RBCC Red Blood Cell Collection

MYH7 (MYHCB) [Confidence: low (only semi-automatic identification from reviews)]
Myosin-7 (Myosin heavy chain 7; Myosin heavy chain slow isoform; MyHC-slow; Myosin heavy chain, cardiac muscle beta isoform; MyHC-beta)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P12883
ID MYH7_HUMAN Reviewed; 1935 AA.
AC P12883; A2TDB6; B6D424; Q14836; Q14837; Q14904; Q16579; Q2M1Y6;
read moreAC Q92679; Q9H1D5; Q9UDA2; Q9UMM8;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
DT 06-DEC-2005, sequence version 5.
DT 22-JAN-2014, entry version 171.
DE RecName: Full=Myosin-7;
DE AltName: Full=Myosin heavy chain 7;
DE AltName: Full=Myosin heavy chain slow isoform;
DE Short=MyHC-slow;
DE AltName: Full=Myosin heavy chain, cardiac muscle beta isoform;
DE Short=MyHC-beta;
GN Name=MYH7; Synonyms=MYHCB;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND VARIANT SER-1124.
RX PubMed=2249844; DOI=10.1016/0888-7543(90)90272-V;
RA Jaenicke T., Diederich K.W., Haas W., Schleich J., Lichter P.,
RA Pfordt M., Bach A., Vosberg H.P.;
RT "The complete sequence of the human beta-myosin heavy chain gene and a
RT comparative analysis of its product.";
RL Genomics 8:194-206(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLU-107.
RX PubMed=2362820; DOI=10.1093/nar/18.12.3647;
RA Liew C.-C., Sole M.J., Yamauchi-Takihara K., Kellam B., Anderson D.H.,
RA Lin L., Liew J.;
RT "Complete sequence and organization of the human cardiac beta-myosin
RT heavy chain gene.";
RL Nucleic Acids Res. 18:3647-3651(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10996847;
RX DOI=10.1002/1097-4644(20001215)79:4<566::AID-JCB50>3.3.CO;2-5;
RA Wendel B., Reinhard R., Wachtendorf U., Zacharzowsky U.B.,
RA Osterziel K.J., Schulte H.D., Haase H., Hoehe M.R., Morano I.;
RT "The human beta-myosin heavy chain gene: sequence diversity and
RT functional characteristics of the protein.";
RL J. Cell. Biochem. 79:566-575(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Smaniotto G., Melacini P.;
RT "Diverse clinicopathologic profiles and determinants of progressive
RT heart failure in hypertrophic cardiomyopathy.";
RL Submitted (MAY-2008) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (DEC-2006) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-176, AND VARIANT GLU-107.
RX PubMed=2726733; DOI=10.1073/pnas.86.10.3504;
RA Yamauchi-Takihara K., Sole M.J., Liew J., Ing D., Liew C.-C.;
RT "Characterization of human cardiac myosin heavy chain genes.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:3504-3508(1989).
RN [9]
RP ERRATUM.
RA Yamauchi-Takihara K., Sole M.J., Liew J., Ing D., Liew C.-C.;
RL Proc. Natl. Acad. Sci. U.S.A. 86:7416-7417(1989).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 370-434, TISSUE SPECIFICITY, AND VARIANT
RP GLN-403.
RC TISSUE=Skeletal muscle;
RX PubMed=8514894; DOI=10.1172/JCI116530;
RA Cuda G., Fananapazir L., Zhu W.S., Sellers J.R., Epstein N.D.;
RT "Skeletal muscle expression and abnormal function of beta-myosin in
RT hypertrophic cardiomyopathy.";
RL J. Clin. Invest. 91:2861-2865(1993).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 653-720.
RX PubMed=2522082; DOI=10.1007/BF00278991;
RA Diederich K.W., Eisele I., Ried T., Jaenicke T., Lichter P.,
RA Vosberg H.P.;
RT "Isolation and characterization of the complete human beta-myosin
RT heavy chain gene.";
RL Hum. Genet. 81:214-220(1989).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 684-721; 975-1111 AND 1853-1935.
RX PubMed=3021460; DOI=10.1111/j.1432-1033.1986.tb09989.x;
RA Lichter P., Umeda P.K., Levin J.E., Vosberg H.P.;
RT "Partial characterization of the human beta-myosin heavy-chain gene
RT which is expressed in heart and skeletal muscle.";
RL Eur. J. Biochem. 160:419-426(1986).
RN [13]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 785-1935.
RC TISSUE=Skeletal muscle;
RX PubMed=1691980; DOI=10.1111/j.1432-1033.1990.tb15459.x;
RA Bober E., Buchberger-Seidl A., Braun T., Singh S., Goedde H.W.,
RA Arnold H.H.;
RT "Identification of three developmentally controlled isoforms of human
RT myosin heavy chains.";
RL Eur. J. Biochem. 189:55-65(1990).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1310-1935.
RX PubMed=2421254; DOI=10.1093/nar/14.7.2951;
RA Saez L., Leinwand L.A.;
RT "Characterization of diverse forms of myosin heavy chain expressed in
RT adult human skeletal muscle.";
RL Nucleic Acids Res. 14:2951-2969(1986).
RN [15]
RP SEQUENCE REVISION.
RA Leinwand L.A.;
RL Submitted (MAR-1988) to the EMBL/GenBank/DDBJ databases.
RN [16]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1393-1935.
RX PubMed=3032769; DOI=10.1007/BF00283049;
RA Jandreski M.A., Liew C.-C.;
RT "Construction of a human ventricular cDNA library and characterization
RT of a beta myosin heavy chain cDNA clone.";
RL Hum. Genet. 76:47-53(1987).
RN [17]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1412-1935.
RX PubMed=2969919; DOI=10.1172/JCI113627;
RA Kurabayashi M., Tsuchimochi H., Komuro I., Takaku F., Yazaki Y.;
RT "Molecular cloning and characterization of human cardiac alpha- and
RT beta-form myosin heavy chain complementary DNA clones. Regulation of
RT expression during development and pressure overload in human atrium.";
RL J. Clin. Invest. 82:524-531(1988).
RN [18]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1854-1935.
RX PubMed=3037493; DOI=10.1093/nar/15.13.5443;
RA Saez L.J., Gianola K.M., McNally E.M., Feghali R., Eddy R.,
RA Shows T.B., Leinwand L.A.;
RT "Human cardiac myosin heavy chain genes and their linkage in the
RT genome.";
RL Nucleic Acids Res. 15:5443-5459(1987).
RN [19]
RP REVIEW ON VARIANTS.
RX PubMed=8533830; DOI=10.1002/ajmg.1320580314;
RA Arai S., Matsuoka R., Hirayama K., Sukurai H., Tamura M., Ozawa T.,
RA Kimura M., Imamura S., Furutani Y., Joh-o K., Kawana M., Takao A.,
RA Hosoda S., Momma K.;
RT "Missense mutation of the beta-cardiac myosin heavy-chain gene in
RT hypertrophic cardiomyopathy.";
RL Am. J. Med. Genet. 58:267-276(1995).
RN [20]
RP INTERACTION WITH ECM29.
RX PubMed=20682791; DOI=10.1074/jbc.M110.154120;
RA Gorbea C., Pratt G., Ustrell V., Bell R., Sahasrabudhe S.,
RA Hughes R.E., Rechsteiner M.;
RT "A protein interaction network for Ecm29 links the 26 S proteasome to
RT molecular motors and endosomal components.";
RL J. Biol. Chem. 285:31616-31633(2010).
RN [21]
RP VARIANT CMH1 GLN-403.
RX PubMed=1975517; DOI=10.1016/0092-8674(90)90274-I;
RA Geisterfer-Lowrance A.A.T., Kass S., Tanigawa G., Vosberg H.-P.,
RA McKenna W., Seidman C.E., Seidman J.G.;
RT "A molecular basis for familial hypertrophic cardiomyopathy: a beta
RT cardiac myosin heavy chain gene missense mutation.";
RL Cell 62:999-1006(1990).
RN [22]
RP VARIANT CMH1 ASN-615.
RX PubMed=1417858; DOI=10.1016/0006-291X(92)92396-F;
RA Nishi H., Kimura A., Harada H., Toshima H., Sasazuki T.;
RT "Novel missense mutation in cardiac beta myosin heavy chain gene found
RT in a Japanese patient with hypertrophic cardiomyopathy.";
RL Biochem. Biophys. Res. Commun. 188:379-387(1992).
RN [23]
RP VARIANTS CMH1 GLN-403 AND VAL-908.
RX PubMed=1638703;
RA Epstein N.D., Cohn G.M., Cyran F., Fananapazir L.;
RT "Differences in clinical expression of hypertrophic cardiomyopathy
RT associated with two distinct mutations in the beta-myosin heavy chain
RT gene. A 908Leu-->Val mutation and a 403Arg-->Gln mutation.";
RL Circulation 86:345-352(1992).
RN [24]
RP VARIANTS CMH1 GLN-249; GLN-403; CYS-453 AND MET-606.
RX PubMed=1552912;
RA Watkins H., Rosenzweig A., Hwang D.S., Levi T., McKenna W.,
RA Seidmann C.E., Seidmann J.G.;
RT "Characteristics and prognostic implications of myosin missense
RT mutations in familial hypertrophic cardiomyopathy.";
RL N. Engl. J. Med. 326:1108-1114(1992).
RN [25]
RP VARIANTS CMH1 GLN-403; CYS-453; ARG-584 AND MET-606.
RX PubMed=8250038;
RA Watkins H., Thierfelder L., Anan R., Jarcho J., Matsumori A.,
RA McKenna W., Seidman J.G., Seidman C.E.;
RT "Independent origin of identical beta cardiac myosin heavy-chain
RT mutations in hypertrophic cardiomyopathy.";
RL Am. J. Hum. Genet. 53:1180-1185(1993).
RN [26]
RP VARIANT CMH1 GLY-778.
RX PubMed=8343162; DOI=10.1006/bbrc.1993.1891;
RA Harada H., Kimura A., Nishi H., Sasazuki T., Toshima H.;
RT "A missense mutation of cardiac beta-myosin heavy chain gene linked to
RT familial hypertrophic cardiomyopathy in affected Japanese families.";
RL Biochem. Biophys. Res. Commun. 194:791-798(1993).
RN [27]
RP VARIANT CMH1 VAL-908.
RX PubMed=8435239;
RA Al-Mahdawi S., Chamberlain S., Cleland J., Nihoyannopoulos P.,
RA Gilligan D., French J., Choudhury L., Williamson R., Oakley C.;
RT "Identification of a mutation in the beta cardiac myosin heavy chain
RT gene in a family with hypertrophic cardiomyopathy.";
RL Br. Heart J. 69:136-141(1993).
RN [28]
RP VARIANT CMH1 TRP-403.
RX PubMed=8268932; DOI=10.1093/hmg/2.10.1731;
RA Moolman J.C., Brink P.A., Corfield V.A.;
RT "Identification of a new missense mutation at Arg403, a CpG mutation
RT hotspot, in exon 13 of the beta-myosin heavy chain gene in
RT hypertrophic cardiomyopathy.";
RL Hum. Mol. Genet. 2:1731-1732(1993).
RN [29]
RP VARIANTS CMH1 LEU-403 AND TRP-403.
RX PubMed=8254035; DOI=10.1172/JCI116900;
RA Dausse E., Komajda M., Fetler L., Dubourg O., Dufour C., Carrier L.,
RA Wisnewsky C., Bercovici J., Hengstenberg C., Al-Mahdawi S.;
RT "Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and
RT identification of a hot spot for mutations in the beta-myosin heavy
RT chain gene.";
RL J. Clin. Invest. 92:2807-2813(1993).
RN [30]
RP VARIANTS CMH1 GLU-256 AND ARG-741.
RX PubMed=8483915; DOI=10.1073/pnas.90.9.3993;
RA Fananapazir L., Dalakas M.C., Cyran F., Cohn G., Epstein N.D.;
RT "Missense mutations in the beta-myosin heavy-chain gene cause central
RT core disease in hypertrophic cardiomyopathy.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:3993-3997(1993).
RN [31]
RP VARIANT CMH1 GLN-719.
RX PubMed=7848441; DOI=10.1093/hmg/3.6.1025;
RA Consevage M.W., Salada G.C., Baylen B.G., Ladda R.L., Rogan P.K.;
RT "A new missense mutation, Arg719Gln, in the beta-cardiac heavy chain
RT myosin gene of patients with familial hypertrophic cardiomyopathy.";
RL Hum. Mol. Genet. 3:1025-1026(1994).
RN [32]
RP VARIANT CMH1 TRP-719.
RX PubMed=7874131;
RA Greve G., Bachinski L., Friedman D.L., Czernuzewicz G., Anan R.,
RA Towbin J.A., Seidman C.E., Roberts R.;
RT "Isolation of a de novo mutant myocardial beta MHC protein in a
RT pedigree with hypertrophic cardiomyopathy.";
RL Hum. Mol. Genet. 3:2073-2075(1994).
RN [33]
RP VARIANTS CMH1 CYS-513; ARG-716 AND TRP-719.
RX PubMed=8282798; DOI=10.1172/JCI116957;
RA Anan R., Greve G., Thierfelder L., Watkins H., McKenna W., Solomon S.,
RA Vecchio C., Shono H., Nakao S., Tanaka H., Mares A. Jr., Towbin J.A.,
RA Spirito P., Roberts R., Seidman J.G., Seidman C.E.;
RT "Prognostic implications of novel beta cardiac myosin heavy chain gene
RT mutations that cause familial hypertrophic cardiomyopathy.";
RL J. Clin. Invest. 93:280-285(1994).
RN [34]
RP VARIANT CMH1 THR-797.
RX PubMed=7581410; DOI=10.1002/humu.1380060219;
RA Moolman J.C., Brink P.A., Corfield V.A.;
RT "Identification of a novel Ala797Thr mutation in exon 21 of the beta-
RT myosin heavy chain gene in hypertrophic cardiomyopathy.";
RL Hum. Mutat. 6:197-198(1995).
RN [35]
RP VARIANTS CMH1 ILE-124; CYS-162; LYS-187; LYS-222; LEU-244; HIS-663;
RP ASN-782 AND HIS-870.
RX PubMed=7731997; DOI=10.1073/pnas.92.9.3864;
RA Rayment I., Holden H.M., Sellers J.R., Fananapazir L., Epstein N.D.;
RT "Structural interpretation of the mutations in the beta-cardiac myosin
RT that have been implicated in familial hypertrophic cardiomyopathy.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:3864-3868(1995).
RN [36]
RP VARIANT CMH1 CYS-453.
RX PubMed=8655135; DOI=10.1007/s004390050099;
RA Ko Y.-L., Chen J.-J., Tang T.-K., Cheng J.-J., Lin S.-Y., Liou Y.-C.,
RA Kuan P., Wu C.-W., Lien W.-P., Liew C.-C.;
RT "Malignant familial hypertrophic cardiomyopathy in a family with a
RT 453Arg-->Cys mutation in the beta-myosin heavy chain gene: coexistence
RT of sudden death and end-stage heart failure.";
RL Hum. Genet. 97:585-590(1996).
RN [37]
RP VARIANT CMH1 ASN-383.
RX PubMed=8899546; DOI=10.1006/jmcc.1996.0180;
RA Kuang S.-Q., Yu J.-D., Lu L., He L.-M., Gong L.-S., Chen S.-J.,
RA Chen Z.;
RT "Identification of a novel missense mutation in the cardiac beta-
RT myosin heavy chain gene in a Chinese patient with sporadic
RT hypertrophic cardiomyopathy.";
RL J. Mol. Cell. Cardiol. 28:1879-1883(1996).
RN [38]
RP VARIANTS CMH1 GLN-249 AND GLU-450.
RX PubMed=10065021;
RA Arbustini E., Fasani R., Morbini P., Diegoli M., Grasso M.,
RA Dal Bello B., Marangoni E., Banfi P., Banchieri N., Bellini O.,
RA Comi G., Narula J., Campana C., Gavazzi A., Danesino C., Vigano M.;
RT "Coexistence of mitochondrial DNA and beta myosin heavy chain
RT mutations in hypertrophic cardiomyopathy with late congestive heart
RT failure.";
RL Heart 80:548-558(1998).
RN [39]
RP ERRATUM.
RA Arbustini E., Fasani R., Morbini P., Diegoli M., Grasso M.,
RA Dal Bello B., Marangoni E., Banfi P., Banchieri N., Bellini O.,
RA Comi G., Narula J., Campana C., Gavazzi A., Danesino C., Vigano M.;
RL Heart 81:330-330(1999).
RN [40]
RP VARIANTS CMH1 THR-349 AND TRP-719.
RX PubMed=9544842; DOI=10.1007/s004390050695;
RA Jeschke B., Uhl K., Weist B., Schroder D., Meitinger T., Dohlemann C.,
RA Vosberg H.-P.;
RT "A high risk phenotype of hypertrophic cardiomyopathy associated with
RT a compound genotype of two mutated beta-myosin heavy chain genes.";
RL Hum. Genet. 102:299-304(1998).
RN [41]
RP VARIANTS CMH1 THR-263; TRP-719; CYS-723 AND GLU-930 DEL.
RX PubMed=9829907;
RX DOI=10.1002/(SICI)1098-1004(1998)12:6<385::AID-HUMU4>3.0.CO;2-E;
RA Tesson F., Richard P., Charron P., Mathieu B., Cruaud C., Carrier L.,
RA Dubourg O., Lautie N., Desnos M., Millaire A., Isnard R., Hagege A.A.,
RA Bouhour J.-B., Bennaceur M., Hainque B., Guicheney P., Schwartz K.,
RA Komajda M.;
RT "Genotype-phenotype analysis in four families with mutations in beta-
RT myosin heavy chain gene responsible for familial hypertrophic
RT cardiomyopathy.";
RL Hum. Mutat. 12:385-392(1998).
RN [42]
RP VARIANTS CMH1 SER-696 AND TRP-719.
RX PubMed=9822100; DOI=10.1016/S0735-1097(98)00448-3;
RA Jaeaeskelaeinen P., Soranta M., Miettinen R., Saarinen L.,
RA Pihlajamaeki J., Silvennoinen K., Tikanoja T., Laakso M., Kuusisto J.;
RT "The cardiac beta-myosin heavy chain gene is not the predominant gene
RT for hypertrophic cardiomyopathy in the Finnish population.";
RL J. Am. Coll. Cardiol. 32:1709-1716(1998).
RN [43]
RP VARIANTS CMH1 TRP-403; LYS-499; GLN-719 AND THR-797.
RX PubMed=10521296; DOI=10.1086/302623;
RA Moolman-Smook J.C., De Lange W.J., Bruwer E.C.D., Brink P.A.,
RA Corfield V.A.;
RT "The origins of hypertrophic cardiomyopathy-causing mutations in two
RT South African subpopulations: a unique profile of both independent and
RT founder events.";
RL Am. J. Hum. Genet. 65:1308-1320(1999).
RN [44]
RP VARIANT CMH1 CYS-694.
RX PubMed=10563488; DOI=10.1034/j.1399-0004.1999.560313.x;
RA Andersen P.S., Havndrup O., Bundgaard H., Larsen L.A., Vuust J.,
RA Kjeldsen K., Christiansen M.;
RT "Adult-onset familial hypertrophic cardiomyopathy caused by a novel
RT mutation, R694C, in the MYH7 gene.";
RL Clin. Genet. 56:244-246(1999).
RN [45]
RP VARIANT CMH1 THR-190.
RX PubMed=10329202; DOI=10.1006/jmcc.1998.0911;
RA Bundgaard H., Havndrup O., Andersen P.S., Larsen L.A., Brandt N.J.,
RA Vuust J., Kjeldsen K., Christiansen M.;
RT "Familial hypertrophic cardiomyopathy associated with a novel missense
RT mutation affecting the ATP-binding region of the cardiac beta-myosin
RT heavy chain.";
RL J. Mol. Cell. Cardiol. 31:745-750(1999).
RN [46]
RP VARIANT CMH1 LEU-712.
RX PubMed=10679957;
RX DOI=10.1002/(SICI)1098-1004(200003)15:3<298::AID-HUMU22>3.0.CO;2-7;
RA Sakthivel S., Joseph P.K., Tharakan J.M., Vosberg H.-P.,
RA Rajamanickam C.;
RT "A novel missense mutation (R712L) adjacent to the 'active thiol'
RT region of the cardiac beta-myosin heavy chain gene causing
RT hypertrophic cardiomyopathy in an Indian family.";
RL Hum. Mutat. 15:298-299(2000).
RN [47]
RP VARIANTS CMH1 CYS-869 AND CYS-870.
RX PubMed=10862102;
RX DOI=10.1002/1098-1004(200006)15:6<584::AID-HUMU25>3.0.CO;2-R;
RA Anan R., Shono H., Tei C.;
RT "Novel cardiac beta-myosin heavy chain gene missense mutations (R869C
RT and R870C) that cause familial hypertrophic cardiomyopathy.";
RL Hum. Mutat. 15:584-584(2000).
RN [48]
RP VARIANT CMH1 GLY-723.
RX PubMed=11113006; DOI=10.1006/jmcc.2000.1260;
RA Enjuto M., Francino A., Navarro-Lopez F., Viles D., Pare J.-C.,
RA Ballesta A.M.;
RT "Malignant hypertrophic cardiomyopathy caused by the Arg723Gly
RT mutation in beta-myosin heavy chain gene.";
RL J. Mol. Cell. Cardiol. 32:2307-2313(2000).
RN [49]
RP VARIANTS CMD1S PRO-532 AND LEU-764.
RX PubMed=11106718; DOI=10.1056/NEJM200012073432304;
RA Kamisago M., Sharma S.D., DePalma S.R., Solomon S., Sharma P.,
RA McDonough B., Smoot L., Mullen M.P., Woolf P.K., Wigle E.D.,
RA Seidman J.G., Seidman C.E.;
RT "Mutations in sarcomere protein genes as a cause of dilated
RT cardiomyopathy.";
RL N. Engl. J. Med. 343:1688-1696(2000).
RN [50]
RP VARIANT CMH1 VAL-390.
RX PubMed=11214007; DOI=10.1080/140174300750064477;
RA Havndrup O., Bundgaard H., Andersen P.S., Larsen L.A., Vuust J.,
RA Kjeldsen K., Christiansen M.;
RT "A novel missense mutation, Leu390Val, in the cardiac beta-myosin
RT heavy chain associated with pronounced septal hypertrophy in two
RT families with hypertrophic cardiomyopathy.";
RL Scand. Cardiovasc. J. 34:558-563(2000).
RN [51]
RP VARIANT CMH1 ASP-743.
RX PubMed=11733062; DOI=10.1016/S0092-8674(01)00586-4;
RA Davis J.S., Hassanzadeh S., Winitsky S., Lin H., Satorius C.,
RA Vemuri R., Aletras A.H., Wen H., Epstein N.D.;
RT "The overall pattern of cardiac contraction depends on a spatial
RT gradient of myosin regulatory light chain phosphorylation.";
RL Cell 107:631-641(2001).
RN [52]
RP VARIANT CMH1 VAL-728.
RX PubMed=11424919; DOI=10.1136/jmg.38.6.385;
RA Blair E., Price S.J., Baty C.J., Oestman-Smith I., Watkins H.;
RT "Mutations in cis can confound genotype-phenotype correlations in
RT hypertrophic cardiomyopathy.";
RL J. Med. Genet. 38:385-388(2001).
RN [53]
RP VARIANTS CMH1 GLN-249; MET-406; CYS-453; MET-606; HIS-663 AND LYS-877.
RX PubMed=11133230; DOI=10.1006/jmcc.2000.1287;
RA Greber-Platzer S., Marx M., Fleischmann C., Suppan C., Dobner M.,
RA Wimmer M.;
RT "Beta-myosin heavy chain gene mutations and hypertrophic
RT cardiomyopathy in Austrian children.";
RL J. Mol. Cell. Cardiol. 33:141-148(2001).
RN [54]
RP VARIANTS CMD1S THR-223 AND LEU-642.
RX PubMed=12379228; DOI=10.1016/S0006-291X(02)02374-4;
