, B.; Meloni,
I.; Di Bari, F.; Koivisto, P. A.; Bolognesi, M.; Ghiggeri, G. M.;
Landolfi, R.; Balduini, C. L.; Zelante, L.; Ravazzolo, R.; Renieri,
A.; Savoia, A.: Epstein syndrome: another renal disorder with mutations
in the nonmuscle myosin heavy chain 9 gene. Hum. Genet. 110: 182-186,
2002.
38. Simons, M.; Wang, M.; McBride, O. W.; Kawamoto, S.; Yamakawa,
K.; Gdula, D.; Adelstein, R. S.; Weir, L.: Human nonmuscle myosin
heavy chains are encoded by two genes located on different chromosomes. Circulation
Res. 69: 530-539, 1991.
39. Toothaker, L. E.; Gonzalez, D. A.; Tung, N.; Lemons, R. S.; Le
Beau, M. M.; Arnaout, M. A.; Clayton, L. K.; Tenen, D. G.: Cellular
myosin heavy chain in human leukocytes: isolation of 5-prime cDNA
clones, characterization of the protein, chromosomal localization,
and upregulation during myeloid differentiation. Blood 78: 1826-1833,
1991.
40. Utsch, B.; DiFeo, A.; Kujat, A.; Karle, S.; Schuster, V.; Lenk,
H.; Jacobs, U.; Muller, M.; Dotsch, J.; Rascher, W.; Reutter, H.;
Martignetti, J. A.; Ludwig, M.; Trobs, R.-B.: Bladder exstrophy and
Epstein type congenital macrothrombocytopenia: evidence for a common
cause? (Letter) Am. J. Med. Genet. 140A: 2251-2253, 2006.
41. Wilson, C. A.; Tsuchida, M. A.; Allen, G. M.; Barnhart, E. L.;
Applegate, K. T.; Yam, P. T.; Ji, L.; Keren, K.; Danuser, G.; Theriot,
J. A.: Myosin II contributes to cell-scale actin network treadmilling
through network disassembly. Nature 465: 373-377, 2010.
*FIELD* CN
Paul J. Converse - updated: 3/1/2012
Ada Hamosh - updated: 11/11/2010
Cassandra L. Kniffin - updated: 10/11/2010
Cassandra L. Kniffin - updated: 9/22/2010
Ada Hamosh - updated: 6/7/2010
George E. Tiller - updated: 7/21/2009
Ada Hamosh - updated: 1/16/2009
Cassandra L. Kniffin - updated: 6/26/2008
Cassandra L. Kniffin - updated: 12/18/2006
Patricia A. Hartz - updated: 2/9/2006
Victor A. McKusick - updated: 3/21/2005
Paul J. Converse - updated: 4/9/2004
Victor A. McKusick - updated: 10/15/2003
Patricia A. Hartz - updated: 1/16/2003
Victor A. McKusick - updated: 5/10/2002
Victor A. McKusick - updated: 3/6/2002
Victor A. McKusick - updated: 3/4/2002
Victor A. McKusick - updated: 11/27/2001
Victor A. McKusick - updated: 4/3/2001
Victor A. McKusick - updated: 11/21/2000
Victor A. McKusick - updated: 8/29/2000
*FIELD* CD
Victor A. McKusick: 3/1/1990
*FIELD* ED
mgross: 03/02/2012
terry: 3/1/2012
alopez: 12/6/2011
terry: 12/1/2011
alopez: 11/15/2010
terry: 11/11/2010
alopez: 11/3/2010
wwang: 10/29/2010
ckniffin: 10/11/2010
carol: 9/23/2010
ckniffin: 9/22/2010
alopez: 6/7/2010
wwang: 8/7/2009
terry: 7/21/2009
alopez: 3/12/2009
alopez: 1/23/2009
alopez: 1/22/2009
terry: 1/16/2009
terry: 12/2/2008
wwang: 7/2/2008
ckniffin: 6/26/2008
terry: 9/17/2007
carol: 2/23/2007
wwang: 12/27/2006
ckniffin: 12/18/2006
carol: 5/22/2006
mgross: 3/10/2006
mgross: 3/9/2006
terry: 2/9/2006
wwang: 3/23/2005
terry: 3/21/2005
alopez: 5/3/2004
mgross: 4/9/2004
terry: 11/11/2003
cwells: 10/15/2003
cwells: 1/22/2003
terry: 1/16/2003
cwells: 5/29/2002
terry: 5/10/2002
terry: 3/25/2002
alopez: 3/19/2002
terry: 3/6/2002
terry: 3/4/2002
alopez: 11/30/2001
terry: 11/27/2001
cwells: 4/6/2001
cwells: 4/4/2001
mcapotos: 4/3/2001
mcapotos: 2/2/2001
mcapotos: 12/11/2000
mcapotos: 11/29/2000
terry: 11/21/2000
alopez: 8/31/2000
terry: 8/29/2000
alopez: 4/30/1999
mimadm: 4/14/1994
carol: 12/14/1992
carol: 12/7/1992
supermim: 3/16/1992
carol: 11/13/1991
carol: 11/6/1991
MIM
600208
*RECORD*
*FIELD* NO
600208
*FIELD* TI
#600208 MACROTHROMBOCYTOPENIA AND PROGRESSIVE SENSORINEURAL DEAFNESS
*FIELD* TX
A number sign (#) is used with this entry because the disorder can be
read morecaused by mutation in the nonmuscle myosin heavy chain-9 gene (MYH9;
160775).
Other disorders caused by mutation in the MYH9 gene include May-Hegglin
anomaly (155100), Fechtner syndrome (153640), Sebastian syndrome
(605249), and Epstein syndrome (153650).
CLINICAL FEATURES
Brodie et al. (1992) reported a kindred with hereditary
macrothrombocytopenia and progressive sensorineural hearing loss. None
of the family members had any evidence of renal dysfunction. The
disorder was inherited by and through females in 4 generations. Hearing
impairment began before the third decade and progressed to
severe-to-profound bilateral hearing loss by the fourth decade. The
platelet disorder manifested in early childhood and persisted lifelong,
although it tended to remain asymptomatic.
Kunishima et al. (2005) reported a 45-year-old Japanese man with
macrothrombocytopenia and severe bilateral sensorineural deafness, but
no evidence of renal dysfunction. Leukocyte morphology on conventional
Giemsa staining was ambiguous, but immunofluorescent staining showed
abnormal subcellular localization of MYH9. The MYH9-positive structures
showed a thread-like appearance, not punctuated or granular as often
described in other MYH9-related disorders.
MOLECULAR GENETICS
In affected members of the family reported by Brodie et al. (1992),
Mhatre et al. (2003) identified a missense mutation in the MYH9 gene
(160775.0010). They noted that the same mutation has been found in
May-Hegglin anomaly (155100), Fechtner syndrome (153640), and Sebastian
syndrome (605249).
In a Japanese patient with macrothrombocytopenia and deafness, Kunishima
et al. (2005) identified a heterozygous mutation in the MYH9 gene
(160775.0015).
*FIELD* RF
1. Brodie, H. A.; Chole, R. A.; Griffin, G. C.; White, J. G.: Macrothrombocytopenia
and progressive deafness: a new genetic syndrome. Am. J. Otol. 13:
507-511, 1992.
2. Kunishima, S.; Matsushita, T.; Shiratsuchi, M.; Ikuta, T.; Nishimura,
J.; Hamaguchi, M.; Naoe, T.; Saito, H.: Detection of unique neutrophil
non-muscle myosin heavy chain-A localization by immunofluorescence
analysis in MYH9 disorder presented with macrothrombocytopenia without
leukocyte inclusions and deafness. Europ. J. Haematol. 74: 1-5,
2005.
3. Mhatre, A. N.; Kim, Y.; Brodie, H. A.; Lalwani, A. K.: Macrothrombocytopenia
and progressive deafness is due to a mutation in MYH9. Otol. Neurootol. 24:
205-209, 2003.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Hearing loss, progressive sensorineural;
[Eyes];
No cataracts
GENITOURINARY:
[Kidneys];
No kidney disease
HEMATOLOGY:
Thrombocytopenia;
Giant platelets;
No leukocyte inclusions on Giemsa staining;
MYH9-positive inclusions on immunohistochemical staining;
Variable bleeding episodes;
Asymptomatic (easy bruisability, postoperative hemorrhage)
LABORATORY ABNORMALITIES:
Thrombocytopenia (33-120 x 10(9)/L);
Normal to prolonged bleeding time
MISCELLANEOUS:
Onset of hearing loss in late childhood
MOLECULAR BASIS:
Caused by mutations in the myosin, heavy polypeptide-9, nonmuscle
gene (MYH9, 160775.0010)
*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Kelly A. Przylepa - updated: 6/2/2006
Kelly A. Przylepa - revised: 5/12/2006
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
wwang: 10/29/2010
ckniffin: 10/11/2010
joanna: 6/2/2006
joanna: 5/12/2006
*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Kelly A. Przylepa - updated: 5/22/2006
*FIELD* CD
Victor A. McKusick: 11/29/1994
*FIELD* ED
wwang: 10/29/2010
ckniffin: 10/11/2010
carol: 2/23/2007
carol: 5/22/2006
mimadm: 9/23/1995
terry: 11/29/1994
*RECORD*
*FIELD* NO
600208
*FIELD* TI
#600208 MACROTHROMBOCYTOPENIA AND PROGRESSIVE SENSORINEURAL DEAFNESS
*FIELD* TX
A number sign (#) is used with this entry because the disorder can be
read morecaused by mutation in the nonmuscle myosin heavy chain-9 gene (MYH9;
160775).