RA Daehmlow S., Erdmann J., Knueppel T., Gille C., Froemmel C.,
RA Hummel M., Hetzer R., Regitz-Zagrosek V.;
RT "Novel mutations in sarcomeric protein genes in dilated
RT cardiomyopathy.";
RL Biochem. Biophys. Res. Commun. 298:116-120(2002).
RN [55]
RP VARIANTS CMH1 HIS-663; TRP-719; ARG-768 AND GLY-906.
RX PubMed=12081993; DOI=10.1161/01.CIR.0000019070.70491.6D;
RA Ho C.Y., Sweitzer N.K., McDonough B., Maron B.J., Casey S.A.,
RA Seidman J.G., Seidman C.E., Solomon S.D.;
RT "Assessment of diastolic function with Doppler tissue imaging to
RT predict genotype in preclinical hypertrophic cardiomyopathy.";
RL Circulation 105:2992-2997(2002).
RN [56]
RP VARIANTS CMH1 THR-1379 AND GLY-1776, AND VARIANT CYS-1491.
RX PubMed=11861413; DOI=10.1161/hh0302.104532;
RA Blair E., Redwood C., de Jesus Oliveira M., Moolman-Smook J.C.,
RA Brink P., Corfield V.A., Oestman-Smith I., Watkins H.;
RT "Mutations of the light meromyosin domain of the beta-myosin heavy
RT chain rod in hypertrophic cardiomyopathy.";
RL Circ. Res. 90:263-269(2002).
RN [57]
RP VARIANTS CMH1 GLN-249; THR-349; GLN-403; ARG-595; MET-606; GLN-719;
RP TRP-719; GLU-927 DEL AND LYS-1555.
RX PubMed=11968089; DOI=10.1002/humu.10074;
RA Waldmueller S., Freund P., Mauch S., Toder R., Vosberg H.-P.;
RT "Low-density DNA microarrays are versatile tools to screen for known
RT mutations in hypertrophic cardiomyopathy.";
RL Hum. Mutat. 19:560-569(2002).
RN [58]
RP VARIANT MYOMS TRP-1845.
RX PubMed=14520662; DOI=10.1002/ana.10693;
RA Tajsharghi H., Thornell L.-E., Lindberg C., Lindvall B.,
RA Henriksson K.-G., Oldfors A.;
RT "Myosin storage myopathy associated with a heterozygous missense
RT mutation in MYH7.";
RL Ann. Neurol. 54:494-500(2003).
RN [59]
RP VARIANTS CMH1 CYS-453; MET-517 AND GLU-734.
RX PubMed=12951062; DOI=10.1016/j.bbrc.2003.08.014;
RA Nanni L., Pieroni M., Chimenti C., Simionati B., Zimbello R.,
RA Maseri A., Frustaci A., Lanfranchi G.;
RT "Hypertrophic cardiomyopathy: two homozygous cases with 'typical'
RT hypertrophic cardiomyopathy and three new mutations in cases with
RT progression to dilated cardiomyopathy.";
RL Biochem. Biophys. Res. Commun. 309:391-398(2003).
RN [60]
RP VARIANTS CMH1 THR-190; MET-320; VAL-390; VAL-601; MET-606; CYS-694;
RP GLU-778 AND GLN-846.
RX PubMed=12566107; DOI=10.1016/S0008-6363(02)00711-3;
RA Havndrup O., Bundgaard H., Andersen P.S., Larsen L.A., Vuust J.,
RA Kjeldsen K., Christiansen M.;
RT "Outcome of clinical versus genetic family screening in hypertrophic
RT cardiomyopathy with focus on cardiac beta-myosin gene mutations.";
RL Cardiovasc. Res. 57:347-357(2003).
RN [61]
RP VARIANTS CMH1 MET-39; ASN-188; HIS-204; SER-232; GLN-249; THR-263;
RP THR-355; LEU-403; GLN-403; TRP-403; VAL-428; THR-443; CYS-453;
RP SER-479; LYS-483; MET-606; ILE-659; SER-663; HIS-663; CYS-671;
RP ARG-716; GLN-719; TRP-719; CYS-723; GLU-733; ARG-741; ARG-768;
RP GLU-778; HIS-787; THR-852; GLY-869; GLU-883 DEL; GLU-930 DEL;
RP ARG-1135; GLN-1218; MET-1377; THR-1379; TRP-1382 AND THR-1777, AND
RP VARIANT MET-1692.
RX PubMed=12707239; DOI=10.1161/01.CIR.0000066323.15244.54;
RA Richard P., Charron P., Carrier L., Ledeuil C., Cheav T.,
RA Pichereau C., Benaiche A., Isnard R., Dubourg O., Burban M.,
RA Gueffet J.-P., Millaire A., Desnos M., Schwartz K., Hainque B.,
RA Komajda M.;
RT "Hypertrophic cardiomyopathy: distribution of disease genes, spectrum
RT of mutations, and implications for a molecular diagnosis strategy.";
RL Circulation 107:2227-2232(2003).
RN [62]
RP ERRATUM.
RA Richard P., Charron P., Carrier L., Ledeuil C., Cheav T.,
RA Pichereau C., Benaiche A., Isnard R., Dubourg O., Burban M.,
RA Gueffet J.-P., Millaire A., Desnos M., Schwartz K., Hainque B.,
RA Komajda M.;
RL Circulation 109:3258-3258(2004).
RN [63]
RP VARIANTS CMH1 TRP-143; TRP-403; ILE-411; SER-584; HIS-694; TRP-719;
RP THR-736; PHE-796; ILE-824; HIS-870; PHE-905; GLN-924 AND ASN-928.
RX PubMed=12974739; DOI=10.1034/j.1399-0004.2003.00151.x;
RA Erdmann J., Daehmlow S., Wischke S., Senyuva M., Werner U., Raible J.,
RA Tanis N., Dyachenko S., Hummel M., Hetzer R., Regitz-Zagrosek V.;
RT "Mutation spectrum in a large cohort of unrelated consecutive patients
RT with hypertrophic cardiomyopathy.";
RL Clin. Genet. 64:339-349(2003).
RN [64]
RP VARIANTS CMH1 GLY-143; ILE-148; GLN-207; LEU-211; GLU-351; GLN-403;
RP SER-479; ALA-500; ARG-571; HIS-663; CYS-671; THR-736; GLY-763;
RP ASN-782; LEU-822; GLU-882 AND VAL-908.
RX PubMed=12820698; DOI=10.1089/109065703321560895;
RA Mohiddin S.A., Begley D.A., McLam E., Cardoso J.-P., Winkler J.B.,
RA Sellers J.R., Fananapazir L.;
RT "Utility of genetic screening in hypertrophic cardiomyopathy:
RT prevalence and significance of novel and double (homozygous and
RT heterozygous) beta-myosin mutations.";
RL Genet. Test. 7:21-27(2003).
RN [65]
RP VARIANTS CMH1 THR-196; LEU-211; GLN-249; GLN-403; LEU-404; ILE-411;
RP CYS-453; ARG-716; CYS-870; VAL-908 AND LYS-930.
RX PubMed=12975413; DOI=10.1136/heart.89.10.1179;
RA Woo A., Rakowski H., Liew J.C., Zhao M.-S., Liew C.-C., Parker T.G.,
RA Zeller M., Wigle E.D., Sole M.J.;
RT "Mutations of the beta myosin heavy chain gene in hypertrophic
RT cardiomyopathy: critical functional sites determine prognosis.";
RL Heart 89:1179-1185(2003).
RN [66]
RP VARIANTS CMH1 VAL-774 AND ASN-782.
RX PubMed=12590187;
RA Moric E., Mazurek U., Polonska J., Domal-Kwiatkowska D., Smolik S.,
RA Kozakiewicz K., Tendera M., Wilczok T.;
RT "Three novel mutations in exon 21 encoding beta-cardiac myosin heavy
RT chain.";
RL J. Appl. Genet. 44:103-109(2003).
RN [67]
RP VARIANTS CMH1 GLU-430 AND LYS-924.
RX PubMed=12818575; DOI=10.1016/S0022-2828(03)00146-9;
RA Moerner S., Richard P., Kazzam E., Hellman U., Hainque B.,
RA Schwartz K., Waldenstroem A.;
RT "Identification of the genotypes causing hypertrophic cardiomyopathy
RT in northern Sweden.";
RL J. Mol. Cell. Cardiol. 35:841-849(2003).
RN [68]
RP LACK OF ASSOCIATION OF VARIANT MET-1692 WITH HYPERTROPHIC
RP CARDIOMYOPATHY.
RA Richard P.;
RL Unpublished observations (OCT-2004).
RN [69]
RP VARIANTS MPD1 PRO-1500; LYS-1617 DEL; PRO-1663; PRO-1706 AND LYS-1729
RP DEL.
RX PubMed=15322983; DOI=10.1086/424760;
RA Meredith C., Herrmann R., Parry C., Liyanage K., Dye D.E.,
RA Durling H.J., Duff R.M., Beckman K., de Visser M.,
RA van der Graaff M.M., Hedera P., Fink J.K., Petty E.M., Lamont P.,
RA Fabian V., Bridges L., Voit T., Mastaglia F.L., Laing N.G.;
RT "Mutations in the slow skeletal muscle fiber myosin heavy chain gene
RT (MYH7) cause Laing early-onset distal myopathy (MPD1).";
RL Am. J. Hum. Genet. 75:703-708(2004).
RN [70]
RP VARIANTS CMH1 HIS-115; GLN-143; MET-263; CYS-312; THR-349; VAL-385;
RP GLN-403; MET-404; VAL-407; VAL-428; MET-440; CYS-453; THR-511;
RP ARG-515; CYS-663; HIS-663; CYS-694; ARG-716; GLN-719; ARG-741;
RP VAL-778; THR-797; LYS-847 DEL; CYS-858; HIS-869; GLY-894; VAL-908;
RP LYS-921; LYS-924; LYS-931; HIS-953; SER-1057; LYS-1356; MET-1377;
RP TRP-1420; ASN-1459; SER-1513; LYS-1768; MET-1854 AND MET-1929, AND
RP VARIANTS CYS-1491 AND ASN-1919.
RX PubMed=15358028; DOI=10.1016/j.jacc.2004.04.039;
RA Van Driest S.L., Jaeger M.A., Ommen S.R., Will M.L., Gersh B.J.,
RA Tajik A.J., Ackerman M.J.;
RT "Comprehensive analysis of the beta-myosin heavy chain gene in 389
RT unrelated patients with hypertrophic cardiomyopathy.";
RL J. Am. Coll. Cardiol. 44:602-610(2004).
RN [71]
RP VARIANT MYOMS LEU-1901.
RX PubMed=15136674;
RA Bohlega S., Abu-Amero S.N., Wakil S.M., Carroll P., Al-Amr R.,
RA Lach B., Al-Sayed Y., Cupler E.J., Meyer B.F.;
RT "Mutation of the slow myosin heavy chain rod domain underlies hyaline
RT body myopathy.";
RL Neurology 62:1518-1521(2004).
RN [72]
RP VARIANTS CMH1 VAL-26; GLN-143; ARG-425; THR-450; PHE-511; GLN-615;
RP CYS-663; HIS-663; PRO-734; ARG-741; THR-822; GLU-823; HIS-858; LYS-924
RP AND LYS-930.
RX PubMed=15563892; DOI=10.1016/j.cccn.2004.09.016;
RA Song L., Zou Y., Wang J., Wang Z., Zhen Y., Lou K., Zhang Q., Wang X.,
RA Wang H., Li J., Hui R.;
RT "Mutations profile in Chinese patients with hypertrophic
RT cardiomyopathy.";
RL Clin. Chim. Acta 351:209-216(2005).
RN [73]
RP VARIANTS CMD1S THR-201; ASN-412; VAL-550; ASN-1019; SER-1193; LYS-1426
RP AND CYS-1634, AND VARIANT CYS-1491.
RX PubMed=15769782; DOI=10.1093/eurheartj/ehi193;
RA Villard E., Duboscq-Bidot L., Charron P., Benaiche A., Conraads V.,
RA Sylvius N., Komajda M.;
RT "Mutation screening in dilated cardiomyopathy: prominent role of the
RT beta myosin heavy chain gene.";
RL Eur. Heart J. 26:794-803(2005).
RN [74]
RP VARIANTS CMH1 LYS-1327; TRP-1712 AND LYS-1753, AND VARIANTS CYS-1475
RP AND CYS-1491.
RX PubMed=15483641; DOI=10.1038/sj.ejhg.5201310;
RA Hougs L., Havndrup O., Bundgaard H., Koeber L., Vuust J., Larsen L.A.,
RA Christiansen M., Andersen P.S.;
RT "One third of Danish hypertrophic cardiomyopathy patients with MYH7
RT mutations have mutations in MYH7 rod region.";
RL Eur. J. Hum. Genet. 13:161-165(2005).
RN [75]
RP VARIANTS CMH1 VAL-227; GLY-328; GLU-351; GLN-403; TRP-403; ILE-411;
RP THR-435; CYS-453; HIS-453; MET-606; CYS-663; GLN-719; TRP-719;
RP HIS-787; GLY-894; VAL-908 AND LYS-927, AND VARIANT CYS-1519.
RX PubMed=15858117; DOI=10.1136/jcp.2004.021642;
RA Yu B., Sawyer N.A., Caramins M., Yuan Z.G., Saunderson R.B.,
RA Pamphlett R., Richmond D.R., Jeremy R.W., Trent R.J.;
RT "Denaturing high performance liquid chromatography: high throughput
RT mutation screening in familial hypertrophic cardiomyopathy and SNP
RT genotyping in motor neurone disease.";
RL J. Clin. Pathol. 58:479-485(2005).
RN [76]
RP VARIANTS CMH1 ASN-146; LEU-186; MET-606; HIS-663; ALA-698; GLN-719;
RP CYS-723; THR-736; GLU-742 AND ASP-1057.
RX PubMed=16199542; DOI=10.1136/jmg.2005.033886;
RA Ingles J., Doolan A., Chiu C., Seidman J., Seidman C., Semsarian C.;
RT "Compound and double mutations in patients with hypertrophic
RT cardiomyopathy: implications for genetic testing and counselling.";
RL J. Med. Genet. 42:E59-E59(2005).
RN [77]
RP VARIANTS CMH1 LEU-211; TRP-403; CYS-453; CYS-501; ARG-576; THR-736;
RP TRP-741; GLY-901; ASN-928; LYS-1356 AND THR-1454.
RX PubMed=15856146; DOI=10.1007/s00109-005-0635-7;
RA Perrot A., Schmidt-Traub H., Hoffmann B., Prager M., Bit-Avragim N.,
RA Rudenko R.I., Usupbaeva D.A., Kabaeva Z., Imanov B., Mirrakhimov M.M.,
RA Dietz R., Wycisk A., Tendera M., Gessner R., Osterziel K.J.;
RT "Prevalence of cardiac beta-myosin heavy chain gene mutations in
RT patients with hypertrophic cardiomyopathy.";
RL J. Mol. Med. 83:468-477(2005).
RN [78]
RP VARIANT CMH1 HIS-870.
RX PubMed=16650083; DOI=10.1111/j.1399-0004.2006.00599.x;
RA Tanjore R.R., Sikindlapuram A.D., Calambur N., Thakkar B.,
RA Kerkar P.G., Nallari P.;
RT "Genotype-phenotype correlation of R870H mutation in hypertrophic
RT cardiomyopathy.";
RL Clin. Genet. 69:434-436(2006).
RN [79]
RP VARIANTS CMH1 VAL-515 AND CYS-858.
RX PubMed=16938236;
RA Mora R., Merino J.L., Peinado R., Olias F., Garcia-Guereta L.,
RA del Cerro M.J., Tarin M.N., Molano J.;
RT "Hypertrophic cardiomyopathy: infrequent mutation of the cardiac beta-
RT myosin heavy-chain gene.";
RL Rev. Esp. Cardiol. 59:846-849(2006).
RN [80]
RP VARIANT CMH1 LYS-1883.
RX PubMed=17372140; DOI=10.1212/01.wnl.0000257131.13438.2c;
RA Tajsharghi H., Oldfors A., Macleod D.P., Swash M.;
RT "Homozygous mutation in MYH7 in myosin storage myopathy and
RT cardiomyopathy.";
RL Neurology 68:962-962(2007).
RN [81]
RP VARIANT MPD1 MET-441.
RX PubMed=17548557; DOI=10.1212/01.wnl.0000264430.55233.72;
RA Darin N., Tajsharghi H., Oestman-Smith I., Gilljam T., Oldfors A.;
RT "New skeletal myopathy and cardiomyopathy associated with a missense
RT mutation in MYH7.";
RL Neurology 68:2041-2042(2007).
RN [82]
RP VARIANT MYOMS TRP-1845, AND VARIANT SPMM TRP-1845.
RX PubMed=17336526; DOI=10.1016/j.nmd.2007.01.010;
RA Pegoraro E., Gavassini B.F., Borsato C., Melacini P., Vianello A.,
RA Stramare R., Cenacchi G., Angelini C.;
RT "MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal
RT myopathy.";
RL Neuromuscul. Disord. 17:321-329(2007).
RN [83]
RP VARIANTS CMH1 ASN-146; MET-606; HIS-663; GLN-719; MET-763; CYS-787;
RP VAL-908; LYS-924 AND MET-1414.
RX PubMed=18403758; DOI=10.1056/NEJMoa075463;
RA Morita H., Rehm H.L., Menesses A., McDonough B., Roberts A.E.,
RA Kucherlapati R., Towbin J.A., Seidman J.G., Seidman C.E.;
RT "Shared genetic causes of cardiac hypertrophy in children and
RT adults.";
RL N. Engl. J. Med. 358:1899-1908(2008).
RN [84]
RP VARIANTS CMD1S 1101-GLY--LEU-1104 DEL; ALA-1044; GLU-1263 AND
RP VAL-1297.
RX PubMed=21846512; DOI=10.1016/j.ejmg.2011.07.005;
RA Millat G., Bouvagnet P., Chevalier P., Sebbag L., Dulac A.,
RA Dauphin C., Jouk P.S., Delrue M.A., Thambo J.B., Le Metayer P.,
RA Seronde M.F., Faivre L., Eicher J.C., Rousson R.;
RT "Clinical and mutational spectrum in a cohort of 105 unrelated
RT patients with dilated cardiomyopathy.";
RL Eur. J. Med. Genet. 54:E570-E575(2011).
CC -!- FUNCTION: Muscle contraction.
CC -!- SUBUNIT: Muscle myosin is a hexameric protein that consists of 2
CC heavy chain subunits (MHC), 2 alkali light chain subunits (MLC)
CC and 2 regulatory light chain subunits (MLC-2). Interacts with
CC ECM29.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, myofibril. Note=Thick filaments
CC of the myofibrils.
CC -!- TISSUE SPECIFICITY: Both wild type and variant Gln-403 are
CC detected in skeletal muscle (at protein level).
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 -!- DOMAIN: Each myosin heavy chain can be split into 1 light
CC meromyosin (LMM) and 1 heavy meromyosin (HMM). It can later be
CC split further into 2 globular subfragments (S1) and 1 rod-shaped
CC subfragment (S2).
CC -!- DISEASE: Cardiomyopathy, familial hypertrophic 1 (CMH1)
CC [MIM:192600]: A hereditary heart disorder characterized by
CC ventricular hypertrophy, which is usually asymmetric and often
CC involves the interventricular septum. The symptoms include
CC dyspnea, syncope, collapse, palpitations, and chest pain. They can
CC be readily provoked by exercise. The disorder has inter- and
CC intrafamilial variability ranging from benign to malignant forms
CC with high risk of cardiac failure and sudden cardiac death.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Myopathy, myosin storage (MYOMS) [MIM:608358]: A rare
CC congenital myopathy characterized by subsarcolemmal hyalinized
CC bodies in type 1 muscle fibers. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Scapuloperoneal myopathy MYH7-related (SPMM)
CC [MIM:181430]: Progressive muscular atrophia beginning in the lower
CC legs and affecting the shoulder region earlier and more severely
CC than distal arm. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: Cardiomyopathy, dilated 1S (CMD1S) [MIM:613426]: A
CC disorder characterized by ventricular dilation and impaired
CC systolic function, resulting in congestive heart failure and
CC arrhythmia. Patients are at risk of premature death. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Myopathy, distal, 1 (MPD1) [MIM:160500]: A muscular
CC disorder characterized by early-onset selective weakness of the
CC great toe and ankle dorsiflexors, followed by weakness of the
CC finger extensors. Mild proximal weakness occasionally develops
CC years later after the onset of the disease. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: The cardiac alpha isoform is a 'fast' ATPase
CC myosin, while the beta isoform is a 'slow' ATPase.
CC -!- SIMILARITY: Contains 1 IQ domain.
CC -!- SIMILARITY: Contains 1 myosin head-like domain.
CC -!- CAUTION: Represents a conventional myosin. This protein should not
CC be confused with the unconventional myosin-7 (MYO7).
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MYH7";
CC -----------------------------------------------------------------------
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DR EMBL; M57965; AAA51837.1; -; Genomic_DNA.
DR EMBL; M58018; AAA62830.1; -; mRNA.
DR EMBL; X52889; CAA37068.1; -; Genomic_DNA.
DR EMBL; AJ238393; CAC20413.1; -; Genomic_DNA.
DR EMBL; EU747717; ACH92815.1; -; mRNA.
DR EMBL; EF179180; ABN05283.1; -; Genomic_DNA.
DR EMBL; CH471078; EAW66152.1; -; Genomic_DNA.
DR EMBL; BC112171; AAI12172.1; -; mRNA.
DR EMBL; BC112173; AAI12174.1; -; mRNA.
DR EMBL; M25135; AAA60384.1; -; Genomic_DNA.
DR EMBL; M25133; AAA60384.1; JOINED; Genomic_DNA.
DR EMBL; M25134; AAA60384.1; JOINED; Genomic_DNA.
DR EMBL; M27636; AAA79019.1; -; Genomic_DNA.
DR EMBL; X04627; CAA28300.1; -; Genomic_DNA.
DR EMBL; X04628; CAA28300.1; JOINED; Genomic_DNA.
DR EMBL; X04629; CAA28300.1; JOINED; Genomic_DNA.
DR EMBL; X04630; CAA28300.1; JOINED; Genomic_DNA.
DR EMBL; X04631; CAA28300.1; JOINED; Genomic_DNA.
DR EMBL; X04632; CAA28300.1; JOINED; Genomic_DNA.
DR EMBL; X04633; CAA28300.1; JOINED; Genomic_DNA.
DR EMBL; X51591; CAA35940.1; -; mRNA.
DR EMBL; X03741; CAA27381.1; ALT_SEQ; mRNA.
DR EMBL; X06976; CAA30039.1; -; mRNA.
DR EMBL; M17712; AAA36343.1; -; mRNA.
DR EMBL; M21665; AAA36345.1; -; mRNA.
DR EMBL; X05631; CAA29119.1; -; mRNA.
DR PIR; A37102; A37102.
DR RefSeq; NP_000248.2; NM_000257.2.
DR RefSeq; XP_005267753.1; XM_005267696.1.
DR UniGene; Hs.719946; -.
DR PDB; 1IK2; Model; -; A=1-841.
DR PDB; 2FXM; X-ray; 2.70 A; A/B=838-963.
DR PDB; 2FXO; X-ray; 2.50 A; A/B/C/D=838-963.
DR PDB; 3DTP; EM; 20.00 A; A=842-961, B=842-963.
DR PDB; 4DB1; X-ray; 2.60 A; A/B=2-783.
DR PDBsum; 1IK2; -.
DR PDBsum; 2FXM; -.
DR PDBsum; 2FXO; -.
DR PDBsum; 3DTP; -.
DR PDBsum; 4DB1; -.
DR ProteinModelPortal; P12883; -.
DR SMR; P12883; 2-963.
DR IntAct; P12883; 7.
DR MINT; MINT-1512407; -.
DR PhosphoSite; P12883; -.
DR DMDM; 83304912; -.
DR UCD-2DPAGE; P12883; -.
DR UCD-2DPAGE; Q92679; -.
DR PaxDb; P12883; -.
DR PRIDE; P12883; -.
DR Ensembl; ENST00000355349; ENSP00000347507; ENSG00000092054.
DR GeneID; 4625; -.
DR KEGG; hsa:4625; -.
DR UCSC; uc001wjx.3; human.
DR CTD; 4625; -.
DR GeneCards; GC14M023881; -.
DR H-InvDB; HIX0172409; -.
DR HGNC; HGNC:7577; MYH7.
DR HPA; CAB015384; -.
DR HPA; HPA001239; -.
DR HPA; HPA001349; -.
DR MIM; 160500; phenotype.
DR MIM; 160760; gene.
DR MIM; 181430; phenotype.
DR MIM; 192600; phenotype.
DR MIM; 608358; phenotype.
DR MIM; 613426; phenotype.
DR neXtProt; NX_P12883; -.
DR Orphanet; 324604; Classic multiminicore myopathy.
DR Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR Orphanet; 155; Familial isolated hypertrophic cardiomyopathy.
DR Orphanet; 53698; Hyaline body myopathy.
DR Orphanet; 59135; Laing distal myopathy.
DR Orphanet; 54260; Left ventricular noncompaction.
DR Orphanet; 85146; Scapuloperoneal amyotrophy.
DR PharmGKB; PA31374; -.
DR eggNOG; COG5022; -.
DR HOVERGEN; HBG004704; -.
DR KO; K10352; -.
DR OMA; ITAIQAR; -.
DR OrthoDB; EOG7RBZ7G; -.
DR Reactome; REACT_11123; Membrane Trafficking.
DR ChiTaRS; MYH7; human.
DR EvolutionaryTrace; P12883; -.
DR GeneWiki; MYH7; -.
DR GenomeRNAi; 4625; -.
DR NextBio; 17802; -.
DR PRO; PR:P12883; -.
DR ArrayExpress; P12883; -.
DR Bgee; P12883; -.
DR Genevestigator; P12883; -.
DR GO; GO:0005925; C:focal adhesion; IDA:HPA.
DR GO; GO:0005859; C:muscle myosin complex; TAS:UniProtKB.
DR GO; GO:0032982; C:myosin filament; IDA:BHF-UCL.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0030017; C:sarcomere; TAS:BHF-UCL.
DR GO; GO:0001725; C:stress fiber; IEA:Ensembl.
DR GO; GO:0030018; C:Z disc; IEA:Ensembl.
DR GO; GO:0030898; F:actin-dependent ATPase activity; IMP:HGNC.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0000146; F:microfilament motor activity; NAS:UniProtKB.
DR GO; GO:0008307; F:structural constituent of muscle; IDA:HGNC.
DR GO; GO:0007512; P:adult heart development; IMP:HGNC.
DR GO; GO:0030049; P:muscle filament sliding; IMP:HGNC.
DR GO; GO:0002027; P:regulation of heart rate; IDA:HGNC.
DR GO; GO:0055010; P:ventricular cardiac muscle tissue morphogenesis; IMP:BHF-UCL.
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 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; SSF52540; SSF52540; 1.
DR PROSITE; PS50096; IQ; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Actin-binding; ATP-binding; Calmodulin-binding;
KW Cardiomyopathy; Coiled coil; Complete proteome; Cytoplasm;
KW Disease mutation; Isopeptide bond; Methylation; Motor protein;
KW Muscle protein; Myosin; Nucleotide-binding; Polymorphism;
KW Reference proteome; Thick filament; Ubl conjugation.
FT CHAIN 1 1935 Myosin-7.
FT /FTId=PRO_0000123407.
FT DOMAIN 1 780 Myosin head-like.
FT DOMAIN 781 810 IQ.
FT NP_BIND 178 185 ATP.
FT REGION 655 677 Actin-binding.
FT REGION 757 771 Actin-binding.
FT COILED 839 1935 Potential.
FT MOD_RES 129 129 N6,N6,N6-trimethyllysine (Potential).
FT CROSSLNK 207 207 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT CROSSLNK 213 213 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT CROSSLNK 1531 1531 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT CROSSLNK 1537 1537 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT VARIANT 3 3 D -> A (in dbSNP:rs3729993).
FT /FTId=VAR_029430.
FT VARIANT 26 26 A -> V (in CMH1; dbSNP:rs186964570).
FT /FTId=VAR_004566.
FT VARIANT 39 39 V -> M (in CMH1).
FT /FTId=VAR_019845.
FT VARIANT 59 59 V -> I (in CMH1).
FT /FTId=VAR_004567.
FT VARIANT 107 107 D -> E (in dbSNP:rs2754166).
FT /FTId=VAR_017745.
FT VARIANT 115 115 Y -> H (in CMH1).
FT /FTId=VAR_042762.
FT VARIANT 124 124 T -> I (in CMH1).
FT /FTId=VAR_020797.
FT VARIANT 143 143 R -> G (in CMH1).
FT /FTId=VAR_042763.
FT VARIANT 143 143 R -> Q (in CMH1).
FT /FTId=VAR_004568.
FT VARIANT 143 143 R -> W (in CMH1).
FT /FTId=VAR_029431.
FT VARIANT 146 146 K -> N (in CMH1).
FT /FTId=VAR_042764.
FT VARIANT 148 148 S -> I (in CMH1).
FT /FTId=VAR_042765.
FT VARIANT 162 162 Y -> C (in CMH1).
FT /FTId=VAR_020798.
FT VARIANT 186 186 V -> L (in CMH1).
FT /FTId=VAR_042766.
FT VARIANT 187 187 N -> K (in CMH1).
FT /FTId=VAR_020799.
FT VARIANT 188 188 T -> N (in CMH1).
FT /FTId=VAR_019846.
FT VARIANT 190 190 R -> T (in CMH1).
FT /FTId=VAR_020800.
FT VARIANT 196 196 A -> T (in CMH1).
FT /FTId=VAR_042767.
FT VARIANT 201 201 I -> T (in CMD1S).
FT /FTId=VAR_042768.
FT VARIANT 204 204 R -> H (in CMH1).
FT /FTId=VAR_019847.
FT VARIANT 207 207 K -> Q (in CMH1).
FT /FTId=VAR_042769.
FT VARIANT 211 211 P -> L (in CMH1).
FT /FTId=VAR_042770.
FT VARIANT 222 222 Q -> K (in CMH1).
FT /FTId=VAR_020801.
FT VARIANT 223 223 A -> T (in CMD1S).
FT /FTId=VAR_017746.
FT VARIANT 227 227 L -> V (in CMH1).
FT /FTId=VAR_042771.
FT VARIANT 232 232 N -> S (in CMH1).
FT /FTId=VAR_019848.
FT VARIANT 244 244 F -> L (in CMH1).
FT /FTId=VAR_020802.
FT VARIANT 249 249 R -> Q (in CMH1; dbSNP:rs3218713).
FT /FTId=VAR_004569.
FT VARIANT 256 256 G -> E (in CMH1).
FT /FTId=VAR_004570.
FT VARIANT 263 263 I -> M (in CMH1).
FT /FTId=VAR_042772.
FT VARIANT 263 263 I -> T (in CMH1).
FT /FTId=VAR_004571.
FT VARIANT 312 312 F -> C (in CMH1).
FT /FTId=VAR_042773.
FT VARIANT 320 320 V -> M (in CMH1).
FT /FTId=VAR_020803.
FT VARIANT 328 328 E -> G (in CMH1).
FT /FTId=VAR_042774.
FT VARIANT 349 349 M -> T (in CMH1).
FT /FTId=VAR_004572.
FT VARIANT 351 351 K -> E (in CMH1).
FT /FTId=VAR_042775.
FT VARIANT 355 355 A -> T (in CMH1).
FT /FTId=VAR_019849.
FT VARIANT 383 383 K -> N (in CMH1).
FT /FTId=VAR_042776.
FT VARIANT 385 385 A -> V (in CMH1).
FT /FTId=VAR_042777.
FT VARIANT 390 390 L -> V (in CMH1).
FT /FTId=VAR_020804.
FT VARIANT 403 403 R -> L (in CMH1).
FT /FTId=VAR_004573.
FT VARIANT 403 403 R -> Q (in CMH1).
FT /FTId=VAR_004574.
FT VARIANT 403 403 R -> W (in CMH1; dbSNP:rs3218714).
FT /FTId=VAR_004575.
FT VARIANT 404 404 V -> L (in CMH1).
FT /FTId=VAR_042778.
FT VARIANT 404 404 V -> M (in CMH1).
FT /FTId=VAR_042779.
FT VARIANT 406 406 V -> M (in CMH1).
FT /FTId=VAR_020805.
FT VARIANT 407 407 G -> V (in CMH1).
FT /FTId=VAR_042780.
FT VARIANT 411 411 V -> I (in CMH1).
FT /FTId=VAR_029432.
FT VARIANT 412 412 T -> N (in CMD1S).
FT /FTId=VAR_042781.
FT VARIANT 425 425 G -> R (in CMH1).
FT /FTId=VAR_042782.
FT VARIANT 428 428 A -> V (in CMH1).
FT /FTId=VAR_019850.
FT VARIANT 430 430 A -> E (in CMH1).
FT /FTId=VAR_029433.
FT VARIANT 435 435 M -> T (in CMH1).
FT /FTId=VAR_042783.
FT VARIANT 440 440 V -> M (in CMH1).
FT /FTId=VAR_042784.
FT VARIANT 441 441 T -> M (in MPD1).
FT /FTId=VAR_042785.
FT VARIANT 443 443 I -> T (in CMH1).
FT /FTId=VAR_019851.
FT VARIANT 450 450 K -> E (in CMH1).
FT /FTId=VAR_042786.
FT VARIANT 450 450 K -> T (in CMH1).
FT /FTId=VAR_042787.
FT VARIANT 453 453 R -> C (in CMH1).
FT /FTId=VAR_004576.
FT VARIANT 453 453 R -> H (in CMH1).
FT /FTId=VAR_042788.
FT VARIANT 466 466 E -> Q (in dbSNP:rs4981473).
FT /FTId=VAR_029434.
FT VARIANT 479 479 N -> S (in CMH1).
FT /FTId=VAR_019852.
FT VARIANT 483 483 E -> K (in CMH1).
FT /FTId=VAR_019853.
FT VARIANT 499 499 E -> K (in CMH1; dbSNP:rs3218715).
FT /FTId=VAR_020806.
FT VARIANT 500 500 E -> A (in CMH1).
FT /FTId=VAR_042789.
FT VARIANT 501 501 Y -> C (in CMH1).
FT /FTId=VAR_042790.
FT VARIANT 511 511 I -> F (in CMH1).
FT /FTId=VAR_042791.
FT VARIANT 511 511 I -> T (in CMH1).
FT /FTId=VAR_042792.
FT VARIANT 513 513 F -> C (in CMH1).
FT /FTId=VAR_004577.
FT VARIANT 515 515 M -> R (in CMH1).
FT /FTId=VAR_042793.
FT VARIANT 515 515 M -> V (in CMH1; infrequent).
FT /FTId=VAR_039562.
FT VARIANT 517 517 L -> M (in CMH1).
FT /FTId=VAR_029435.
FT VARIANT 532 532 S -> P (in CMD1S).
FT /FTId=VAR_017747.
FT VARIANT 550 550 A -> V (in CMD1S).
FT /FTId=VAR_042794.
FT VARIANT 571 571 G -> R (in CMH1).
FT /FTId=VAR_042795.
FT VARIANT 576 576 H -> R (in CMH1).
FT /FTId=VAR_042796.
FT VARIANT 584 584 G -> R (in CMH1).
FT /FTId=VAR_004578.
FT VARIANT 584 584 G -> S (in CMH1).
FT /FTId=VAR_029436.
FT VARIANT 587 587 D -> V (in CMH1).
FT /FTId=VAR_004579.
FT VARIANT 595 595 Q -> R (in CMH1).
FT /FTId=VAR_020807.
FT VARIANT 601 601 L -> V (in CMH1).
FT /FTId=VAR_020808.
FT VARIANT 602 602 N -> S (in CMH1).
FT /FTId=VAR_004580.
FT VARIANT 606 606 V -> M (in CMH1; in cis with V-728 gives
FT a more severe phenotype).
FT /FTId=VAR_004581.
FT VARIANT 615 615 K -> N (in CMH1).
FT /FTId=VAR_004582.
FT VARIANT 615 615 K -> Q (in CMH1).
FT /FTId=VAR_042797.
FT VARIANT 642 642 S -> L (in CMD1S).
FT /FTId=VAR_017748.
FT VARIANT 659 659 M -> I (in CMH1).
FT /FTId=VAR_019854.
FT VARIANT 663 663 R -> C (in CMH1).
FT /FTId=VAR_042798.
FT VARIANT 663 663 R -> H (in CMH1).
FT /FTId=VAR_019855.
FT VARIANT 663 663 R -> S (in CMH1).
FT /FTId=VAR_019856.
FT VARIANT 671 671 R -> C (in CMH1).
FT /FTId=VAR_019857.
FT VARIANT 694 694 R -> C (in CMH1).
FT /FTId=VAR_020809.
FT VARIANT 694 694 R -> H (in CMH1).
FT /FTId=VAR_029437.
FT VARIANT 696 696 N -> S (in CMH1).
FT /FTId=VAR_020810.
FT VARIANT 698 698 V -> A (in CMH1).
FT /FTId=VAR_042799.
FT VARIANT 712 712 R -> L (in CMH1).
FT /FTId=VAR_020811.
FT VARIANT 716 716 G -> R (in CMH1).
FT /FTId=VAR_004583.
FT VARIANT 719 719 R -> Q (in CMH1).
FT /FTId=VAR_017749.
FT VARIANT 719 719 R -> W (in CMH1).
FT /FTId=VAR_004584.
FT VARIANT 723 723 R -> C (in CMH1).
FT /FTId=VAR_004585.
FT VARIANT 723 723 R -> G (in CMH1; malignant phenotype).
FT /FTId=VAR_020812.
FT VARIANT 728 728 A -> V (in CMH1; in cis with M-606 gives
FT a more severe phenotype).
FT /FTId=VAR_017750.
FT VARIANT 731 731 P -> L (in CMH1).
FT /FTId=VAR_004586.
FT VARIANT 733 733 G -> E (in CMH1).
FT /FTId=VAR_019858.
FT VARIANT 734 734 Q -> E (in CMH1).
FT /FTId=VAR_029438.
FT VARIANT 734 734 Q -> P (in CMH1).
FT /FTId=VAR_042800.
FT VARIANT 736 736 I -> M (in CMH1).
FT /FTId=VAR_004587.
FT VARIANT 736 736 I -> T (in CMH1).
FT /FTId=VAR_029439.
FT VARIANT 741 741 G -> R (in CMH1).
FT /FTId=VAR_004588.
FT VARIANT 741 741 G -> W (in CMH1).
FT /FTId=VAR_004589.
FT VARIANT 742 742 A -> E (in CMH1).
FT /FTId=VAR_042801.
FT VARIANT 743 743 E -> D (in CMH1).
FT /FTId=VAR_014199.
FT VARIANT 763 763 V -> G (in CMH1).
FT /FTId=VAR_042802.
FT VARIANT 763 763 V -> M (in CMH1).
FT /FTId=VAR_045926.
FT VARIANT 764 764 F -> L (in CMD1S).
FT /FTId=VAR_017751.
FT VARIANT 768 768 G -> R (in CMH1).
FT /FTId=VAR_019859.
FT VARIANT 774 774 E -> V (in CMH1).
FT /FTId=VAR_042803.
FT VARIANT 778 778 D -> E (in CMH1).
FT /FTId=VAR_019860.
FT VARIANT 778 778 D -> G (in CMH1).
FT /FTId=VAR_004590.
FT VARIANT 778 778 D -> V (in CMH1).
FT /FTId=VAR_042804.
FT VARIANT 782 782 S -> N (in CMH1).
FT /FTId=VAR_020813.
FT VARIANT 787 787 R -> C (in CMH1).
FT /FTId=VAR_045927.
FT VARIANT 787 787 R -> H (in CMH1).
FT /FTId=VAR_019861.
FT VARIANT 796 796 L -> F (in CMH1).
FT /FTId=VAR_029440.
FT VARIANT 797 797 A -> T (in CMH1; dbSNP:rs3218716).
FT /FTId=VAR_004591.
FT VARIANT 822 822 M -> L (in CMH1).
FT /FTId=VAR_042805.
FT VARIANT 822 822 M -> T (in CMH1).
FT /FTId=VAR_042806.
FT VARIANT 823 823 G -> E (in CMH1).
FT /FTId=VAR_042807.
FT VARIANT 824 824 V -> I (in CMH1).
FT /FTId=VAR_029441.
FT VARIANT 846 846 E -> Q (in CMH1).
FT /FTId=VAR_020814.
FT VARIANT 847 847 Missing (in CMH1).
FT /FTId=VAR_042808.
FT VARIANT 852 852 M -> T (in CMH1).
FT /FTId=VAR_019862.
FT VARIANT 858 858 R -> C (in CMH1; infrequent).
FT /FTId=VAR_039563.
FT VARIANT 858 858 R -> H (in CMH1; dbSNP:rs2856897).
FT /FTId=VAR_042809.
FT VARIANT 869 869 R -> C (in CMH1).
FT /FTId=VAR_020815.
FT VARIANT 869 869 R -> G (in CMH1).
FT /FTId=VAR_019863.
FT VARIANT 869 869 R -> H (in CMH1; dbSNP:rs202141173).
FT /FTId=VAR_042810.
FT VARIANT 870 870 R -> C (in CMH1; dbSNP:rs36211715).
FT /FTId=VAR_020816.
FT VARIANT 870 870 R -> H (in CMH1; dbSNP:rs36211715).
FT /FTId=VAR_004592.
FT VARIANT 877 877 M -> K (in CMH1).
FT /FTId=VAR_020817.
FT VARIANT 882 882 Q -> E (in CMH1).
FT /FTId=VAR_042811.
FT VARIANT 883 883 Missing (in CMH1).
FT /FTId=VAR_019864.
FT VARIANT 894 894 E -> G (in CMH1).
FT /FTId=VAR_042812.
FT VARIANT 901 901 A -> G (in CMH1).
FT /FTId=VAR_042813.
FT VARIANT 905 905 C -> F (in CMH1).
FT /FTId=VAR_029442.
FT VARIANT 906 906 D -> G (in CMH1).
FT /FTId=VAR_042814.
FT VARIANT 908 908 L -> V (in CMH1).
FT /FTId=VAR_004593.
FT VARIANT 921 921 E -> K (in CMH1).
FT /FTId=VAR_042815.
FT VARIANT 924 924 E -> K (in CMH1).
FT /FTId=VAR_004594.
FT VARIANT 924 924 E -> Q (in CMH1).
FT /FTId=VAR_029443.
FT VARIANT 927 927 E -> K (in CMH1).
FT /FTId=VAR_042816.
FT VARIANT 927 927 Missing (in CMH1).
FT /FTId=VAR_020818.
FT VARIANT 928 928 D -> N (in CMH1).
FT /FTId=VAR_029444.
FT VARIANT 930 930 E -> K (in CMH1).
FT /FTId=VAR_004595.
FT VARIANT 930 930 Missing (in CMH1).
FT /FTId=VAR_004596.
FT VARIANT 931 931 E -> K (in CMH1).
FT /FTId=VAR_042817.
FT VARIANT 935 935 E -> K (in CMH1).
FT /FTId=VAR_004597.
FT VARIANT 949 949 E -> K (in CMH1).
FT /FTId=VAR_004598.
FT VARIANT 953 953 D -> H (in CMH1).
FT /FTId=VAR_042818.
FT VARIANT 1019 1019 T -> N (in CMD1S).
FT /FTId=VAR_042819.
FT VARIANT 1044 1044 V -> A (in CMD1S).
FT /FTId=VAR_067260.
FT VARIANT 1057 1057 G -> D (in CMH1).
FT /FTId=VAR_042820.
FT VARIANT 1057 1057 G -> S (in CMH1).
FT /FTId=VAR_042821.
FT VARIANT 1101 1104 Missing (in CMD1S).
FT /FTId=VAR_067261.
FT VARIANT 1124 1124 A -> S (in dbSNP:rs1041961).
FT /FTId=VAR_017753.
FT VARIANT 1135 1135 L -> R (in CMH1).
FT /FTId=VAR_019865.
FT VARIANT 1193 1193 R -> S (in CMD1S).
FT /FTId=VAR_042822.
FT VARIANT 1218 1218 E -> Q (in CMH1).
FT /FTId=VAR_019866.
FT VARIANT 1263 1263 A -> E (in CMD1S).
FT /FTId=VAR_067262.
FT VARIANT 1297 1297 L -> V (in CMD1S).
FT /FTId=VAR_067263.
FT VARIANT 1327 1327 N -> K (in CMH1).
FT /FTId=VAR_042823.
FT VARIANT 1356 1356 E -> K (in CMH1).
FT /FTId=VAR_042824.
FT VARIANT 1377 1377 T -> M (in CMH1).
FT /FTId=VAR_019867.
FT VARIANT 1379 1379 A -> T (in CMH1).
FT /FTId=VAR_019868.
FT VARIANT 1382 1382 R -> W (in CMH1).
FT /FTId=VAR_019869.
FT VARIANT 1414 1414 L -> M (in CMH1).
FT /FTId=VAR_045928.
FT VARIANT 1420 1420 R -> W (in CMH1).
FT /FTId=VAR_042825.
FT VARIANT 1426 1426 E -> K (in CMD1S).
FT /FTId=VAR_042826.
FT VARIANT 1454 1454 A -> T (in CMH1).
FT /FTId=VAR_042827.
FT VARIANT 1459 1459 K -> N (in CMH1).
FT /FTId=VAR_042828.
FT VARIANT 1475 1475 R -> C.
FT /FTId=VAR_042829.
FT VARIANT 1491 1491 S -> C (in dbSNP:rs3729823).
FT /FTId=VAR_020819.
FT VARIANT 1500 1500 R -> P (in MPD1).
FT /FTId=VAR_022369.
FT VARIANT 1513 1513 T -> S (in CMH1).
FT /FTId=VAR_042830.
FT VARIANT 1519 1519 S -> C.
FT /FTId=VAR_042831.
FT VARIANT 1555 1555 E -> K (in CMH1).
FT /FTId=VAR_020820.
FT VARIANT 1617 1617 Missing (in MPD1).
FT /FTId=VAR_042832.
FT VARIANT 1634 1634 R -> C (in CMD1S).
FT /FTId=VAR_042833.
FT VARIANT 1663 1663 A -> P (in MPD1).
FT /FTId=VAR_022370.
FT VARIANT 1692 1692 V -> M (probable polymorphism; has been
FT originally reported as a hypertrophic
FT cardiomyopathy mutation).
FT /FTId=VAR_019870.
FT VARIANT 1706 1706 L -> P (in MPD1).
FT /FTId=VAR_022371.
FT VARIANT 1712 1712 R -> W (in CMH1).
FT /FTId=VAR_042834.
FT VARIANT 1729 1729 Missing (in MPD1).
FT /FTId=VAR_042835.
FT VARIANT 1753 1753 E -> K (in CMH1).
FT /FTId=VAR_042836.
FT VARIANT 1768 1768 E -> K (in CMH1).
FT /FTId=VAR_042837.
FT VARIANT 1776 1776 S -> G (in CMH1).
FT /FTId=VAR_020821.
FT VARIANT 1777 1777 A -> T (in CMH1).
FT /FTId=VAR_019871.
FT VARIANT 1845 1845 R -> W (in MYOMS and SPMM;
FT dbSNP:rs28933098).
FT /FTId=VAR_017754.
FT VARIANT 1854 1854 T -> M (in CMH1).
FT /FTId=VAR_042838.
FT VARIANT 1883 1883 E -> K (in CMH1).
FT /FTId=VAR_042839.
FT VARIANT 1901 1901 H -> L (in MYOMS).
FT /FTId=VAR_042840.
FT VARIANT 1919 1919 K -> N.
FT /FTId=VAR_042841.
FT VARIANT 1929 1929 T -> M (in CMH1).
FT /FTId=VAR_042842.
FT CONFLICT 88 88 E -> Q (in Ref. 8; AAA60384).
FT CONFLICT 397 397 K -> G (in Ref. 10).
FT CONFLICT 672 674 CII -> LYH (in Ref. 2; CAA37068).
FT CONFLICT 858 858 R -> A (in Ref. 2; CAA37068).
FT CONFLICT 942 943 KL -> NV (in Ref. 2; CAA37068).
FT CONFLICT 1077 1077 D -> E (in Ref. 13; CAA35940).
FT CONFLICT 1159 1159 V -> C (in Ref. 2; CAA37068 and 3;
FT CAC20413).
FT CONFLICT 1207 1207 I -> M (in Ref. 4; ACH92815).
FT CONFLICT 1313 1313 E -> G (in Ref. 14; CAA27381).
FT CONFLICT 1356 1356 E -> R (in Ref. 14; CAA27381).
FT CONFLICT 1359 1360 RV -> GD (in Ref. 14; CAA27381).
FT CONFLICT 1575 1576 KL -> NV (in Ref. 17; AAA36345).
FT CONFLICT 1576 1577 LA -> RQ (in Ref. 14; CAA27381).
FT CONFLICT 1681 1681 Missing (in Ref. 2; CAA37068).
FT CONFLICT 1703 1704 EQ -> DE (in Ref. 13; CAA35940).
FT CONFLICT 1703 1704 EQ -> DR (in Ref. 2; CAA37068 and 16;
FT AAA36343).
FT CONFLICT 1866 1866 D -> A (in Ref. 18; CAA29119).
FT HELIX 4 15
FT HELIX 20 28
FT TURN 33 35
FT STRAND 36 40
FT STRAND 42 54
FT STRAND 56 63
FT TURN 64 66
FT STRAND 67 72
FT HELIX 73 75
FT HELIX 82 84
FT HELIX 90 92
FT HELIX 98 110
FT STRAND 115 118
FT STRAND 121 125
FT HELIX 136 142
FT HELIX 147 149
FT HELIX 154 168
FT STRAND 172 177
FT HELIX 184 198
FT HELIX 216 231
FT STRAND 244 252
FT STRAND 256 266
FT HELIX 270 273
FT HELIX 284 290
FT HELIX 295 300
FT HELIX 307 309
FT HELIX 311 313
FT HELIX 325 338
FT HELIX 343 359
FT STRAND 364 366
FT STRAND 373 376
FT HELIX 379 387
FT HELIX 392 400
FT HELIX 417 447
FT STRAND 454 461
FT HELIX 473 504
FT HELIX 513 517
FT HELIX 518 525
FT HELIX 530 534
FT HELIX 545 556
FT TURN 557 559
FT STRAND 577 581
FT STRAND 584 588
FT HELIX 593 598
FT HELIX 603 610
FT HELIX 615 622
FT HELIX 647 663
FT STRAND 665 673
FT HELIX 686 695
FT HELIX 698 706
FT STRAND 711 714
FT HELIX 744 747
FT STRAND 748 751
FT HELIX 753 755
FT STRAND 756 758
FT STRAND 760 765
FT HELIX 769 776
SQ SEQUENCE 1935 AA; 223097 MW; C58B22F914215718 CRC64;
MGDSEMAVFG AAAPYLRKSE KERLEAQTRP FDLKKDVFVP DDKQEFVKAK IVSREGGKVT
AETEYGKTVT VKEDQVMQQN PPKFDKIEDM AMLTFLHEPA VLYNLKDRYG SWMIYTYSGL
FCVTVNPYKW LPVYTPEVVA AYRGKKRSEA PPHIFSISDN AYQYMLTDRE NQSILITGES
GAGKTVNTKR VIQYFAVIAA IGDRSKKDQS PGKGTLEDQI IQANPALEAF GNAKTVRNDN
SSRFGKFIRI HFGATGKLAS ADIETYLLEK SRVIFQLKAE RDYHIFYQIL SNKKPELLDM
LLITNNPYDY AFISQGETTV ASIDDAEELM ATDNAFDVLG FTSEEKNSMY KLTGAIMHFG
NMKFKLKQRE EQAEPDGTEE ADKSAYLMGL NSADLLKGLC HPRVKVGNEY VTKGQNVQQV
IYATGALAKA VYERMFNWMV TRINATLETK QPRQYFIGVL DIAGFEIFDF NSFEQLCINF
TNEKLQQFFN HHMFVLEQEE YKKEGIEWTF IDFGMDLQAC IDLIEKPMGI MSILEEECMF
PKATDMTFKA KLFDNHLGKS ANFQKPRNIK GKPEAHFSLI HYAGIVDYNI IGWLQKNKDP
LNETVVGLYQ KSSLKLLSTL FANYAGADAP IEKGKGKAKK GSSFQTVSAL HRENLNKLMT
NLRSTHPHFV RCIIPNETKS PGVMDNPLVM HQLRCNGVLE GIRICRKGFP NRILYGDFRQ
RYRILNPAAI PEGQFIDSRK GAEKLLSSLD IDHNQYKFGH TKVFFKAGLL GLLEEMRDER
LSRIITRIQA QSRGVLARME YKKLLERRDS LLVIQWNIRA FMGVKNWPWM KLYFKIKPLL
KSAEREKEMA SMKEEFTRLK EALEKSEARR KELEEKMVSL LQEKNDLQLQ VQAEQDNLAD
AEERCDQLIK NKIQLEAKVK EMNERLEDEE EMNAELTAKK RKLEDECSEL KRDIDDLELT
LAKVEKEKHA TENKVKNLTE EMAGLDEIIA KLTKEKKALQ EAHQQALDDL QAEEDKVNTL
TKAKVKLEQQ VDDLEGSLEQ EKKVRMDLER AKRKLEGDLK LTQESIMDLE NDKQQLDERL
KKKDFELNAL NARIEDEQAL GSQLQKKLKE LQARIEELEE ELEAERTARA KVEKLRSDLS
RELEEISERL EEAGGATSVQ IEMNKKREAE FQKMRRDLEE ATLQHEATAA ALRKKHADSV
AELGEQIDNL QRVKQKLEKE KSEFKLELDD VTSNMEQIIK AKANLEKMCR TLEDQMNEHR
SKAEETQRSV NDLTSQRAKL QTENGELSRQ LDEKEALISQ LTRGKLTYTQ QLEDLKRQLE
EEVKAKNALA HALQSARHDC DLLREQYEEE TEAKAELQRV LSKANSEVAQ WRTKYETDAI
QRTEELEEAK KKLAQRLQEA EEAVEAVNAK CSSLEKTKHR LQNEIEDLMV DVERSNAAAA
ALDKKQRNFD KILAEWKQKY EESQSELESS QKEARSLSTE LFKLKNAYEE SLEHLETFKR
ENKNLQEEIS DLTEQLGSSG KTIHELEKVR KQLEAEKMEL QSALEEAEAS LEHEEGKILR
AQLEFNQIKA EIERKLAEKD EEMEQAKRNH LRVVDSLQTS LDAETRSRNE ALRVKKKMEG
DLNEMEIQLS HANRMAAEAQ KQVKSLQSLL KDTQIQLDDA VRANDDLKEN IAIVERRNNL
LQAELEELRA VVEQTERSRK LAEQELIETS ERVQLLHSQN TSLINQKKKM DADLSQLQTE
VEEAVQECRN AEEKAKKAIT DAAMMAEELK KEQDTSAHLE RMKKNMEQTI KDLQHRLDEA
EQIALKGGKK QLQKLEARVR ELENELEAEQ KRNAESVKGM RKSERRIKEL TYQTEEDRKN
LLRLQDLVDK LQLKVKAYKR QAEEAEEQAN TNLSKFRKVQ HELDEAEERA DIAESQVNKL
RAKSRDIGTK GLNEE
//