Other disorders caused by mutation in the MYH9 gene include May-Hegglin
anomaly (155100), Fechtner syndrome (153640), Sebastian syndrome
(605249), and Epstein syndrome (153650).
CLINICAL FEATURES
Brodie et al. (1992) reported a kindred with hereditary
macrothrombocytopenia and progressive sensorineural hearing loss. None
of the family members had any evidence of renal dysfunction. The
disorder was inherited by and through females in 4 generations. Hearing
impairment began before the third decade and progressed to
severe-to-profound bilateral hearing loss by the fourth decade. The
platelet disorder manifested in early childhood and persisted lifelong,
although it tended to remain asymptomatic.
Kunishima et al. (2005) reported a 45-year-old Japanese man with
macrothrombocytopenia and severe bilateral sensorineural deafness, but
no evidence of renal dysfunction. Leukocyte morphology on conventional
Giemsa staining was ambiguous, but immunofluorescent staining showed
abnormal subcellular localization of MYH9. The MYH9-positive structures
showed a thread-like appearance, not punctuated or granular as often
described in other MYH9-related disorders.
MOLECULAR GENETICS
In affected members of the family reported by Brodie et al. (1992),
Mhatre et al. (2003) identified a missense mutation in the MYH9 gene
(160775.0010). They noted that the same mutation has been found in
May-Hegglin anomaly (155100), Fechtner syndrome (153640), and Sebastian
syndrome (605249).
In a Japanese patient with macrothrombocytopenia and deafness, Kunishima
et al. (2005) identified a heterozygous mutation in the MYH9 gene
(160775.0015).
*FIELD* RF
1. Brodie, H. A.; Chole, R. A.; Griffin, G. C.; White, J. G.: Macrothrombocytopenia
and progressive deafness: a new genetic syndrome. Am. J. Otol. 13:
507-511, 1992.
2. Kunishima, S.; Matsushita, T.; Shiratsuchi, M.; Ikuta, T.; Nishimura,
J.; Hamaguchi, M.; Naoe, T.; Saito, H.: Detection of unique neutrophil
non-muscle myosin heavy chain-A localization by immunofluorescence
analysis in MYH9 disorder presented with macrothrombocytopenia without
leukocyte inclusions and deafness. Europ. J. Haematol. 74: 1-5,
2005.
3. Mhatre, A. N.; Kim, Y.; Brodie, H. A.; Lalwani, A. K.: Macrothrombocytopenia
and progressive deafness is due to a mutation in MYH9. Otol. Neurootol. 24:
205-209, 2003.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Hearing loss, progressive sensorineural;
[Eyes];
No cataracts
GENITOURINARY:
[Kidneys];
No kidney disease
HEMATOLOGY:
Thrombocytopenia;
Giant platelets;
No leukocyte inclusions on Giemsa staining;
MYH9-positive inclusions on immunohistochemical staining;
Variable bleeding episodes;
Asymptomatic (easy bruisability, postoperative hemorrhage)
LABORATORY ABNORMALITIES:
Thrombocytopenia (33-120 x 10(9)/L);
Normal to prolonged bleeding time
MISCELLANEOUS:
Onset of hearing loss in late childhood
MOLECULAR BASIS:
Caused by mutations in the myosin, heavy polypeptide-9, nonmuscle
gene (MYH9, 160775.0010)
*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Kelly A. Przylepa - updated: 6/2/2006
Kelly A. Przylepa - revised: 5/12/2006
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
wwang: 10/29/2010
ckniffin: 10/11/2010
joanna: 6/2/2006
joanna: 5/12/2006
*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Kelly A. Przylepa - updated: 5/22/2006
*FIELD* CD
Victor A. McKusick: 11/29/1994
*FIELD* ED
wwang: 10/29/2010
ckniffin: 10/11/2010
carol: 2/23/2007
carol: 5/22/2006
mimadm: 9/23/1995
terry: 11/29/1994
MIM
603622
*RECORD*
*FIELD* NO
603622
*FIELD* TI
#603622 DEAFNESS, AUTOSOMAL DOMINANT 17; DFNA17
COCHLEOSACCULAR DEGENERATION, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because this specific form of
deafness has been found to be caused by mutation in the MYH9 gene
(160775).
CLINICAL FEATURES
Lalwani et al. (1999) studied a 5-generation American family, previously
reported by Lalwani et al. (1997), with deafness caused by
cochleosaccular degeneration (CSD). CSD is the most common
histopathologic finding in cases of profound congenital deafness and is
estimated to occur in approximately 70% of cases. CSD was first
described by Scheibe (1892) and is commonly known as Scheibe dysplasia.