MIM 160500
*RECORD*
*FIELD* NO
160500
*FIELD* TI
#160500 MYOPATHY, DISTAL, 1; MPD1
;;MYOPATHY, LATE DISTAL HEREDITARY;;
LAING DISTAL MYOPATHY;;
read moreMYOPATHY, DISTAL, EARLY-ONSET, AUTOSOMAL DOMINANT
*FIELD* TX
A number sign (#) is used with this entry because distal myopathy-1
(MPD1), also known as Laing distal myopathy, can be caused by
heterozygous mutation in the MYH7 gene (160760), which encodes the
myosin heavy chain of type 1 fibers of skeletal muscle and cardiac
ventricles.

The MYH7 gene is mutated in both hypertrophic (see 192600) and dilated
(see 115200) cardiomyopathy as well as in myosin storage myopathy
(608358).

CLINICAL FEATURES

Laing et al. (1995) described a family with an autosomal dominant distal
myopathy closely resembling that described in the original report of
Gowers (1902).

Scoppetta et al. (1995) and Voit et al. (2001) reported 2 families with
autosomal dominant distal myopathy with clinical features similar to
those reported by Laing et al. (1995). Characteristics common to both
families included onset in the second or third year of life, selective
wasting and weakness of the anterior tibial and extensor digitorum
longus muscles, a slowly progressive course, and, at later stages,
involvement of hand extensors, neck flexor, and abdominal muscles. Some
patients developed tremor. Zimprich et al. (2000) described an Austrian
family with a similar phenotype.

In a family with 9 affected members spanning 3 generations, Mastaglia et
al. (2002) described selective weakness of the ankle dorsiflexors and
toe extensors, in particular the extensor hallucis longus. Ankle plantar
flexors were normal, even in the most advanced cases. There was also
weakness and atrophy of the anterior compartment muscles. Most cases had
selective weakness of the long finger extensor muscles. None of the
affected individuals had cardiomyopathy. Age at onset varied from 4 to 5
years to the early twenties. Muscle MRI showed atrophy of affected
muscles, EMG gave a myopathic pattern, and muscle biopsy of 2 affected
patients showed myopathic changes without rimmed vacuoles.

Hedera et al. (2003) reported a large Italian American kindred in which
at least 11 members spanning 3 generations were affected with an
autosomal dominant distal myopathy. Clinical features included weakness
of foot and toe extensor muscles, and some patients had proximal
weakness. No patient had distal weakness of the upper extremities or
neck muscles, even in advanced stages of the disease. The average age at
symptom onset was 20 years. Two affected patients had signs of
idiopathic dilated cardiomyopathy. Hedera et al. (2003) noted that their
family differed from the family reported by Laing et al. (1995) by the
absence of upper extremity weakness and neck muscle weakness.

Darin et al. (2007) reported a Tanzanian boy with distal myopathy and
mild dilated cardiomyopathy. He began walking on the toes at age 11
months and had Achilles tenotomy at age 6 years. Examination at age 7
showed weakness of the great toe and ankle dorsiflexors, atrophy of the
anterior tibial muscles, weakness of the hip flexors, and decreased
reflexes. Echocardiography showed mild left atrial enlargement and
prolonged isovolumetric relaxation time. Skeletal muscle biopsy showed
hypotrophy of type 1 fibers and apparent absence of type 2B fibers.
Serum creatine kinase was mildly elevated.

- Clinical Variability

Muelas et al. (2010) identified the same mutation in the MYH7 gene
(lys1729del; 160760.0044) in 29 clearly affected individuals from 4
unrelated families in the Safor region of Spain. There was great
phenotypic variability. The age at onset ranged from congenital to 50
years, with a mean of 14 years. All patients presented with weakness of
great toe/ankle dorsiflexors, and many had associated neck flexor (78%),
finger extensor (78%), mild facial (70%), or proximal muscle (65%)
weakness. There was atrophy of the anterior lower leg compartment
muscles, which contrasted with calf hypertrophy. Some had more
widespread proximal muscle involvement, resembling that seen in the
allelic disorder myosin storage myopathy (608358). Variable findings
included quadriceps atrophy, ankle retraction, pes cavus, scoliosis,
claw toes, and high-arched palate. Five patients had cardiac
abnormalities, including dilated cardiomyopathy, left ventricular
relaxation impairment, and conduction abnormalities. The spectrum of
disability ranged from asymptomatic to wheelchair-confined, but life
expectancy was not affected. EMG showed myopathic as well as neurogenic
features, and muscle biopsies yielded various findings, such as fiber
type disproportion, core/minicore lesions, and mitochondrial
abnormalities. Most patients had slow progression, but some were
severely disabled, and many had myalgias. These findings expanded the
phenotypic spectrum of Laing myopathy, but the wide spectrum associated
with a single mutation was noteworthy. Muelas et al. (2010) also noted
that the variable features could lead to misdiagnosis of neurogenic
atrophy, congenital myopathies, or even mitochondrial myopathies.

MAPPING

The disorder in the family studied by Laing et al. (1995) showed linkage
of the locus, symbolized MPD1, to chromosome 14. A multipoint analysis
assuming 100% penetrance and using MYH7 (160760) and 5 other markers
gave a lod score of exactly 3 at MYH7. Analysis at a penetrance of 80%
gave a lod score of 2.8 at this marker.

Linkage analysis in a large family with autosomal dominant distal
myopathy reported by Mastaglia et al. (2002) yielded a maximum 2-point
lod score of 2.9 at marker D14S262, and further analysis refined the
candidate locus to a 24-cM region between D14S283 and D14S49.

In a large family with autosomal dominant distal myopathy, Hedera et al.
(2003) found linkage to chromosome 14q11-q13 (maximum 2-point lod score
of 3.99 at marker D14S1459). Mutation analysis excluded the PABP2 gene
(602279).

MOLECULAR GENETICS

In affected members of 7 separate families with Laing distal myopathy,
Meredith et al. (2004) sequenced the MYH7 gene, a positional candidate
for the site of the causative mutation. They identified 5 heterozygous
mutations in 6 families (see 160760.0029-160760.0030) and no mutations
in the seventh family. The family reported by Hedera et al. (2003) had a
deletion of lys1729 (160760.0044).

In a Tanzanian boy with Laing myopathy and mild cardiac involvement,
Darin et al. (2007) identified a heterozygous mutation in the MYH7 gene
(160760.0036).

POPULATION GENETICS

Meredith et al. (2004) identified a heterozygous mutation in the MYH7
gene (lys1729del; 160760.0044) in affected members of an Italian
American family with Laing distal myopathy reported by Hedera et al.
(2003). Muelas et al. (2010) identified the lys1729del mutation in 29
clearly affected individuals from 4 unrelated families in the Safor
region of Spain. Muelas et al. (2012) demonstrated a common 41.2-kb
short haplotype including the lys1729del mutation in both Spanish
patients from the Safor region and in the Italian American family
reported by Hedera et al. (2003), indicating a founder effect. However,
microsatellite markers both up- and downstream of the mutation did not
match, indicating multiple recombination events. The mutation was
estimated to have been introduced into the Safor population about 375 to
420 years ago (15 generations ago). The region is located in the
southeast of Valencia on the Mediterranean coast of Spain. Muelas et al.
(2012) hypothesized that the families from Safor were descendants of the
Genoese who had repopulated this Spanish region in the 17th century
after the Muslims were expelled; in fact, many of the surnames of the
Safor families with Laing myopathy had an Italian origin.

*FIELD* RF
1. Darin, N.; Tajsharghi, H.; Ostman-Smith, I.; Gilljam, T.; Oldfors,
A.: New skeletal myopathy and cardiomyopathy associated with a missense
mutation in MYH7. Neurology 68: 2041-2042, 2007.

2. Gowers, W. R.: A lecture on myopathy and a distal form. Brit.
Med. J. 2: 89-92, 1902.

3. Hedera, P.; Petty, E. M.; Bui, M. R.; Blaivas, M.; Fink, J. K.
: The second kindred with autosomal dominant distal myopathy linked
to chromosome 14q: genetic and clinical analysis. Arch. Neurol. 60:
1321-1325, 2003.

4. Laing, N. G.; Laing, B. A.; Meredith, C.; Wilton, S. D.; Robbins,
P.; Honeyman, K.; Dorosz, S.; Kozman, H.; Mastaglia, F. L.; Kakulas,
B. A.: Autosomal dominant distal myopathy: linkage to chromosome
14. Am. J. Hum. Genet. 56: 422-427, 1995.

5. Mastaglia, F. L.; Phillips, B. A.; Cala, L. A.; Meredith, C.; Egli,
S.; Akkari, P. A.; Laing, N. G.: Early onset chromosome 14-linked
distal myopathy (Laing). Neuromusc. Disord. 12: 350-357, 2002.

6. Meredith, C.; Herrmann, R.; Parry, C.; Liyanage, K.; Dye, D. E.;
Durling, H. J.; Duff, R. M.; Beckman, K.; de Visser, M.; van der Graaff,
M. M.; Hedera, P.; Fink, J. K.; Petty, E. M.; Lamont, P.; Fabian,
V.; Bridges, L.; Voit, T.; Mastaglia, F. L.; Laing, N. G.: Mutations
in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause
Laing early-onset distal myopathy (MPD1). Am. J. Hum. Genet. 75:
703-708, 2004.

7. Muelas, N.; Hackman, P.; Luque, H.; Garces-Sanchez, M.; Azorin,
I.; Suominen, T.; Sevilla, T.; Mayordomo, F.; Gomez, L.; Marti, P.;
Maria Millan, J.; Udd, B.; Vilchez, J. J.: MYH7 gene tail mutation
causing myopathic profiles beyond Laing distal myopathy. Neurology 75:
732-741, 2010.

8. Muelas, N.; Hackman, P.; Luque, H.; Suominen, T.; Espinos, C.;
Garces-Sanchez, M.; Sevilla, T.; Azorin, I.; Millan, J. M.; Udd, B.;
Vilchez, J. J.: Spanish MYH7 founder mutation of Italian ancestry
causing a large cluster of Laing myopathy patients. Clin. Genet. 81:
491-494, 2012.

9. Scoppetta, C.; Casali, C.; La Cesa, I.; Sermoni, A.; Mercuri, B.;
Pierelli, F.; Vaccario, M. L.: Infantile autosomal dominant distal
myopathy. Acta Neurol. Scand. 92: 122-126, 1995.

10. Voit, T.; Kutz, P.; Leube, B.; Neuen-Jacob, E.; Schroder, J. M.;
Cavallotti, D.; Vaccario, M. L.; Schaper, J.; Broich, P.; Cohn, R.;
Baethmann, M.; Gohlich-Ratmann, G.; Scoppetta, C.; Herrmann, R.:
Autosomal dominant distal myopathy: further evidence of a chromosome
14 locus. Neuromusc. Disord. 11: 11-19, 2001.

11. Zimprich, F.; Djamshidian, A.; Hainfellner, J. A.; Budka, H.;
Zeitlhofer, J.: An autosomal dominant early adult-onset distal muscular
dystrophy. Muscle Nerve 23: 1876-1879, 2000.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Face];
Facial muscle weakness, mild;
[Mouth];
High-arched palate;
[Neck];
Neck muscle weakness

CARDIOVASCULAR:
[Heart];
Dilated cardiomyopathy may occur

SKELETAL:
[Spine];
Scoliosis;
[Feet];
Pes cavus

MUSCLE, SOFT TISSUE:
Weakness of ankle and toe extensor (dorsiflexor) muscles;
Atrophy of ankle and toe extensor (dorsiflexor) muscles;
Weakness of anterior compartment tibial muscles;
Atrophy of anterior compartment tibial muscles;
'Hanging' big toe;
Gait difficulties;
Myalgia;
Hypertrophy of calf muscles;
Weakness of long finger extensor muscles (occurs later);
Weakness of neck muscles may occur later;
Atrophy of neck muscles may occur later;
Proximal muscle weakness (occasional);
EMG shows myopathic or neurogenic changes;
Biopsy shows nonspecific myopathy without rimmed vacuoles;
Angulated atrophic fibers;
Hypotrophy of type 1 fibers;
Type 1 fiber predominance;
Fiber type grouping;
Mitochondrial proliferation;
Ragged red fibers;
Sarcoplasmic inclusions;
Cores or minicores;
Abnormalities in myofibril organization

LABORATORY ABNORMALITIES:
Normal to mildly increased serum creatine kinase

MISCELLANEOUS:
Onset in infancy or childhood;
Later onset has been reported;
Slowly progressive;
Variable phenotype;
Allelic to myosin storage myopathy (608358)

MOLECULAR BASIS:
Caused by mutation in the myosin, heavy polypeptide-7, cardiac muscle,
beta gene (MYH7, 160760.0029)

*FIELD* CN
Cassandra L. Kniffin - updated: 10/20/2010
Cassandra L. Kniffin - updated: 1/7/2008
Cassandra L. Kniffin - revised: 1/22/2004

*FIELD* ED
joanna: 04/02/2012
ckniffin: 10/20/2010
ckniffin: 1/7/2008
ckniffin: 1/22/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 5/3/2012
Cassandra L. Kniffin - updated: 1/7/2008
Victor A. McKusick - updated: 9/9/2004
Cassandra L. Kniffin - updated: 1/22/2004
Victor A. McKusick - updated: 1/19/2000

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

*FIELD* ED
terry: 05/10/2012
carol: 5/9/2012
ckniffin: 5/3/2012
wwang: 7/7/2011
wwang: 7/1/2011
wwang: 11/29/2010
ckniffin: 10/26/2010
wwang: 1/17/2008
ckniffin: 1/7/2008
tkritzer: 9/9/2004
terry: 9/9/2004
joanna: 3/19/2004
tkritzer: 1/28/2004
ckniffin: 1/22/2004
carol: 2/21/2003
mgross: 1/21/2000
terry: 1/19/2000
carol: 11/18/1998
carol: 2/27/1995
mimadm: 12/2/1994
carol: 7/9/1993
supermim: 3/16/1992
carol: 2/28/1992
carol: 4/23/1991

MIM 160760
*RECORD*
*FIELD* NO
160760
*FIELD* TI
*160760 MYOSIN, HEAVY CHAIN 7, CARDIAC MUSCLE, BETA; MYH7
;;MYOSIN, CARDIAC, HEAVY CHAIN, BETA; MYHCB
read more*FIELD* TX

CLONING

The structural gene for the beta heavy chain of myosin is expressed
predominantly in fetal life and is switched on in older animals under
conditions of thyroid hormone depletion/replacement and in response to
some physical stresses. Jandreski et al. (1987) presented evidence
indicating that the cardiac beta-myosin heavy chain mRNA is expressed in
skeletal muscle tissue. The expression of cardiac beta-myosin heavy
chain mRNA was particularly prominent in the soleus muscle, which is
rich in slow-twitch type I muscle fibers. There were only trace amounts
in the vastus lateralis and vastus medialis, which consist predominantly
of fast-twitch type II fibers.

Diederich et al. (1989) cloned the entire gene.

By scanning mouse myosin genes for intronic microRNAs (miRNAs), van
Rooij et al. (2009) identified Mir208b (613613) within intron 31 of the
Myh7 gene. Northern blot analysis showed that Myh7 and Mir208b were
highly expressed in mouse slow-twitch soleus muscle. Little to no
expression was detected in heart and in the fast-twitch
gastrocnemius/plantaris, tibialis anterior, and extensor digitorum
longus muscles. However, van Rooij et al. (2009) noted that Myh7 is the
predominant myosin in adult heart in large animals, whereas Myh6
(160710) predominates in adult mouse heart.

GENE STRUCTURE

Jaenicke et al. (1990) demonstrated that the MYH7 gene is 22,883 bp
long. The 1,935 amino acids of this protein are encoded by 38 exons. The
5-prime untranslated region (86 bp) is split by 2 introns. The 3-prime
untranslated region is 114 bp long. Three Alu repeats were identified
within the gene and a fourth one in the 3-prime flanking intergenic
region.

Liew et al. (1990) found that like the rat skeletal myosin heavy chain
gene, the cardiac beta-myosin heavy chain gene is divided into 41 exons,
the first 2 of which are noncoding. However, exons 37 and 38 are fused;
they do not have an intervening intron. The gene extends for 21,828
nucleotides and encodes a deduced 1,1939-amino acid protein with a
molecular mass of 222,937 Da.

Van Rooij et al. (2009) identified a microRNA (miRNA), Mir208b (613613),
within intron 31 of the mouse Myh7 gene.

MAPPING

Matsuoka et al. (1989) found that both the alpha and the beta human
cardiac myosin heavy chain genes are located in the 14cen-q13 region;
the assignment was by somatic cell hybridization and in situ
hybridization. Qin et al. (1990) localized the MYH7 gene to 14q12 by in
situ hybridization.

The beta cardiac myosin heavy chain is located on chromosome 14, 3.6 kb
upstream from the alpha cardiac myosin gene. The 2 genes are oriented in
a head-to-tail tandem fashion (Yamauchi-Takihara et al., 1989;
Geisterfer-Lowrance et al., 1990).

GENE FUNCTION

Van Rooij et al. (2007) found that miRNA208A (MIR208A; 611116), a
cardiac-specific miRNA encoded by intron 27 of the mouse and human MYH6
gene, was required for cardiomyocyte hypertrophy, fibrosis, and
expression of Myh7 in response to stress and hypothyroidism in mice.

Van Rooij et al. (2009) found that expression of Myh7 and its
intronically encoded miRNA, Mir208b, was upregulated in mouse heart by
hypothyroidism caused by inhibition of triiodothyronine (T3; see 188450)
synthesis. This upregulation was reversed by T3 administration. Gain-
and loss-of-function experiments in mice showed that expression of Myh7
and Mir208b was controlled by the dominant miRNA in mouse heart,
Mir208a. However, van Rooij et al. (2009) noted that, in large animals,
Myh7 is the predominant myosin in adult heart. In contrast, the
predominant myosin in adult mouse heart is Myh6, the host gene of
Mir208a. Thus, van Rooij et al. (2009) suggested that Mir208b, which
shares the same seed sequence as Mir208a, may fulfill the function of
Mir208a in large animals.

In mice, adult cardiomyocytes primarily express alpha-myosin heavy chain
(alpha-MHC, also known as Myh6; 160710), whereas embryonic
cardiomyocytes express beta-MHC (Myh7). Cardiac stress triggers adult
hearts to undergo hypertrophy and a shift from alpha-MHC to fetal
beta-MHC expression. Hang et al. (2010) showed that BRG1 (603254), a
chromatin-remodeling protein, has a critical role in regulating cardiac
growth, differentiation, and gene expression. In embryos, Brg1 promotes
myocyte proliferation by maintaining Bmp10 (608748) and suppressing
p57(kip2) (600856) expression. It preserves fetal cardiac
differentiation by interacting with histone deacetylases (HDACs; see
601241) and poly(ADP ribose) polymerase (PARP; 173870) to repress
alpha-MHC and activate beta-MHC. In adults, Brg1 (also known as Smarca4)
is turned off in cardiomyocytes. It is reactivated by cardiac stresses
and forms a complex with its embryonic partners, HDAC and PARP, to
induce a pathologic alpha-MHC-to-beta-MHC shift. Preventing Brg1
reexpression decreases hypertrophy and reverses this MHC switch. BRG1 is
activated in certain patients with hypertrophic cardiomyopathy, its
level correlating with disease severity and MHC changes. Hang et al.
(2010) concluded that their studies showed that BRG1 maintains
cardiomyocytes in an embryonic state, and demonstrated an epigenetic
mechanism by which 3 classes of chromatin-modifying factors, BRG1, HDAC,
and PARP, cooperate to control developmental and pathologic gene
expression.

MOLECULAR GENETICS

- Hypertrophic Cardiomyopathy 1

McKenna (1993) estimated that 40 to 50% of cases of hypertrophic
cardiomyopathy (CMH; 192600) are due to mutations in the MYH7 gene. He
stated that Kaplan-Meier survival curves for these mutations showed that
the val606-to-met mutation (160760.0005) was associated with normal
survivorship, whereas the arg453-to-cys mutation (160760.0003) was
associated with death in about half the affected individuals by age 40
years.

Anan et al. (1994) presented a schematic of 15 mutations within the MYH7
gene that cause CMH. They described a phe513-to-cys mutation
(160760.0016) in which affected family members had near-normal life
expectancy, and an arg719-to-trp mutation (160760.0017) in 4 unrelated
CMH families with a high incidence of premature death and an average
life expectancy in affected individuals of 38 years. They suggested that
these findings supported the hypothesis that mutations that alter the
charge of the encoded amino acid affects survival more significantly
than those that produce a conservative amino acid change. Kelly and
Strauss (1994) pointed out that all but one of the known mutations of
the MYH7 gene that produce hypertrophic cardiomyopathy result in amino
acid substitutions in the protein head or the region in which the head
and rod of the molecule intersect. In their Figure 2, they diagrammed
the cardiac myosin heavy-chain dimer and the site of the mutations. They
suggested that these mutations represent dominant negatives by
disturbing contractile function despite the production of a normal
protein by the remaining normal allele. Consistent with this conclusion
is the finding of Cuda et al. (1993) that mutant beta-myosin separated
from the heart muscle in cases of hypertrophic cardiomyopathy of the
chromosome 14 type translocate actin filaments with an abnormally low
sliding velocity in motility assays in vitro.

Lankford et al. (1995) compared the contractile properties of single
slow-twitch muscle fibers from patients with 3 distinct CMH-causing MYH7
mutations with those from normal controls. Fibers from the gly741-to-arg
mutation (160760.0011), located near the binding site of essential light
chain, demonstrated decreased maximum velocity of shortening (39% of
normal) and decreased isometric force generation (42% of normal). Fibers
with the arg403-to-gln mutation (160760.0001) (at the actin interface of
myosin) showed lower force/stiffness ratio (56% of normal) and depressed
velocity of shortening (50% of normal). Both of these
mutation-containing fibers displayed abnormal force-velocity
relationships and reduced power output. Fibers from the gly256-to-glu
mutation (160760.0012), located at the end of the ATP-binding pocket,
had contractile properties that were indistinguishable from normal.
Thus, variability was found in the nature and extent of functional
impairments in skeletal fibers containing different MYH7 gene mutations,
and this variability may correlate with the severity and penetrance of
the disease resulting from each mutation.

Rayment et al. (1995) examined 29 missense mutations in the MYH7 gene
that are responsible for 10 to 30% of familial hypertrophic
cardiomyopathy cases and analyzed their effects on the 3-dimensional
structure of skeletal muscle myosin. Arai et al. (1995) reported a
thirtieth missense mutation and stated that these had been found in 49
families worldwide at that time. Almost all were located in the region
of the gene coding for the globular head of the molecule and only 1
mutation was found in both Caucasian and Japanese families.

Seidman (2000) pointed out that correlations between genotype and
prognosis in hypertrophic cardiomyopathy is possible. Life expectancy is
markedly diminished in individuals with the R719W (160760.0017) and
R403Q (160760.0001) mutations in the MYH7 gene but near normal in
individuals with the E542Q (600958.0006) and 791insG (600958.0011)
mutations in the MYBPC3 gene.

Woo et al. (2003) screened 70 probands with hypertrophic cardiomyopathy
for mutations in the beta-MHC gene. Mutations in this gene were detected
in 15 of 70 probands (21%). Eleven mutations were detected, including 4
novel mutations. Median survival was 66 years (95% CI 64 to 77 years) in
all affected subjects. There was a significant difference in survival
between subjects according to the affected functional domain.
Significant independent predictors of decreased survival were the
nonconservative missense mutations that affected the actin binding site
and those that affected the rod portion of beta-MHC.

Hougs et al. (2005) screened for mutations in the rod region (exons 24
to 40) of MYH7 in 92 Danish patients with hypertrophic cardiomyopathy.
Using capillary electrophoresis single-strand conformation polymorphism,
3 disease-causing mutations of the rod region were identified in 4
patients, including the R1712W (160760.0032) mutation in 2 patients. Two
of the patients had already been shown to carry other FHC-associated
mutations.

Arad et al. (2005) identified 2 different MYH7 missense mutations in 2
probands with apical hypertrophy from families in which the mutations
also caused other CMH morphologies (see 160760.0038 and 160760.0039,
respectively), and 1 in a sporadic patient with apical hypertrophy
(R243H; 160760.0040).

In a consanguineous British family in which 3 sibs developed
hypertrophic cardiomyopathy, respiratory failure, and myosin storage
myopathy (608358), Tajsharghi et al. (2007) identified homozygosity for
a missense mutation in the MYH7 gene (160760.0035).