It affects structures that are derived from the pars inferior of the
otocyst. Thus, the membranous cochlea and saccule are affected, but the
osseous labyrinth, the membranous utricle, and the semicircular canals
are normal. The family studied by Lalwani et al. (1997, 1999) had been
identified through a temporal bone database; because there is no
clinically available test to diagnose CSD, postmortem histologic
examination of the temporal bone is required. The affected family
members exhibited nonsyndromic hearing loss with an autosomal dominant
mode of transmission; there was no pigmentary abnormality. The hearing
impairment began at age 10 years and involved only the high frequencies;
by the third decade of life, affected family members had moderate to
severe deafness.
Hildebrand et al. (2006) reported a 5-generation Australian family of
Anglo Celtic origin with nonsyndromic DFNA17. The self-reported age of
onset ranged from 6 years to the mid-twenties. The hearing loss was
progressive with a general trend of initial mild high-frequency loss
during childhood and adolescence and with a flattening of the audiogram
over time. The hearing loss became severe to profound by the second to
third decades, although there was some intrafamilial variability.
CLINICAL MANAGEMENT
Hildebrand et al. (2006) reported that 5 individuals in their Australian
family received cochlear implants with excellent results and noted the
contrast between the results of cochlear implant in their family and the
poor results after cochlear implant reported in 1 patient from the
family of Lalwani et al. (2000). Hildebrand et al. (2006) speculated
that early intervention plays an important role in the therapeutic
response.
MAPPING
Lalwani et al. (1999) mapped the nonsyndromic hereditary hearing
impairment in the family studied by them to chromosome 22q12.2-q13.3 by
linkage analysis.
MOLECULAR GENETICS
DFNA17 maps to the same region as MYH9 (160775), a nonmuscle-myosin
heavy-chain gene. Because of the importance of myosins in hearing,
Lalwani et al. (2000) tested MYH9 as a candidate gene for DFNA17.
Expression of MYH9 in the rat cochlea was confirmed using RT-PCR and
immunohistochemistry analysis. MYH9 was immunolocalized in the organ of
Corti, the subcentral region of the spiral ligament, and the Reissner
membrane. Sequence analysis of MYH9 in the family previously studied by
Lalwani et al. (1997, 1999) demonstrated that a heterozygous mutation
(R705H; 160775.0008) cosegregated with deafness.
In affected members of a 5-generation Australian family of Anglo Celtic
origin with nonsyndromic DFNA17, Hildebrand et al. (2006) identified a
heterozygous R705H mutation in the MYH9 gene.
*FIELD* RF
1. Hildebrand, M. S.; de Silva, M. G.; Gardner, R. J. M.; Rose, E.;
de Graaf, C. A.; Bahlo, M.; Dahl, H.-H. M.: Cochlear implants for
DFNA17 deafness. Laryngoscope 116: 2211-2215, 2006.
2. Lalwani, A. K.; Goldstein, J. A.; Kelley, M. J.; Luxford, W.; Castelein,
C. M.; Mhatre, A. N.: Human nonsyndromic hereditary deafness DFNA17
is due to a mutation in nonmuscle myosin MYH9. Am. J. Hum. Genet. 67:
1121-1128, 2000.
3. Lalwani, A. K.; Linthicum, F. H.; Wilcox, E. R.; Moore, J. K.;
Walters, F. C.; San Agustin, T. B.; Mislinski, J.; Miller, M. R.;
Sinninger, Y.; Attaie, A.; Luxford, W. M.: A five-generation family
with late-onset progressive hereditary hearing impairment due to cochleosaccular
degeneration. Audiol. Neurootol. 2: 139-154, 1997.
4. Lalwani, A. K.; Luxford, W. M.; Mhatre, A. N.; Attaie, A.; Wilcox,
E. R.; Castelein, C. M.: A new locus for nonsyndromic hereditary
hearing impairment, DFNA17, maps to chromosome 22 and represents a
gene for cochleosaccular degeneration. (Letter) Am. J. Hum. Genet. 64:
318-323, 1999.
5. Scheibe, A.: A case of deaf-mutism, with auditory atrophy and
anomalies of development in the membranous labyrinth of both ears. Arch.
Otolaryng. 21: 12-22, 1892.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Hearing loss, high-frequency (onset in childhood-adolescence);
Deafness, moderate-severe (onset in third decade);
Cochleosaccular dysplasia;
Organ of Corti degeneration
MISCELLANEOUS:
Onset of hearing loss in late childhood or adolescence;
Allelic to Fechtner syndrome (153640), May-Hegglin anomaly (155100),
Sebastian syndrome (605249), and Epstein syndrome (153650)
MOLECULAR BASIS:
Caused by mutation in the myosin, heavy chain 9, nonmuscle gene (MYH9,
160775.0008)
*FIELD* CD
Kelly A. Przylepa: 3/13/2007
*FIELD* ED
terry: 02/19/2009
joanna: 3/13/2007
*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Victor A. McKusick - updated: 11/21/2000
*FIELD* CD
Victor A. McKusick: 3/10/1999
*FIELD* ED
wwang: 10/29/2010
ckniffin: 10/11/2010
alopez: 6/25/2009
terry: 12/2/2008
carol: 12/11/2000
mcapotos: 12/11/2000
mcapotos: 11/29/2000
terry: 11/21/2000
mgross: 3/16/1999
carol: 3/10/1999
*RECORD*
*FIELD* NO
603622
*FIELD* TI
#603622 DEAFNESS, AUTOSOMAL DOMINANT 17; DFNA17
COCHLEOSACCULAR DEGENERATION, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because this specific form of
deafness has been found to be caused by mutation in the MYH9 gene
(160775).
CLINICAL FEATURES
Lalwani et al. (1999) studied a 5-generation American family, previously
reported by Lalwani et al. (1997), with deafness caused by
cochleosaccular degeneration (CSD). CSD is the most common
histopathologic finding in cases of profound congenital deafness and is
estimated to occur in approximately 70% of cases. CSD was first
described by Scheibe (1892) and is commonly known as Scheibe dysplasia.
It affects structures that are derived from the pars inferior of the
otocyst. Thus, the membranous cochlea and saccule are affected, but the
osseous labyrinth, the membranous utricle, and the semicircular canals
are normal. The family studied by Lalwani et al. (1997, 1999) had been
identified through a temporal bone database; because there is no
clinically available test to diagnose CSD, postmortem histologic
examination of the temporal bone is required. The affected family
members exhibited nonsyndromic hearing loss with an autosomal dominant
mode of transmission; there was no pigmentary abnormality. The hearing
impairment began at age 10 years and involved only the high frequencies;
by the third decade of life, affected family members had moderate to
severe deafness.
Hildebrand et al. (2006) reported a 5-generation Australian family of
Anglo Celtic origin with nonsyndromic DFNA17. The self-reported age of
onset ranged from 6 years to the mid-twenties. The hearing loss was
progressive with a general trend of initial mild high-frequency loss
during childhood and adolescence and with a flattening of the audiogram
over time. The hearing loss became severe to profound by the second to
third decades, although there was some intrafamilial variability.
CLINICAL MANAGEMENT
Hildebrand et al. (2006) reported that 5 individuals in their Australian
family received cochlear implants with excellent results and noted the
contrast between the results of cochlear implant in their family and the
poor results after cochlear implant reported in 1 patient from the
family of Lalwani et al. (2000). Hildebrand et al. (2006) speculated
that early intervention plays an important role in the therapeutic
response.
MAPPING
Lalwani et al. (1999) mapped the nonsyndromic hereditary hearing
impairment in the family studied by them to chromosome 22q12.2-q13.3 by
linkage analysis.
MOLECULAR GENETICS
DFNA17 maps to the same region as MYH9 (160775), a nonmuscle-myosin
heavy-chain gene. Because of the importance of myosins in hearing,
Lalwani et al. (2000) tested MYH9 as a candidate gene for DFNA17.
Expression of MYH9 in the rat cochlea was confirmed using RT-PCR and
immunohistochemistry analysis. MYH9 was immunolocalized in the organ of
Corti, the subcentral region of the spiral ligament, and the Reissner
membrane. Sequence analysis of MYH9 in the family previously studied by
Lalwani et al. (1997, 1999) demonstrated that a heterozygous mutation
(R705H; 160775.0008) cosegregated with deafness.
In affected members of a 5-generation Australian family of Anglo Celtic
origin with nonsyndromic DFNA17, Hildebrand et al. (2006) identified a
heterozygous R705H mutation in the MYH9 gene.
*FIELD* RF
1. Hildebrand, M. S.; de Silva, M. G.; Gardner, R. J. M.; Rose, E.;
de Graaf, C. A.; Bahlo, M.; Dahl, H.-H. M.: Cochlear implants for
DFNA17 deafness. Laryngoscope 116: 2211-2215, 2006.
2. Lalwani, A. K.; Goldstein, J. A.; Kelley, M. J.; Luxford, W.; Castelein,
C. M.; Mhatre, A. N.: Human nonsyndromic hereditary deafness DFNA17
is due to a mutation in nonmuscle myosin MYH9. Am. J. Hum. Genet. 67:
1121-1128, 2000.
3. Lalwani, A. K.; Linthicum, F. H.; Wilcox, E. R.; Moore, J. K.;
Walters, F. C.; San Agustin, T. B.; Mislinski, J.; Miller, M. R.;
Sinninger, Y.; Attaie, A.; Luxford, W. M.: A five-generation family
with late-onset progressive hereditary hearing impairment due to cochleosaccular
degeneration. Audiol. Neurootol. 2: 139-154, 1997.
4. Lalwani, A. K.; Luxford, W. M.; Mhatre, A. N.; Attaie, A.; Wilcox,
E. R.; Castelein, C. M.: A new locus for nonsyndromic hereditary
hearing impairment, DFNA17, maps to chromosome 22 and represents a
gene for cochleosaccular degeneration. (Letter) Am. J. Hum. Genet. 64:
318-323, 1999.