In a Japanese proband with CMH (CMH17; 613873), Matsushita et al. (2007)
identified heterozygosity for a missense mutation in the JPH2 gene
(605267.0004); subsequent analysis of 15 known CMH-associated genes
revealed that the proband also carried 2 mutations in MYH7, F513C
(160760.0016) and A26V. The authors suggested that mutations in both
JPH2 and MYH7 could be associated with the pathogenesis of CMH in this
proband.

In a 32-year-old African American woman with severe hypertrophic
cardiomyopathy and a family history of CMH and sudden cardiac death,
Frazier et al. (2008) identified a heterozygous mutation in the TNNI3
gene (P82S; 191044.0003) and a heterozygous mutation in the MYH7 gene
(R453S; 160760.0043).

- Dilated Cardiomyopathy 1S

Kamisago et al. (2000) performed clinical evaluations in 21 kindreds
with familial dilated cardiomyopathy (CMD1S; 613426). In a genomewide
linkage study, a genetic locus for mutations associated with dilated
cardiomyopathy was identified at chromosome 14q11.2-q13 (maximum lod
score = 5.11 at theta = 0.0). Analysis of MYH7 and other genes for
sarcomere proteins revealed heterozygous missense mutations in MYH7 in 2
kindreds (S532P, 160760.0022 and P764L, 160760.0023, respectively).
Affected individuals had neither antecedent cardiac hypertrophy nor
histopathologic findings characteristic of hypertrophy.

- Myosin Storage Myopathy, Laing Distal Myopathy, and Scapuloperoneal
Myopathy

In affected members of a family and in an unrelated patient with myosin
storage myopathy (608358), Tajsharghi et al. (2003) identified a
heterozygous mutation in the MYH7 gene (160760.0028).

Laing et al. (1995) mapped Laing distal myopathy (160500) to chromosome
14. In affected members of 7 separate families with Laing distal
myopathy, Meredith et al. (2004) sequenced the MYH7 gene, a positional
candidate for the site of the causative mutation. They identified 5
heterozygous mutations in 6 families (see 160760.0029-160760.0030) and
no mutations in the seventh family. All 5 mutations were predicted, by
in silico analysis, to disrupt locally the ability of the myosin tail to
form a coiled coil, which is its normal structure. The findings
demonstrated that heterozygous mutations toward the 3-prime end of MYH7
can cause Laing distal myopathy.

Pegoraro et al. (2007) conducted MYH7 gene analysis by
RT-PCR/SSCP/sequencing in 2 patients diagnosed with myosin storage
myopathy and 17 patients diagnosed with scapuloperoneal myopathy of
unknown etiology. They found the R1845W mutation of the MYH7 gene in
both cases of myosin storage myopathy and in 2 of the 17 scapuloperoneal
patients (181430) studied. 5533C-T segregation analysis in the mutation
carrier families identified 11 additional patients. The clinical
spectrum in this cohort of patients included asymptomatic hyperCKemia
(elevated serum creatine kinase), scapuloperoneal myopathy, and proximal
and distal myopathy with muscle hypertrophy. Muscle MRI identified a
unique pattern in the posterior compartment of the thigh, characterized
by early involvement of the biceps femoris and semimembranosus, with
relative sparing of the semitendinosus. Muscle biopsy revealed hyaline
bodies characteristic of myosin storage myopathy in only half of
biopsied patients (2 of 4). These patients without hyaline bodies had
been diagnosed with scapuloperoneal myopathy prior to the identification
of hyaline bodies in other family members, prompting MYH7 gene analysis.
The authors pointed out that patients without hyaline bodies presented
later onset and milder severity.

Armel and Leinwand (2009) analyzed the functional effects of 4 different
MYH7 mutations in the rod or tail domain that were found to be
responsible for myosin storage myopathy: R1845W (160760.0028), H1901L
(160760.0031), E1886K (160760.0035), and L1793P (160760.0037). None of
the mutations altered the secondary structure of the protein, but L1793P
and H1901L showed decreased thermodynamic stability. All mutations
decreased the extent of self-assembly of the light meromyosin rod (less
than 50 to 60%) compared to the wildtype protein. R1845W and H1901L
showed formation of more stable and larger filaments, whereas L1793P and
E1886K showed more rapid filament degradation. Armel and Leinwand (2009)
noted that the assembly of muscle filaments is a multistep process that
involves both the proper folding of alpha-helices into coiled-coils, and
the assembly of these coiled-coils, in proper register, into filaments,
and concluded that defects in any one of these steps can result in
improper filament formation leading to muscle disease.

- Left Ventricular Noncompaction 5

Klaassen et al. (2008) analyzed 6 genes encoding sarcomere proteins in
63 unrelated adult probands with left ventricular noncompaction (LVNC)
but no other congenital heart anomalies (see LVNC5; 613426), and
identified 7 different heterozygous mutations in the MYH7 gene in the
probands from 4 families and in 4 sporadic patients (see, e.g.,
160760.0040-160760.0042). Klaassen et al. (2008) noted that 5 of the 7
mutations were located within the genomic sequence of exon 8 to exon 9
of MYH7, which appeared to be a cluster for LVNC mutations.

In a mother with myosin storage myopathy, who later developed CMH, and
in her daughter, who had early-symptomatic LVNC, Uro-Coste et al. (2009)
identified heterozygosity for the L1793P mutation in MYH7 (160760.0037).

In an analysis of the MYH7 gene in 141 white probands of western
European descent diagnosed with Ebstein anomaly (see 224700), Postma et
al. (2011) identified heterozygous mutations in 8 (see, e.g.,
160760.0045 and 160760.0046). Of these 8 probands, LVNC was present in 7
and uncertain in 1, whereas none of the 133 mutation-negative probands
had LVNC. Evaluation of all available family members of
mutation-positive probands revealed 3 families in which additional
mutation-positive individuals had cardiomyopathy or congenital heart
malformations, including type II atrial septal defect, ventricular
septal defect, bicuspid aortic valve, aortic coarctation, and pulmonary
artery stenosis/hypoplasia.

ANIMAL MODEL

Geisterfer-Lowrance et al. (1996) engineered the human CMH cardiac
myosin heavy chain gene mutation arg403-to-gln (R403Q) into the mouse
genome to create a murine model of familial hypertrophic cardiomyopathy.
Homozygous mice died within a week after birth, while heterozygous mice
displayed both histologic and hemodynamic abnormalities characteristic
of CMH. In addition, the CMH mice demonstrated gender and developmental
differences. Male CMH mice demonstrated more severe myocyte hypertrophy,
disarray, and interstitial fibrosis than their female littermates, and
both sexes showed increased cardiac dysfunction and histopathology as
they aged. Heterozygous CMH mice also had sudden death of uncertain
etiology, especially during periods of exercise. Berul et al. (1997)
found that in contrast to wildtype mice which had completely normal
cardiac electrophysiology, CMH mice demonstrated (a)
electrocardiographic abnormalities including prolonged repolarization
intervals and rightward axis; (b) electrophysiologic abnormalities
including heterogeneous ventricular conduction properties and prolonged
sinus node recovery time; and (c) inducible ventricular ectopy.

Fatkin et al. (1999) reported further studies of the CMH mouse in which
the arg403-to-gln mutation had been introduced by homologous
recombination. Heterozygous mice developed myocardial histologic
abnormalities similar to those in human CMH by 15 weeks of age.
Sedentary heterozygous mice had a normal life span. Homozygous mutant
mice were liveborn, but, unlike their heterozygous littermates, all died
within 1 week. Fatkin et al. (1999) found that neonatal lethality was
caused by a fulminant dilated cardiomyopathy characterized by myocyte
dysfunction and loss. They studied cardiac dimensions and functions for
the first time in neonatal mice by high frequency (45 MHz)
echocardiography and found that both were normal at birth. Between days
4 and 6, homozygous deficient mice developed a rapidly progressive
cardiomyopathy with left ventricular dilation, wall thinning, and
reduced systolic contraction. Histopathology revealed myocardial
necrosis with dystrophic calcification. Electron microscopy showed
normal architecture intermixed with focal myofibrillar disarray. Fatkin
et al. (1999) speculated that variable incorporation of mutant and
normal MYHC into sarcomeres of heterozygotes may account for focal
myocyte death in familial hypertrophic cardiomyopathy.

In R403Q-knockin mice, Gao et al. (1999) observed that during twitch
contractions, peak intracellular Ca(2+) was higher in mutant muscles
than in wildtype muscles, but force development was equivalent in both.
Developed force fell at higher stimulation rates in the mutants but not
in controls. Gao et al. (1999) concluded that calcium cycling and
myofilament properties are both altered in CMH mutant mice.

Marian et al. (1999) created a transgenic rabbit model of hypertrophic
cardiomyopathy by injecting a transgene carrying the R403Q mutation into
fertilized zygotes. Expression of transgene mRNA and protein were
confirmed by Northern blotting and 2-dimensional gel electrophoresis
followed by immunoblotting, respectively. Animals carrying the mutant
transgene showed substantial myocyte disarray and a 3-fold increase in
interstitial collagen expression in the myocardium. Mean septal
thickness was comparable between rabbits carrying the wildtype transgene
and nontransgenic littermates, but was significantly increased in the
mutant transgenic animals. Posterior wall thickness and left ventricular
mass were also increased, but dimensions and systolic function were
normal. Premature death was more common in mutant than in wildtype
transgenic rabbits or in nontransgenic littermates. Thus, the phenotype
of patients with the R403Q mutation of the MYH7 was reproduced.

To minimize confounding variables while assessing relationships between
CMH histopathology and arrhythmia vulnerability, Wolf et al. (2005)
generated inbred CMH mice carrying the R403Q mutation and observed
variable susceptibility to arrhythmias, differences in ventricular
hypertrophy, and variable amounts and distribution of fibrosis and
myocyte disarray. There was no correlation between the amount and/or
pattern of fibrosis or the quantity of myocyte disarray and the
propensity for arrhythmia as assessed by ex vivo high-resolution mapping
and in vivo electrophysiologic study; however, the amount of ventricular
hypertrophy was significantly associated with increased arrhythmia
susceptibility. Wolf et al. (2005) concluded that the 3 cardinal
manifestations of CMH (cardiac hypertrophy, myocyte fibrosis, and
disarray) reflect independent pathologic processes within myocytes
carrying a sarcomere gene mutation and that the severity of fibrosis and
disarray is substantially influenced by unknown somatic factors, and
they suggested that a shared pathway triggered by sarcomere gene
mutations links cardiac hypertrophy and arrhythmias in CMH.

The human hypertrophic cardiomyopathy-causing mutation MYH7 R403Q
(160760.0001) causes particularly severe disease characterized by
early-onset and progressive myocardial dysfunction, with a high
incidence of cardiac sudden death. MHC(403/+) mice express an R403Q
mutation in Myh6 (160710) under the control of the endogenous Myh locus.
Jiang et al. (2013) found that expression of the Myh6 R403Q mutation in
mice can be selectively silenced by an RNA interference (RNAi) cassette
delivered by an adeno-associated virus vector. RNAi-transduced
MHC(403/+) mice developed neither hypertrophy nor myocardial fibrosis,
the pathologic manifestations of hypertrophic cardiomyopathy, for at
least 6 months. Because inhibition of hypertrophic cardiomyopathy was
achieved by only a 25% reduction in the levels of mutant transcripts,
Jiang et al. (2013) suggested that the variable clinical phenotype in
hypertrophic cardiomyopathy patients reflects allele-specific expression
and that partial silencing of mutant transcripts may have therapeutic
benefit.

*FIELD* AV
.0001
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ARG403GLN

In the large French-Canadian kindred originally reported by Pare et al.
(1961) and shown to have linkage of the cardiac disorder (192600) to
markers on the proximal portion of 14q, Geisterfer-Lowrance et al.
(1990) found a missense mutation in the beta cardiac myosin heavy chain
that converted arginine-403 to glutamine (R403Q). A guanine residue at
position 10,162 (enumerated as in Jaenicke et al., 1990) was mutated to
an adenine residue. The mutation generated a new DdeI site and changed
the CGG(arg) codon to CAG(gln). Perryman et al. (1992) found that the
R403Q mutation was identifiable in myocardial mRNA. Ross and Knowlton
(1992) reviewed this discovery beginning with the patients first seen by
Pare in the 1950s.

Using an isolated, isovolumic heart preparation where cardiac
performance was measured simultaneously with cardiac energetics using
(31)P nuclear magnetic resonance spectroscopy, Spindler et al. (1998)
studied the effects of the codon 403 missense mutation. They observed 3
major alterations in the physiology and bioenergetics of the mutant
mouse hearts. First, while there was no evidence for systolic
dysfunction, diastolic function was impaired during inotropic
stimulation. Diastolic dysfunction was manifest as both a decreased rate
of left ventricular relaxation and an increase in end-diastolic
pressure. Second, under baseline conditions the mutant R403Q mouse
hearts had lower phosphocreatine and increased inorganic phosphate
contents resulting in a decrease in the calculated value for the free
energy released from ATP hydrolysis. Third, mutant hearts that were
studied unpaced responded to increased perfusate calcium by decreasing
heart rate approximately twice as much as wildtypes. The authors
concluded that the hearts from mice carrying the R403Q mutation have
workload-dependent diastolic dysfunction resembling the human form of
familial hypertrophic cardiomyopathy. Changes in high-energy phosphate
content suggested that an energy-requiring process may contribute to the
observed diastolic dysfunction.

Bashyam et al. (2003) pointed out that polymorphism in the ACE1 gene
(106180) had been shown to affect the prognosis in familial hypertrophic
cardiomyopathy. The DD allele of the ACE1 gene (106180.0001) was
associated with a severe form of hypertrophy and sudden death in
patients with familial hypertrophic cardiomyopathy (Iwai et al., 1994).
Tesson et al. (1997) established an association of the D allele at the
ACE1 locus with the R403Q mutation in MYH7, but not with MYBPC3 (600958)
mutations.

.0002
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ARG249GLN

Using a ribonuclease protection assay, Watkins et al. (1992) screened
the beta cardiac myosin heavy-chain genes of probands from 25 unrelated
families with familial hypertrophic cardiomyopathy (192600). Seven
different mutations were identified in 12 of the 25 families; see
160760.0003-160760.0007. All were missense mutations; 5 were clustered
in the head of the beta-chain, which comprises the 5-prime 866 amino
acids, and 2 were located in the 5-prime or hinge portion of the rod
part. Six of the mutations resulted in a change in the charge of the
amino acid. These patients had a shorter life expectancy (mean age at
death, 33 years) than did patients with the one mutation that did not
produce a change in charge, val606-to-met. One of the mutations they
found was a substitution of glutamine for arginine-249.

.0003
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ARG453CYS

See 160760.0002. Watkins et al. (1992) found substitution of cysteine
for arginine-453 in 2 unrelated families with familial hypertrophic
cardiomyopathy (192600). One of the families also had an alpha/beta
cardiac myosin heavy chain hybrid gene which was presumably of no
functional significance, inasmuch as the 5-prime promoter region was
derived from the alpha subunit.

In a 3-generation Chinese family, Ko et al. (1996) observed the
coexistence of sudden death and end-stage heart failure due to the
arg453-to-cys mutation. The average age of death in affected members of
the family was 34 years.

.0004
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, GLY584ARG

See 160760.0002. Watkins et al. (1992) found the gly584-to-arg mutation
in 2 unrelated families with familial hypertrophic cardiomyopathy
(192600).

.0005
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, VAL606MET

See 160760.0002. Watkins et al. (1992) found this mutation in 3
unrelated families with familial hypertrophic cardiomyopathy (192600).
Of the 7 mutations they found, this was the only one that produced no
change in the charge of the amino acid. Although the affected patients
did not differ in other clinical manifestations of familial hypertrophic
cardiomyopathy, patients in this family had nearly normal survival; mean
age at death was 33 years in the 11 families with one or another
mutation that substituted an amino acid with a different charge.

Blair et al. (2001) identified the val606-to-met mutation in a family in
which 2 individuals had suffered sudden death at an early age. The
mutation was found to be in cis with an ala728-to-val (A728V) mutation
(160760.0025).

.0006
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, GLU924LYS

See 160760.0002. Watkins et al. (1992) found this mutation in 1 family
with familial hypertrophic cardiomyopathy (192600). The mutation was
found in exon 23 by RNase protection assay. It occurred as a new
mutation in a 44-year-old female; the parents lacked the mutation which,
however, was transmitted to her 24-year-old daughter.

.0007
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, GLU949LYS

See 160760.0002. Watkins et al. (1992) found this mutation in 1 family
with familial hypertrophic cardiomyopathy (192600).

.0008
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ARG723CYS

Among 7 individuals with sporadic hypertrophic cardiomyopathy (192600),
Watkins et al. (1992) identified mutations in the beta cardiac MHC genes
in 2. Since the parents were neither clinically nor genetically
affected, the authors concluded that the mutations in each proband arose
de novo. Transmission of the mutation and disease to an offspring
occurred in 1 pedigree (160760.0006), predicting that these were
germline mutations. One proband, a 40-year-old female, was shown by
RNase protection assay to have a C-to-T transition in exon 20 at
nucleotide 2253, leading to a change from arginine to cysteine at codon
723. Arginine residue 723 is conserved among all known cardiac MHCs and
all vertebrate striated muscle MHCs except the human perinatal and
rabbit skeletal isoforms; mutation of a cysteine residue constitutes a
nonconservative substitution with a change in net charge.

.0009
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, 2.4-KB DEL

In a family with several members affected with hypertrophic
cardiomyopathy (192600), Marian et al. (1992) identified a novel 9.5-kb
BamHI RFLP detected by an MYH7 probe on Southern blots of DNA from the
proband. PCR was used to amplify the segment of the gene; sequence
analysis showed a 2.4-kb deletion involving 1 allele. The deletion
included part of intron 39, exon 40 including the 3-prime untranslated
region and the polyadenylation signal, and part of the region between
the beta and alpha myosin heavy chain genes. The deletion was inherited
by 2 daughters of the proband and a grandson, aged 33, 32, and 10 years,
respectively, who were, however, free of signs of the disorder. The
67-year-old proband had late onset of the disorder which was first
diagnosed in him at the age of 59 when he presented with atypical chest
pain, lightheadedness, and decreased exercise tolerance. On cardiac
examination, he showed an S4 heart sound and a systolic ejection murmur.
EKG showed left ventricular hypertrophy with repolarization
abnormalities. Ventricular hypertrophy was demonstrated by
echocardiogram which also showed systolic anterior motion of the
anterior leaflet of the mitral valve. There was a 25-mm Hg left
ventricular outflow tract gradient. From observations in C. elegans, it
was predicted that an unstable mRNA might result from this mutation.

.0010
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, LEU908VAL

Fananapazir et al. (1993) found evidence, on soleus muscle biopsy, of
central core disease (117000) in 10 of 13 hypertrophic cardiomyopathy
patients with the leu908-to-val mutation. Although the mutations in the
MYH7 gene were associated with skeletal muscle changes characteristic of
central core disease, such was not found in patients with hypertrophic
cardiomyopathy unlinked to MYH7. Notably, in 1 branch of a family with
the L908V mutation, 2 adults and 3 children had histologic changes of
central core disease without evidence of cardiac hypertrophy by
echocardiogram. One of the adults had skeletal myopathic changes.
McKenna (1993), who stated that he had never seen clinical evidence of
skeletal myopathy in patients with CMH1 (192600), doubted the
significance of the findings.

.0011
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, GLY741ARG

In 1 of 3 patients with hypertrophic cardiomyopathy (192600) and the
G741R mutation, Fananapazir et al. (1993) found microscopic changes of
central core disease on soleus muscle biopsy.

.0012
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, GLY256GLU

In 1 patient with the G256E mutation and familial hypertrophic
cardiomyopathy (192600), Fananapazir et al. (1993) found histologic
changes on soleus muscle biopsy consistent with central core disease.

.0013
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ASP778GLY

Using PCR-DNA conformation polymorphism analysis, Harada et al. (1993)
found an A-to-G transition at codon 778 leading to replacement of the
asp residue by gly. The mutation was found in 5 unrelated Japanese
patients and their affected family members with hypertrophic
cardiomyopathy (192600).

.0014
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ARG403LEU

In 2 French pedigrees with familial hypertrophic cardiomyopathy
(192600), Dausse et al. (1993) performed linkage analysis using 2
microsatellite markers located in the MYH7 gene, as well as 4 highly
informative markers that mapped to the 14q11-q12 region. Linkage to the
markers was found in pedigree 720, but results were not conclusive for
pedigree 730. Haplotype of 6 markers allowed identification of affected
individuals and of some unaffected subjects who were carrying the
disease gene. Two novel missense mutations were identified in exon 13 by
direct sequencing: arg403-to-leu and arg403-to-trp in families 720 and
730, respectively. The arg403-to-leu mutation was associated with
incomplete penetrance, a high incidence of sudden deaths and severe
cardiac events, whereas the consequences of the arg403-to-trp mutation
appeared to be less severe. Codon 403 of the MYH7 gene appears,
therefore, to be a hotspot for mutations causing CMH. The first mutation
identified in this disorder involved codon 403 (160760.0001).