5. Scheibe, A.: A case of deaf-mutism, with auditory atrophy and
anomalies of development in the membranous labyrinth of both ears. Arch.
Otolaryng. 21: 12-22, 1892.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Hearing loss, high-frequency (onset in childhood-adolescence);
Deafness, moderate-severe (onset in third decade);
Cochleosaccular dysplasia;
Organ of Corti degeneration
MISCELLANEOUS:
Onset of hearing loss in late childhood or adolescence;
Allelic to Fechtner syndrome (153640), May-Hegglin anomaly (155100),
Sebastian syndrome (605249), and Epstein syndrome (153650)
MOLECULAR BASIS:
Caused by mutation in the myosin, heavy chain 9, nonmuscle gene (MYH9,
160775.0008)
*FIELD* CD
Kelly A. Przylepa: 3/13/2007
*FIELD* ED
terry: 02/19/2009
joanna: 3/13/2007
*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Victor A. McKusick - updated: 11/21/2000
*FIELD* CD
Victor A. McKusick: 3/10/1999
*FIELD* ED
wwang: 10/29/2010
ckniffin: 10/11/2010
alopez: 6/25/2009
terry: 12/2/2008
carol: 12/11/2000
mcapotos: 12/11/2000
mcapotos: 11/29/2000
terry: 11/21/2000
mgross: 3/16/1999
carol: 3/10/1999
MIM
605249
*RECORD*
*FIELD* NO
605249
*FIELD* TI
#605249 SEBASTIAN SYNDROME; SBS
;;SEBASTIAN PLATELET SYNDROME;;
MACROTHROMBOCYTOPENIA WITH DISPERSED LEUKOCYTIC INCLUSIONS
read more*FIELD* TX
A number sign (#) is used with this entry because Sebastian syndrome is
caused by heterozygous mutation in the MYH9 gene (160775) on chromosome
22q11.2.
DESCRIPTION
Sebastian syndrome is an autosomal dominant disorder characterized by
the triad of thrombocytopenia, giant platelets, and inclusions in
peripheral blood leukocytes (Greinacher et al., 1990).
There are several other disorders caused by mutation in the MYH9 gene
that share overlapping features with Sebastian syndrome. May-Hegglin
anomaly (155100) shares the same triad as Sebastian syndrome, but has a
different ultrastructural appearance of the leukocyte inclusions. In
May-Hegglin anomaly, the inclusions are composed of clusters of
ribosomes oriented along parallel microfilaments, whereas in Sebastian
syndrome, the leukocyte inclusions are composed of highly dispersed
filaments and few ribosomes. Fechtner syndrome (153640) has the platelet
defect accompanied by nephritis, hearing loss, and eye abnormalities,
mostly cataracts. Epstein syndrome (153650) has the platelet defect,
deafness, and nephritis, but does not have cataract and lacks leukocyte
inclusion bodies on classic staining of peripheral blood smears. The
findings of nephritis, hearing loss, and occasional cataracts in
Fechtner and Epstein syndromes are reminiscent of Alport syndrome
(301050). Seri et al. (2003) suggested that these 4 disorders,
May-Hegglin, Sebastian, Epstein, and Fechtner syndromes, are not
distinct entities, but rather represent a single disorder with a
continuous clinical spectrum, for which they proposed the term
'MYH9-related disease.' However, other disorders, e.g.,
macrothrombocytopenia and progressive sensorineural deafness (600208)
and a form of nonsyndromic deafness (DFNA17; 603622), are also caused by
mutation in the MYH9 gene.
CLINICAL FEATURES
Greinacher et al. (1990) described the Sebastian platelet syndrome, a
variant of hereditary macrothrombocytopenia combined with the presence
of neutrophil inclusions that differed from those found in patients with
May-Hegglin anomaly (155100), the Chediak-Higashi syndrome (214500), or
individuals with septicemia, and toxic Dohle bodies in polymorphonuclear
leukocytes. The inclusions in polymorphonuclear leukocytes were similar
to those found in patients with Fechtner syndrome (153640).
Greinacher and Mueller-Eckhardt (1990) referred to the Sebastian
platelet syndrome as an autosomal dominant disorder characterized by the
same hematologic changes as those in the Fechtner syndrome, but without
the manifestations of Alport syndrome (301050).
Using immunocytochemical analysis, Seri et al. (2003) detected an
irregular distribution of myosin in neutrophil cytoplasm of all 22
patients with mutations in the MYH9 gene, including 2 patients with a
diagnosis of Sebastian syndrome. Large myosin aggregates appeared as
Dohle-like bodies, whereas the smaller ones were not readily
recognizable on Giemsa-stained peripheral blood smears.
- Clinical Variability
Seri et al. (2003) found sensorineural hearing loss for high tones in 9
(82%) of 11 patients initially diagnosed as having May-Hegglin anomaly
or Sebastian syndrome. Three patients with May-Hegglin anomaly or
Sebastian syndrome were found to have cataracts. In addition,
microscopic hematuria or proteinuria was found in 4 patients with
May-Hegglin anomaly and 2 with Sebastian syndrome. These clinical
findings emphasized the phenotypic overlap among MYH9-related disorders.
MOLECULAR GENETICS
The May-Hegglin/Fechtner Syndrome Consortium (2000) identified a
heterozygous mutation in the MYH9 gene (160775.0003) in a patient with
Sebastian syndrome.
*FIELD* RF
1. Greinacher, A.; Mueller-Eckhardt, C.: Hereditary types of thrombocytopenia
with giant platelets and inclusion bodies in the leukocytes. Blut 60:
53-60, 1990.
2. Greinacher, A.; Nieuwenhuis, H. K.; White, J. C.: Sebastian platelet
syndrome: a new variant of hereditary macrothrombocytopenia with leukocyte
inclusions. Blut 61: 282-288, 1990.
3. May-Hegglin/Fechtner Syndrome Consortium: Mutations in MYH9
result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. Nature
Genet. 26: 103-105, 2000.
4. Seri, M.; Pecci, A.; Di Bari, F.; Cusano, R.; Savino, M.; Panza,
E.; Nigro, A.; Noris, P.; Gangarossa, S.; Rocca, B.; Gresele, P.;
Bizzaro, N.; and 13 others: MYH9-related disease: May-Hegglin anomaly,
Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not
distinct entities but represent a variable expression of a single
illness. Medicine 82: 203-215, 2003.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
No deafness;
[Eyes];
No cataracts
GENITOURINARY:
[Kidneys];
No nephritis
HEMATOLOGY:
Asymptomatic to mild bleeding episodes (epistaxis, postoperative hemorrhage);
Thrombocytopenia;
Giant platelets;
Leukocyte inclusion bodies (Dohle-like bodies)
LABORATORY ABNORMALITIES:
Mild to moderate thrombocytopenia (40-120 x 10(9)/l);
Median mean platelet volume (MPV) 18fl;
Mildly prolonged bleeding time 10-12 minutes;
Normal platelet aggregation response to arachidonic acid (AA), adenosine
5'-diphosphate (ADP), collagen, and ristocetin
MISCELLANEOUS:
Allelic to May-Hegglin anomaly (155100), Fechtner syndrome (153640),
Epstein syndrome (153650) and deafness, autosomal dominant 17 (603622)
MOLECULAR BASIS:
Caused by mutation in myosin, heavy chain 9, non-muscle gene (MYH9,
160775.0001)
*FIELD* CD
Kelly A. Przylepa: 3/1/2007
*FIELD* ED
wwang: 02/07/2011
terry: 2/19/2009
joanna: 1/15/2008
joanna: 3/2/2007
*FIELD* CN
Cassandra L. Kniffin - updated: 9/22/2010
*FIELD* CD
Victor A. McKusick: 8/31/2000
*FIELD* ED
carol: 01/08/2013
carol: 9/23/2010
ckniffin: 9/22/2010
carol: 5/22/2006
alopez: 8/31/2000
*RECORD*
*FIELD* NO
605249
*FIELD* TI
#605249 SEBASTIAN SYNDROME; SBS
;;SEBASTIAN PLATELET SYNDROME;;
MACROTHROMBOCYTOPENIA WITH DISPERSED LEUKOCYTIC INCLUSIONS
read more*FIELD* TX
A number sign (#) is used with this entry because Sebastian syndrome is
caused by heterozygous mutation in the MYH9 gene (160775) on chromosome
22q11.2.
DESCRIPTION
Sebastian syndrome is an autosomal dominant disorder characterized by
the triad of thrombocytopenia, giant platelets, and inclusions in
peripheral blood leukocytes (Greinacher et al., 1990).
There are several other disorders caused by mutation in the MYH9 gene
that share overlapping features with Sebastian syndrome. May-Hegglin
anomaly (155100) shares the same triad as Sebastian syndrome, but has a
different ultrastructural appearance of the leukocyte inclusions. In
May-Hegglin anomaly, the inclusions are composed of clusters of
ribosomes oriented along parallel microfilaments, whereas in Sebastian
syndrome, the leukocyte inclusions are composed of highly dispersed
filaments and few ribosomes. Fechtner syndrome (153640) has the platelet
defect accompanied by nephritis, hearing loss, and eye abnormalities,
mostly cataracts. Epstein syndrome (153650) has the platelet defect,
deafness, and nephritis, but does not have cataract and lacks leukocyte
inclusion bodies on classic staining of peripheral blood smears. The
findings of nephritis, hearing loss, and occasional cataracts in
Fechtner and Epstein syndromes are reminiscent of Alport syndrome
(301050). Seri et al. (2003) suggested that these 4 disorders,
May-Hegglin, Sebastian, Epstein, and Fechtner syndromes, are not
distinct entities, but rather represent a single disorder with a
continuous clinical spectrum, for which they proposed the term
'MYH9-related disease.' However, other disorders, e.g.,
macrothrombocytopenia and progressive sensorineural deafness (600208)
and a form of nonsyndromic deafness (DFNA17; 603622), are also caused by
mutation in the MYH9 gene.