.0015
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ARG403TRP

See 160760.0014.

.0016
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, PHE513CYS

In a family of Japanese ancestry in which a mild form of familial
hypertrophic cardiomyopathy (192600) occurred, Anan et al. (1994) found
a 1624T-G transversion in exon 15, resulting in a phe513-to-cys (F513C)
substitution. The F513C mutation did not alter the charge of the encoded
amino acid, which may be related to the finding of near-normal life
expectancy in this family.

In a Japanese proband with CMH (CMH17; 613873), Matsushita et al. (2007)
identified heterozygosity for a missense mutation in the JPH2 gene
(605267.0004); subsequent analysis of 15 known CMH-associated genes
revealed that the proband also carried 2 heterozygous mutations in MYH7,
F513C and A26V. Her newborn son, who had no signs of CMH on
echocardiography at 1 day of age, carried both the JPH2 G505S mutation
and the MYH7 A26V mutation. The authors suggested that mutations in both
JPH2 and MYH7 could be associated with the pathogenesis of CMH in this
proband.

.0017
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ARG719TRP

In 4 unrelated families with hypertrophic cardiomyopathy (192600) with a
high incidence of premature death and an average life expectancy in
affected individuals of 38 years, Anan et al. (1994) found an R719W
mutation in exon 19 changing the charge of the amino acid by -1. The
difference in survival of individuals bearing the R719W mutation as
compared with those with the F513C mutation (160760.0016) was
demonstrated by Kaplan-Meier product-limit curves (their Figure 4).

In a 6.5-year-old boy with a severe form of hypertrophic cardiomyopathy,
Jeschke et al. (1998) identified 2 missense mutations: one was the R719W
mutation and the other was an M349T mutation (160760.0020), which was
inherited through the maternal grandmother. Six family members who were
carriers of the M349T mutation were clinically unaffected. The authors
hypothesized that compound heterozygosity for the R719W and M349T
mutations resulted in the particularly severe phenotype of early onset.

.0018
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, GLY716ARG

In a small family from the U.K. in which 2 individuals affected by
hypertrophic cardiomyopathy (192600) were alive, including one who had
been resuscitated after sudden death at age 19, Anan et al. (1994) found
a G-to-A transition at nucleotide 2232 resulting in a gly716-to-arg
(G716R) substitution (charge change = +1) of the encoded amino acid.

.0019
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, GLU935LYS

In 2 brothers with hypertrophic cardiomyopathy (192600) who died in
their thirties, Nishi et al. (1994) found a G-to-A transition in codon
935 of the MYH7 gene, leading to a replacement of glutamic acid with
lysine. The brothers were homozygous, whereas the parents, who were
first cousins, were heterozygous for the mutation and had cardiac
hypertrophy without clinical symptoms. An elder sister was also
heterozygous for the mutation but did not manifest cardiac hypertrophy.
Nishi et al. (1994) suggested that there was a gene dosage effect on
clinical manifestations in this family.

.0020
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, MET349THR

See 160760.0017 and Jeschke et al. (1998).

.0021
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ARG719GLN

In a study of mutations causing hypertrophic cardiomyopathy (192600) in
2 South African subpopulations, Moolman-Smook et al. (1999) identified
an arg719-to-gln (R719Q) mutation in the MYH7 gene. The mutation
occurred in a family of white ancestry and had previously been described
by Watkins et al. (1992) in a Canadian family. The codon is the same as
that involved in the arg719-to-trp mutation (160760.0017).

.0022
CARDIOMYOPATHY, DILATED, 1S
MYH7, SER532PRO

In a family with familial dilated cardiomyopathy-1S (613426), Kamisago
et al. (2000) demonstrated a T-to-C change at nucleotide 1680 in exon 16
of the cardiac beta-myosin heavy chain gene, causing a ser532-to-pro
missense mutation. An affected member of this family had received a
cardiac transplant cardiac beta-myosin heavy chain gene. An affected
member of this family had received a cardiac transplant at 23 years of
age. A 20-year-old female suffered postpartum congestive heart failure
and sudden death. A female child developed congestive heart failure at 2
years of age.

.0023
CARDIOMYOPATHY, DILATED, 1S
MYH7, PHE764LEU

In a family with familial dilated cardiomyopathy-1S (613426), Kamisago
et al. (2000) found a C-to-G transversion at nucleotide 2378 in exon 21
of the cardiac beta-myosin heavy chain gene, causing a phe764-to-leu
missense mutation. The 33-year-old father was given a diagnosis of
dilated cardiomyopathy at age 11 years. A daughter died suddenly at the
age of 2 months. A 4-year-old daughter, diagnosed with dilated
cardiomyopathy at the time of birth, was found to have fetal left
ventricular dilatation.

.0024
CARDIOMYOPATHY, HYPERTROPHIC, MIDVENTRICULAR, DIGENIC
MYH7, GLU743ASP

Davis et al. (2001) identified a double point mutation in the MYLK2 gene
(606566) on the maternal haplotype in a 13-year-old white male proband
with early midventricular hypertrophic cardiomyopathy (see 192600). The
MYLK2 mutations were ala87 to val (A87V; 606566.0001) and ala95 to glu
(A95E; 606566.0002). The proband also inherited a glu743-to-asp mutation
(E743D) in the beta-myosin gene (MYH7) from his father. Although the son
had significant disease at an early age, the father and mother came to
medical attention only after the diagnosis of the son. Echocardiographic
evaluation showed that both parents had similarly abnormal
asymmetrically thickened hearts. The kindred was too small for linkage
analysis, and the authors proposed that the mutant MYLK2 may be
functionally abnormal and may consequently stimulate cardiac
hypertrophy. Davis et al. (2001) concluded that the increased severity
of the disease at such a young age in the proband suggests a compound
effect.

.0025
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ALA728VAL

Blair et al. (2001) identified a C-to-T transition in exon 20 resulting
in an ala728-to-val (A728V) mutation in cis with a val606-to-met (V606M;
160760.0005) mutation in a family in which 3 individuals had suffered
sudden death. Blair et al. (2001) suggested that this second mutation in
cis with the V606M mutation was responsible for the more severe
phenotype in this family.

.0026
CARDIOMYOPATHY, DILATED, 1S
MYH7, ALA223THR

In a series of 46 young patients with dilated cardiomyopathy-1S
(613426), Daehmlow et al. (2002) identified 2 mutations in the MYH7
gene, one of which was a G-to-A transition in exon 8 at nucleotide 7799,
resulting in an ala223-to-thr (A223T) substitution. The mutation
affected a buried residue near the ATP-binding site. The patient with
this mutation was 35 years old when diagnosed with dilated
cardiomyopathy.

.0027
CARDIOMYOPATHY, DILATED, 1S
MYH7, SER642LEU

In a series of 46 young patients with dilated cardiomyopathy-1S
(613426), Daehmlow et al. (2002) found 2 mutations in the MYH7 gene, one
of which was a C-to-T transition in exon 17 at nucleotide 12164,
resulting in a ser642-to-leu (S642L) substitution at a highly conserved
residue. The mutation occurred at the actin-myosin interface. The
patient with this mutation was 18 years old when diagnosed with dilated
cardiomyopathy.

.0028
MYOPATHY, MYOSIN STORAGE
SCAPULOPERONEAL MYOPATHY, MYH7-RELATED, INCLUDED
MYH7, ARG1845TRP

In affected members of a family and in an unrelated patient with myosin
storage myopathy (608358) without cardiomyopathy, Tajsharghi et al.
(2003) identified a heterozygous 23014C-T transition in the MYH7 gene,
resulting in an arg1845-to-trp (R1845W) substitution. The mutation is
located in the distal end of the filament-forming rod region of the
protein. Tajsharghi et al. (2003) suggested that the mutation may
interfere with the interaction of MYH7 with myosin-binding proteins and
inhibit myosin assembly into thick filaments.

Laing et al. (2005) identified the R1845W mutation in 2 unrelated
Belgian patients with myosin storage myopathy. Neither patient had a
family history of the disease. The mutation was predicted to impair the
coiled-coil structure of the protein.

Pegoraro et al. (2007) conducted MYH7 gene analysis by
RT-PCR/SSCP/sequencing in 2 patients diagnosed with myosin storage
myopathy and 17 patients diagnosed with scapuloperoneal myopathy of
unknown etiology. They found the arg1845-to-trp mutation of the MYH7
gene in both cases of myosin storage myopathy and in 2 of the 17
scapuloperoneal patients (181430) studied. 5533C-T segregation analysis
in the mutation carrier families identified 11 additional patients. The
clinical spectrum in this cohort of patients included asymptomatic
hyperCKemia (elevated serum creatine kinase), scapuloperoneal myopathy,
and proximal and distal myopathy with muscle hypertrophy. Muscle MRI
identified a unique pattern in the posterior compartment of the thigh,
characterized by early involvement of the biceps femoris and
semimembranosus, with relative sparing of the semitendinosus. Pegoraro
et al. (2007) concluded that phenotypic and histopathologic variability
may underlie MYH7 gene mutation and that the absence of hyaline bodies
in muscle biopsies does not rule out MYH7 gene mutations.

By functional analysis, Armel and Leinwand (2009) showed that the R1845W
mutant protein was nearly indistinguishable from wildtype in both
secondary structural characteristics and biophysical parameters.
However, compared to the wildtype protein, the mutant protein was unable
to assemble to the same extent, formed larger structures, and formed
more stable paracrystals. The results suggested that the R1845W mutation
alters the interactions between filaments such that their assembly is
less constrained, causing the formation of abnormally large,
degradation-resistant structures. Similar results were found for H1901L
(160760.0031).

.0029
LAING DISTAL MYOPATHY
MYH7, ARG1500PRO

In an Australian patient with sporadic Laing distal myopathy (160500),
Meredith et al. (2004) identified an arg1500-to-pro (R1500P) mutation in
exon 32 of the MYH7 gene. Mild talipes equinovarus had been noted at
birth but corrected itself. By the time the patient was 4 years old, she
was noted to have weakness of ankle dorsiflexion. Progressive weakness
of legs and hands followed, with involvement of the arms at 11 years of
age.

.0030
LAING DISTAL MYOPATHY
MYH7, LYS1617DEL

In affected members of previously reported families with Laing distal
myopathy (160500) from Germany (Voit et al., 2001) and Austria (Zimprich
et al., 2000), Meredith et al. (2004) identified deletion of a lysine at
position 1617 in exon 34 of the MYH7 gene.

.0031
MYOPATHY, MYOSIN STORAGE
MYH7, HIS1904LEU

In affected members of a Saudi Arabian family with autosomal dominant
hyaline body myopathy, or myosin storage myopathy (608358), reported by
Bohlega et al. (2003), Bohlega et al. (2004) identified a 25596A-T
transversion in the MYH7 gene, resulting in a his1904-to-leu (H1904L)
substitution in a highly conserved residue in the coiled-coil tail
region of the protein. The mutation was not identified in 130 control
chromosomes. None of the patients had cardiac abnormalities. The authors
noted that the H1904L mutation is adjacent to a critical assembly
competent domain and suggested that the mutation may cause improper
assembly of the thick filament or interfere with stability of the
protein.

Oldfors et al. (2005) used a different numbering system and stated that
the mutation described by Bohlega et al. (2004) should be HIS1901LEU.
They asserted that the histidine at residue 1901 occupies the 'f'
position of the heptad repeat of the coiled-coil domain, whereas residue
1904 is not at an 'f' position in the heptad repeat sequence. In
response, Meyer (2005) stated that the mutation occupies an 'f' position
regardless of the numbering system used.

By functional analysis, Armel and Leinwand (2009), who also referred to
this mutation as H1901L, indicated that the mutant protein had decreased
thermodynamic stability. In addition, the extent of assembly of the tail
region was decreased compared to wildtype, and the paracrystals were
much larger and more stable than wildtype. The findings suggested that
the E1901L mutation alters the interactions between filaments such that
larger, more stable structures are formed. Similar results were observed
for R1845W (160760.0028).

.0032
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ARG1712TRP

In 2 Danish patients with familial hypertrophic cardiomyopathy (192600),
Hougs et al. (2005) identified a 21815C-T transition in exon 35 of the
MYH7 gene, resulting in an arg1712-to-trp substitution (R1712W) in the
myosin rod region.

.0033
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, GLU483LYS

In a family with CMH (192600) previously reported by Hengstenberg et al.
(1993, 1994), Richard et al. (1999) found that of 8 affected members, 4
had a G-to-A transition in exon 15 of the MYH7 gene, leading to a
glu483-to-lys (E483K) substitution; 2 had a G-to-T mutation at codon
1096 of the MYBPC3 gene (600958.0014) and 2 were doubly heterozygous for
the 2 mutations. The E483K mutation was thought to affect a protein
domain involved in actin fixation.

.0034
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ARG870HIS

In 3 affected members of a large consanguineous Indian kindred with
familial hypertrophic cardiomyopathy (192600), Tanjore et al. (2006)
identified a G-to-A transition in exon 22 of the MYH7 gene, resulting in
an arg870-to-his (R870H) substitution in the rod region. The 2 affected
homozygotes had asymmetric septal hypertrophy without obstructive
outflow, and one of them died of heart failure at age 37 years. The
third patient was heterozygous for the R870H mutation and had
hypertrophic cardiomyopathy with obstructive outflow. Analysis of family
members identified the heterozygous R870H mutation in 18 individuals, of
whom 10 were symptomatic. Tanjore et al. (2006) estimated the penetrance
of the R870H mutation to be 59% in general, whereas 75% of males and 44%
of females were clinically symptomatic, suggesting that female mutation
carriers have a better prognosis.

.0035
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYOPATHY, MYOSIN STORAGE, INCLUDED
MYH7, GLU1883LYS

In a 44-year-old male with hypertrophic cardiomyopathy and respiratory
failure (192600), born of second-cousin British parents, Tajsharghi et
al. (2007) identified homozygosity for a 24012G-A transition in exon 38
of the MYH7 gene, resulting in a glu1883-to-lys (E1883K) substitution at
a highly conserved residue in the distal end of the filament-forming rod
region. The proband had 2 similarly affected sibs who had died at ages
32 years and 57 years of cardiorespiratory failure; muscle biopsies from
all 3 sibs showed findings typical for myosin storage myopathy (608358).
The unaffected parents were presumed heterozygous carriers of the
mutation, and another sib was unaffected. There was no family history of
muscle weakness.

By functional analysis, Armel and Leinwand (2009), who referred to this
mutation as E1886K, showed that the mutant protein showed no major
differences in secondary structure or biophysical parameters from
wildtype. However, that mutant protein had a decreased ability to
assemble to the same extent as wildtype, and the paracrystals formed
were more readily degraded by proteolysis. The authors concluded that
altered packing of the filaments may destabilize them.

.0036
LAING DISTAL MYOPATHY
MYH7, THR441MET

In a Tanzanian boy with Laing distal myopathy (160500), Darin et al.
(2007) identified a heterozygous 1408C-T transition in the MYH7 gene,
resulting in a thr441-to-met (T441M) substitution in the globular head
of the myosin heavy chain. The patient had distal muscle weakness in the
lower limbs and mild atrial enlargement. Darin et al. (2007) noted that
most patients with Laing myopathy have mutations in the rod region of
the protein and suggested that the cardiac involvement in this child may
be due to the mutation affecting the globular region.

.0037
MYOPATHY, MYOSIN STORAGE
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1, INCLUDED;;
LEFT VENTRICULAR NONCOMPACTION 5, INCLUDED
MYH7, LEU1793PRO

In 1 of 2 sibs with myosin storage myopathy (608358) originally reported
by Cancilla et al. (1971), Dye et al. (2006) identified a heterozygous
5378T-C transition in exon 37 of the MYH7 gene, resulting in a
leu1793-to-pro (L1793P) substitution in the light meromyosin (LMM)
region of the myosin heavy chain tail. The sibs presumably had the
disease because of gonadal mosaicism in 1 of the unaffected parents,
although this could not be confirmed.

By functional analysis, Armel and Leinwand (2009) showed that the L1793P
mutation did not differ in protein secondary structure or in the
alpha-helical content compared to wildtype, but decreased thermodynamic
stability compared to wildtype. The L1793P mutation altered the ability
of LMM to assemble, presumably because of the increased instability of
the molecule. Although the paracrystals formed were similar to wildtype,
they were more susceptible to proteolytic cleavage. The authors
suggested that the L1793P mutation destabilized the dimer interface
under conditions similar to those found in vivo, which affects the
ability of LMM to assemble properly.

In a mother with myosin storage myopathy who later developed
hypertrophic cardiomyopathy (CMH1; 192600) and in her daughter who had
early symptomatic left ventricular noncompaction (LVNC5; see 613426),
Uro-Coste et al. (2009) identified heterozygosity for the L1793P
mutation in MYH7. The daughter did not complain of muscle weakness, but
clinical examination revealed bilateral wasting of the distal leg
anterior compartment, and she had some difficulty with heel-walking.

.0038
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, GLU497ASP

In affected members of a family with hypertrophic cardiomyopathy-1
(192600), Arad et al. (2005) identified heterozygosity for a
glu497-to-asp (E497D) substitution in the MYH7 gene. The proband had
apical hypertrophy with associated electrocardiographic changes of left
ventricular hypertrophy and deeply inverted precordial T waves, whereas
a family member with concurrent coronary artery disease who carried the
mutation had massive concentric hypertrophy with an interventricular
septal thickness of 29 mm.

.0039
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ASP906GLY

In 2 sibs with hypertrophic cardiomyopathy-1 (192600), Arad et al.
(2005) identified heterozygosity for an asp906-to-gly (D906G)
substitution in the MYH7 gene. The proband had apical hypertrophy,
whereas the sib, who had sudden death at 45 years of age, was found on
necropsy to have massive asymmetrical left ventricular hypertrophy with
an interventricular septal thickness greater than 30 mm and a posterior
left ventricular wall that was 18 mm thick. Arad et al. (2005) noted
that the D906G mutation had previously been identified by Ho et al.
(2002) in 22 affected members of a CMH family with a range of maximum
left ventricular wall thickness of 13 to 29 mm; none had apical
hypertrophy.

.0040
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
LEFT VENTRICULAR NONCOMPACTION 5, INCLUDED
MYH7, ARG243HIS

In a 40-year-old man with hypertrophic cardiomyopathy-1 (192600) who
presented with presyncope and was found to have apical hypertrophy, Arad
et al. (2005) identified heterozygosity for an arg243-to-his (R243H)
substitution in the MYH7 gene.

In affected members of a 3-generation family segregating autosomal
dominant left ventricular noncompaction but no other congenital heart
anomalies (LVNC5; see 613426), previously studied by Sasse-Klaassen et
al. (2003) as 'family INVM-107,' Klaassen et al. (2008) identified
heterozygosity for an 814G-A transition in the MYH7 gene, resulting in
the R243H substitution. Noncompaction in all 4 affected individuals
involved the apex and mid-left ventricular wall, and the right ventricle
was involved as well in 2 patients.

.0041
LEFT VENTRICULAR NONCOMPACTION 5
MYH7, IVS8DS, G-A, +1

In affected members of 2 families segregating autosomal dominant left
ventricular noncompaction but no other congenital heart anomalies
(LVNC5; see 613426), 1 of which was previously studied by Sasse-Klaassen
et al. (2003) as 'family INVM-101,' Klaassen et al. (2008) identified
heterozygosity for an 818+1G-A transition at the splice donor site in
intron 8 of the MYH7 gene. The mutation segregated with disease in both
families; haplotype analysis ruled out a founding mutation. Clinical
evaluation in both families was remarkable for the very pronounced
morphology of LVNC. The proband of family INVM-101 was diagnosed because
of inverted T-waves and later had a stroke and systemic peripheral
emboli, whereas his brother initially presented with decompensated heart
failure and pulmonary emboli; both patients remained stable over a
period of 8 years. Other affected members of family INVM-101 fulfilled
morphologic LVNC criteria but were clinically asymptomatic. The proband
of the other family was diagnosed because of atypical chest pain; he and
his affected 8-year-old son had no signs of heart failure.

.0042
LEFT VENTRICULAR NONCOMPACTION 5
MYH7, ALA1766THR

In a 20-year-old man with left ventricular noncompaction but no other
congenital heart anomalies (LVNC5; see 613426), Klaassen et al. (2008)
identified heterozygosity for a de novo 5382G-A transition in exon 37 of
the MYH7 gene, resulting in an ala1766-to-thr (A1766T) substitution. The
proband was initially diagnosed due to arrhythmias on routine
electrocardiogram, but his left ventricular systolic function
subsequently deteriorated over a period of 6 years; sustained
ventricular tachycardia resulted in implantation of an intracardiac
defibrillator. The mutation was not present in his unaffected parents.

.0043
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
MYH7, ARG453SER

In a 32-year-old African American woman with severe hypertrophic
cardiomyopathy and a family history of CMH and sudden cardiac death,
Frazier et al. (2008) identified heterozygosity for a 1357C-A
transversion in exon 14 of the MYH7 gene, resulting in an arg453-to-ser
(R453S) substitution, as well as a heterozygous missense mutation in the
TNNI3 gene (191044.0003). Her affected 8-year-old daughter carried only
the heterozygous MYH7 mutation.