CLINICAL FEATURES
Greinacher et al. (1990) described the Sebastian platelet syndrome, a
variant of hereditary macrothrombocytopenia combined with the presence
of neutrophil inclusions that differed from those found in patients with
May-Hegglin anomaly (155100), the Chediak-Higashi syndrome (214500), or
individuals with septicemia, and toxic Dohle bodies in polymorphonuclear
leukocytes. The inclusions in polymorphonuclear leukocytes were similar
to those found in patients with Fechtner syndrome (153640).
Greinacher and Mueller-Eckhardt (1990) referred to the Sebastian
platelet syndrome as an autosomal dominant disorder characterized by the
same hematologic changes as those in the Fechtner syndrome, but without
the manifestations of Alport syndrome (301050).
Using immunocytochemical analysis, Seri et al. (2003) detected an
irregular distribution of myosin in neutrophil cytoplasm of all 22
patients with mutations in the MYH9 gene, including 2 patients with a
diagnosis of Sebastian syndrome. Large myosin aggregates appeared as
Dohle-like bodies, whereas the smaller ones were not readily
recognizable on Giemsa-stained peripheral blood smears.
- Clinical Variability
Seri et al. (2003) found sensorineural hearing loss for high tones in 9
(82%) of 11 patients initially diagnosed as having May-Hegglin anomaly
or Sebastian syndrome. Three patients with May-Hegglin anomaly or
Sebastian syndrome were found to have cataracts. In addition,
microscopic hematuria or proteinuria was found in 4 patients with
May-Hegglin anomaly and 2 with Sebastian syndrome. These clinical
findings emphasized the phenotypic overlap among MYH9-related disorders.
MOLECULAR GENETICS
The May-Hegglin/Fechtner Syndrome Consortium (2000) identified a
heterozygous mutation in the MYH9 gene (160775.0003) in a patient with
Sebastian syndrome.
*FIELD* RF
1. Greinacher, A.; Mueller-Eckhardt, C.: Hereditary types of thrombocytopenia
with giant platelets and inclusion bodies in the leukocytes. Blut 60:
53-60, 1990.
2. Greinacher, A.; Nieuwenhuis, H. K.; White, J. C.: Sebastian platelet
syndrome: a new variant of hereditary macrothrombocytopenia with leukocyte
inclusions. Blut 61: 282-288, 1990.
3. May-Hegglin/Fechtner Syndrome Consortium: Mutations in MYH9
result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. Nature
Genet. 26: 103-105, 2000.
4. Seri, M.; Pecci, A.; Di Bari, F.; Cusano, R.; Savino, M.; Panza,
E.; Nigro, A.; Noris, P.; Gangarossa, S.; Rocca, B.; Gresele, P.;
Bizzaro, N.; and 13 others: MYH9-related disease: May-Hegglin anomaly,
Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not
distinct entities but represent a variable expression of a single
illness. Medicine 82: 203-215, 2003.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
No deafness;
[Eyes];
No cataracts
GENITOURINARY:
[Kidneys];
No nephritis
HEMATOLOGY:
Asymptomatic to mild bleeding episodes (epistaxis, postoperative hemorrhage);
Thrombocytopenia;
Giant platelets;
Leukocyte inclusion bodies (Dohle-like bodies)
LABORATORY ABNORMALITIES:
Mild to moderate thrombocytopenia (40-120 x 10(9)/l);
Median mean platelet volume (MPV) 18fl;
Mildly prolonged bleeding time 10-12 minutes;
Normal platelet aggregation response to arachidonic acid (AA), adenosine
5'-diphosphate (ADP), collagen, and ristocetin
MISCELLANEOUS:
Allelic to May-Hegglin anomaly (155100), Fechtner syndrome (153640),
Epstein syndrome (153650) and deafness, autosomal dominant 17 (603622)
MOLECULAR BASIS:
Caused by mutation in myosin, heavy chain 9, non-muscle gene (MYH9,
160775.0001)
*FIELD* CD
Kelly A. Przylepa: 3/1/2007
*FIELD* ED
wwang: 02/07/2011
terry: 2/19/2009
joanna: 1/15/2008
joanna: 3/2/2007
*FIELD* CN
Cassandra L. Kniffin - updated: 9/22/2010
*FIELD* CD
Victor A. McKusick: 8/31/2000
*FIELD* ED
carol: 01/08/2013
carol: 9/23/2010
ckniffin: 9/22/2010
carol: 5/22/2006
alopez: 8/31/2000