.0044
LAING DISTAL MYOPATHY
MYH7, 3-BP DEL, AAG

In affected members of an Italian American family with Laing distal
myopathy (160500) reported by Hedera et al. (2003), Meredith et al.
(2004) identified a heterozygous 3-bp deletion of 1 of 3 consecutive AAG
triplets in exon 36 of the MYH7 gene, resulting in the deletion of
lys1729 (lys1729del).

Muelas et al. (2010) identified the lys1729del mutation in 29 clearly
affected individuals from 4 unrelated families in the Safor region of
Spain. There was great phenotypic variability. The age at onset ranged
from congenital to 50 years, with a mean of 14 years. All patients
presented with weakness of great toe/ankle dorsiflexors, and many had
associated neck flexor (78%), finger extensor (78%), mild facial (70%),
or proximal muscle (65%) weakness. Five patients had cardiac
abnormalities, including dilated cardiomyopathy, left ventricular
relaxation impairment, and conduction abnormalities. The spectrum of
disability ranged from asymptomatic to wheelchair-confined, but life
expectancy was not affected. EMG showed myopathic and neurogenic
features, and muscle biopsies showed fiber type disproportion,
core/minicore lesions, and mitochondrial abnormalities. These findings
expanded the phenotypic spectrum of Laing myopathy, but the wide
spectrum associated with a single mutation was noteworthy.

Muelas et al. (2012) identified a common 41.2-kb short haplotype
including the lys1729del mutation in both Spanish patients from the
Safor region and in the Italian American family reported by Hedera et
al. (2003), indicating a founder effect. However, microsatellite markers
both up- and downstream of the mutation did not match, indicating
multiple recombination events. The mutation was estimated to have been
introduced into the Safor population about 375 to 420 years ago (15
generations ago). The region is located in the southeast of Valencia on
the Mediterranean coast of Spain. Muelas et al. (2012) hypothesized that
the families from Safor were descendants of the Genoese who had
repopulated this Spanish region in the 17th century after the Muslims
were expelled; in fact, many of the surnames of the Safor families with
Laing myopathy had an Italian origin.

.0045
LEFT VENTRICULAR NONCOMPACTION 5
MYH7, TYR283ASP

In affected individuals from 2 white families of western European
descent segregating autosomal dominant left ventricular noncompaction
(LVNC5; 613426), Postma et al. (2011) identified heterozygosity for a
mutation at nucleotide 933 in exon 10 of the MYH7 gene, resulting in a
tyr283-to-asp (Y283D) substitution at a highly conserved residue. The
mutation segregated with disease in both families and was not found in
more than 980 ethnically matched control chromosomes. The 2 probands had
other cardiac malformations in addition to LVNC, including Ebstein
anomaly in both as well as type II atrial septal defect in 1 and
pulmonary artery hypoplasia in the other. One family had 5 more affected
individuals over 3 generations, 2 of whom had other cardiac
malformations, including Ebstein anomaly in 1 and perimembranous
ventricular septal defect in 1; 2 of the patients had only mild left
ventricular apical hypertrabeculation. In the other family, the
proband's asymptomatic mutation-positive father was found to have LVNC
by screening echocardiography; in addition, a paternal aunt was reported
to have heart failure, and the paternal grandfather had received an
implantable cardioverter-defibrillator.

.0046
LEFT VENTRICULAR NONCOMPACTION 5
MYH7, ASN1918LYS

In 4 affected individuals over 3 generations of a white family of
western European descent with left ventricular noncompaction (LVNC5;
613426), Postma et al. (2011) identified heterozygosity for a mutation
in exon 39 of the MYH7 gene, resulting in an asn1918-to-lys (N1918K)
substitution at a conserved residue. The mutation segregated with
disease in the family and was not found in more than 980 ethnically
matched control chromosomes. In addition to marked LVNC, the 39-year-old
proband exhibited Ebstein anomaly, which was discovered upon evaluation
of a cardiac murmur at 3 years of age. She remained asymptomatic despite
significant tricuspid regurgitation from age 30 years. She had a
mutation-positive son with bicuspid aortic valve and aortic coarctation
in whom echocardiography at age 5 years also showed LVNC. Her
asymptomatic mutation-positive mother and brother were both found to
have LVNC by echocardiography, and her brother also had LV dilation with
dysfunction. In an asymptomatic mutation-positive cousin, cardiomyopathy
could not be ruled out due to poor imaging quality.

*FIELD* SA
Kurabayashi et al. (1988); Saez et al. (1987)
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58. Pegoraro, E.; Gavassini, B. F.; Borsato, C.; Melacini, P.; Vianello,
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59. Perryman, M. B.; Yu, Q.; Marian, A. J.; Mares, A., Jr.; Czernuszewicz,
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77. Watkins, H.; Rosenzweig, A.; Hwang, D.-S.; Levi, T.; McKenna,
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79. Wolf, C. M.; Moskowitz, I. P. G.; Arno, S.; Branco, D. M.; Semsarian,
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Zeitlhofer, J.: An autosomal dominant early adult-onset distal muscular
dystrophy. Muscle Nerve 23: 1876-1879, 2000.

*FIELD* CN
Ada Hamosh - updated: 01/29/2014
Marla J. F. O'Neill - updated: 10/9/2013
Marla J. F. O'Neill - updated: 9/4/2013
Cassandra L. Kniffin - updated: 5/3/2012
Marla J. F. O'Neill - updated: 4/7/2011
Cassandra L. Kniffin - updated: 10/26/2010
Patricia A. Hartz - updated: 10/6/2010
Ada Hamosh - updated: 9/27/2010
Marla J. F. O'Neill - updated: 8/5/2010
Marla J. F. O'Neill - updated: 6/7/2010
Cassandra L. Kniffin - updated: 10/14/2009
Victor A. McKusick - updated: 2/19/2008
Cassandra L. Kniffin - updated: 1/7/2008
Marla J. F. O'Neill - updated: 12/4/2007
Marla J. F. O'Neill - updated: 11/21/2007
Ada Hamosh - updated: 6/4/2007
Cassandra L. Kniffin - updated: 5/31/2006
Marla J. F. O'Neill - updated: 2/23/2006
Carol A. Bocchini - updated: 8/12/2005
Marla J. F. O'Neill - updated: 7/13/2005
Cassandra L. Kniffin - updated: 6/27/2005
Cassandra L. Kniffin - updated: 6/9/2005
Victor A. McKusick - updated: 4/11/2005
Cassandra L. Kniffin - updated: 1/25/2005
Victor A. McKusick - updated: 9/9/2004
Victor A. McKusick - updated: 1/15/2004
Cassandra L. Kniffin - updated: 12/24/2003
Victor A. McKusick - updated: 5/9/2003
Victor A. McKusick - updated: 3/7/2003
Victor A. McKusick - updated: 11/5/2002
Michael J. Wright - updated: 8/2/2002
Stylianos E. Antonarakis - updated: 12/17/2001
Victor A. McKusick - updated: 1/4/2001
Victor A. McKusick - updated: 1/19/2000
Victor A. McKusick - updated: 11/15/1999
Victor A. McKusick - updated: 5/18/1998
Clair A. Francomano - updated: 5/7/1998

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

*FIELD* ED
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carol: 9/24/1993

MIM 181430
*RECORD*
*FIELD* NO
181430
*FIELD* TI
#181430 SCAPULOPERONEAL MYOPATHY, MYH7-RELATED; SPMM
;;SCAPULOPERONEAL MUSCULAR DYSTROPHY; SPMD;;
read moreSCAPULOPERONEAL SYNDROME, MYOPATHIC TYPE
*FIELD* TX
A number sign (#) is used with this entry because this form of
scapuloperoneal myopathy is caused by mutation in the MYH7 gene
(160760). Another form (300695) is caused by mutation in the FHL1 gene
(300163).

CLINICAL FEATURES

Scapuloperoneal syndrome was initially described by Jules Broussard
(1886) as 'une forme hereditaire d'atrophie musculaire progressive'
beginning in the lower legs and affecting the shoulder region earlier
and more severely than distal arm.

Thomas et al. (1975) described 6 cases of adult-onset scapuloperoneal
myopathy. Four were apparently sporadic. The other 2 cases occurred in
mother and daughter. Progression was relatively slow. Electromyography
and muscle biopsy showed myopathic changes in all. Facial involvement
occurred in some. The authors considered that the disorder resembled
that described by Ricker and Mertens (1968) and Serratrice et al.
(1969). The latter group observed 9 cases in which autosomal dominant
inheritance was suggested.

Tawil et al. (1995) described 4 individuals in 2 generations, 1 female
and 3 males, affected with a scapuloperoneal myopathy. There was
male-to-male transmission. Electromyography demonstrated small
polyphasic units, and muscle biopsy demonstrated necrotic and
regenerating fibers as well as an increase in endomesial connective
tissue, demonstrating this to be a myopathy. Although the index case
fulfilled the diagnostic criteria for facioscapulohumeral dystrophy
(158900), none of the other 3 affected individuals demonstrated facial
weakness. Furthermore, linkage to markers on 4q35 was excluded,
demonstrating this to be a distinct genetic entity.

MOLECULAR GENETICS

In 2 patients diagnosed with myosin storage myopathy (608358) and 2 of
17 patients diagnosed with scapuloperoneal myopathy of unknown etiology,
Pegoraro et al. (2007) detected a 5533C-T mutation in the MYH7 gene
(160760.0028). Eleven other mutation carriers were identified through
segregation analysis. The clinical spectrum in this cohort of patients
included asymptomatic hyperCKemia (elevated serum creatine kinase),
scapuloperoneal myopathy, and proximal and distal myopathy with muscle
hypertrophy. Muscle MRI identified a unique pattern in the posterior
compartment of the thigh, characterized by early involvement of the
biceps femoris and semimembranosus, with relative sparing of the
semitendinosus. Muscle biopsy revealed hyaline bodies characteristic of
myosin storage myopathy in only half of biopsied patients (2 of 4).
These patients without hyaline bodies had been diagnosed with
scapuloperoneal myopathy prior to the identification of hyaline bodies
in other family members, prompting MYH7 gene analysis. The authors
pointed out that patients without hyaline bodies presented later onset
and milder severity. Pegoraro et al. (2007) concluded that the
phenotypic and histopathologic variability may underlie MYH7 gene
mutation and the absence of hyaline bodies in muscle biopsies does not
rule out MYH7 gene mutations.

ANIMAL MODEL

DeRepentigny et al. (2001) described a spontaneous autosomal recessive
mutation in the mouse, which they named 'degenerative muscle' (dmu),
that is characterized by skeletal and cardiac muscle degeneration. Dmu
mice are weak and have great difficulty in moving due to muscle atrophy
and wasting in the hindquarters. Histopathologic observations and
ultrastructural analysis revealed muscle degeneration in both skeletal
and cardiac muscle, but no abnormalities in sciatic nerves. It is
noteworthy that SPM patients with associated cardiomyopathy have been
described. Using linkage analysis, the authors mapped the dmu locus to
the distal portion of mouse chromosome 15 in a region syntenic to human
chromosome 12q13. Intact transcripts for Scn8a (600702), the gene
encoding the sodium channel 8a subunit, were present in dmu mice but
their levels were dramatically reduced. Furthermore, genetic
complementation crosses between dmu and med (mutation in Scn8a) mice
revealed that they are allelic. The authors concluded that at least a
portion of the dmu phenotype may be caused by a downregulation of Scn8a,
and that SCN8A is a candidate gene for human SPM.

*FIELD* RF
1. DeRepentigny, Y.; Cote, P. D.; Pool, M.; Bernier, G.; Girard, G.;
Vidal, S. M.; Kothary, R.: Pathological and genetic analysis of the
degenerating muscle (dmu) mouse: a new allele of Scn8a. Hum. Molec.
Genet. 10: 1819-1827, 2001.

2. Pegoraro, E.; Gavassini, B. F.; Borsato, C.; Melacini, P.; Vianello,
A.; Stramere, R.; Cenacchi, G.; Angelini, C.: MYH7 gene mutation
in myosin storage myopathy and scapulo-peroneal myopathy. Neuromuscular
Disord. 17: 321-329, 2007.

3. Ricker, K.; Mertens, H.-G.: The differential diagnosis of the
myogenic (facio)-scapulo-peroneal syndrome. Europ. Neurol. 1: 275-307,
1968.

4. Serratrice, G.; Roux, H.; Aquaron, R.; Gambarelli, D.; Baret, J.
: Myopathies scapuloperonieres. A propos de 14 observations dont 8
avec atteinte faciale. Sem. Hop. Paris 45: 2678-2683, 1969.

5. Tawil, R.; Myers, G. J.; Weiffenbach, B.; Griggs, R. C.: Scapuloperoneal
syndromes: absence of linkage of the 4q35 FSHD locus. Arch. Neurol. 52:
1069-1072, 1995.

6. Thomas, P. K.; Schott, G. D.; Morgan-Hughes, J. A.: Adult onset
scapuloperoneal myopathy. J. Neurol. Neurosurg. Psychiat. 38: 1008-1015,
1975.

*FIELD* CS

Muscle:
Scapuloperoneal myopathy;
Facial myopathy

Misc:
Slow progression

Lab:
Myopathic electromyography and muscle biopsy

Inheritance:
Autosomal dominant

*FIELD* CN
Victor A. McKusick - updated: 2/19/2008
George E. Tiller - updated: 1/25/2002
Orest Hurko - updated: 2/22/1996

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

*FIELD* ED
alopez: 02/21/2008
alopez: 2/21/2008
alopez: 2/20/2008
terry: 2/19/2008
carol: 2/18/2008
terry: 2/18/2008
mgross: 3/17/2004
cwells: 2/14/2002
cwells: 2/5/2002
cwells: 1/25/2002
mark: 10/23/1996
terry: 10/7/1996
terry: 5/17/1996
terry: 5/14/1996
terry: 4/15/1996
mark: 2/22/1996
terry: 2/12/1996
mimadm: 3/25/1995
carol: 11/30/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988

MIM 192600
*RECORD*
*FIELD* NO
192600
*FIELD* TI
#192600 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1; CMH1
;;CMH;;
VENTRICULAR HYPERTROPHY, HEREDITARY;;
read moreASYMMETRIC SEPTAL HYPERTROPHY; ASH;;
HYPERTROPHIC SUBAORTIC STENOSIS, IDIOPATHIC
*FIELD* TX
A number sign (#) is used with this entry because hypertrophic
cardiomyopathy-1 (CMH1) is caused by heterozygous mutation in the MYH7
gene (160760) on chromosome 14q12.

DESCRIPTION

Hereditary ventricular hypertrophy (CMH, HCM, ASH, or IHSS) in early
stages produces a presystolic gallop due to an atrial heart sound, and
EKG changes of ventricular hypertrophy. Progressive ventricular outflow
obstruction may cause palpitation associated with arrhythmia, congestive
heart failure, and sudden death. Seidman (2000) reviewed studies of
hypertrophic cardiomyopathy in man and mouse.

- Genetic Heterogeneity of Hypertrophic Cardiomyopathy

Additional forms of hypertrophic cardiomyopathy include CMH2 (115195),
caused by mutation in the TNNT2 gene (191045) on chromosome 1q32; CMH3
(115196), caused by mutation in the TPM1 gene (191010) on chromosome
15q22.1; CMH4 (115197), caused by mutation in the MYBPC3 gene (600958)
on chromosome 11p11.2; CMH6 (600858), caused by mutation in the PRKAG2
gene (602743) on chromosome 7q36; CMH7 (613690), caused by mutation in
the TNNI3 gene (191044) on chromosome 19q13.4; CMH8 (608751), caused by
mutation in the MYL3 gene (160790) on chromosome 3p21.3-p21.2; CMH9 (see
188840),is caused by mutation in the TTN gene (188840) on chromosome
2q31; CMH10 (see 160781), caused by mutation in the MYL2 gene (160781)
on chromosome 12q23-q24; CMH11 (612098), caused by mutation in the ACTC1
gene (102540) on chromosome 15q14; CMH12 (612124), caused by mutation in
the CSRP3 gene (600824) on chromosome 11p15.1; CMH13 (613243), caused by
mutation in the TNNC1 gene (191040) on chromosome 3p21.3-p14.3; CMH14
(613251), caused by mutation in the MYH6 gene (160710) on chromosome
14q12; CMH15 (613255), caused by mutation in the VCL gene (193065) on
chromosome 10q22.1-q23; CMH16 (613838), caused by mutation in the MYOZ2
gene (605602) on chromosome 4q26-q27; CMH17 (613873), caused by mutation
in the JPH2 gene (605267) on chromosome 20q12; CMH18 (613874), caused by
mutation in the PLN gene (172405) on chromosome 6q22.1; CMH19 (613875),
caused by mutation in the CALR3 gene (611414) on chromosome 19p13.11;
CMH20 (613876), caused by mutation in the NEXN gene (613121) on
chromosome 1p31.1; CMH21, mapped to chromosome 7p12.1-q21; and CMH22
(see 615248), caused by mutation in the MYPN gene (608517) on chromosome
10q21.

The CMH5 designation was initially assigned to a CMH family showing
genetic heterogeneity. Subsequently, affected individuals were found to
carry mutations in the MYH7 (CMH1) and/or MYBPC3 (CMH4) genes.

Hypertrophic cardiomyopathy has also been associated with mutation in
the gene encoding cardiac myosin light-peptide kinase (MYLK2; see
606566.0001), which resides on chromosome 20q13.3; the gene encoding
caveolin-3 (CAV3; see 601253.0013), which maps to chromosome 3p25; and
with mutations in genes encoding mitochondrial tRNAs: see mitochondrial
tRNA-glycine (MTTG; 590035) and mitochondrial tRNA-isoleucine (MTTI;
590045).

CLINICAL FEATURES

In the first demonstration of asymmetric hypertrophy of the heart in
young adults, Teare (1958) reported the autopsy findings in 9 cases of
sudden death in young subjects distributed in 6 families. This condition
has been called muscular subaortic stenosis but more generalized
ventricular hypertrophy is often an earlier and more impressive feature,
and obstruction to outflow from the right ventricle can also occur.
Study of the families of probands with the full-blown condition shows
that an atrial heart sound ('presystolic gallop') and EKG changes of
ventricular hypertrophy are the earliest signs. Sudden death occurs in
some cases. Braunwald et al. (1964) reported in detail on 64 patients;
multiple cases were observed in 11 families, which contained in all at
least 41 definite or probable cases. As pointed out by Nasser et al.
(1967), outflow obstruction may be absent in some affected members of
families in which others do have outflow obstruction. Maron et al.
(1974) studied 4 infants that died with ASH in the first 5 months of
life, including 1 stillborn. ASH was demonstrated in one first-degree
relative of each infant. Maron et al. (1976) analyzed the clinical
picture of 46 children with ASH. On the basis of a study of an
outpatient population, Spirito et al. (1989) suggested that the
prognosis in hypertrophic cardiomyopathy may be less grave than has
usually been considered on the basis of hospital-study patients.

On morphologic grounds, 4 types of hypertrophic cardiomyopathy have been
described: type 1 with hypertrophy confined to the anterior segment of
the ventricular septum; type 2 with hypertrophy of both the anterior and
the posterior segments of the ventricular septum; type 3 with
involvement of both the ventricular septum and the free wall of the left
ventricle and type 4 with involvement of the posterior segment of the
septum, the anterolateral free wall, or the apical half of the septum
(Maron et al., 1982; Ciro et al., 1983). Apical hypertrophic
cardiomyopathy is, therefore, one form of type IV. It was first
described by Yamaguchi et al. (1979) in Japan (where it appears to be
more frequent than elsewhere) and later by Maron et al. (1982). The
cases of apical hypertrophic cardiomyopathy described by Maron et al.
(1982) belonged to families with different forms of hypertrophic
cardiomyopathy. Malouf et al. (1985) reported apical hypertrophic
cardiomyopathy in father and daughter of a Lebanese Christian family.
The parents were not related; an only sib was normal on examination and
echocardiogram as were 2 sisters of the father and their 6 children.

In a metaanalysis of sudden death from cardiac causes in children and
young adults, Liberthson (1996) found that hypertrophic cardiomyopathy
was the most frequent cause of sudden death in young persons in
association with strenuous physical exertion or sports.

OTHER FEATURES

Maron et al. (1996) collected information on 158 sudden deaths that had
occurred in trained athletes throughout the United States from 1985
through 1995. In 24 athletes (15%), noncardiovascular causes were found.
Among the 134 athletes who had cardiovascular causes of sudden death,
the median age was 17 years. The most common competitive sports involved
were basketball (47 cases) and football (45 cases), together accounting
for 68% of sudden deaths. The most common structural cardiovascular
diseases identified at autopsy as the primary cause of death were
hypertrophic cardiomyopathy (48 athletes, 36%), which was
disproportionately prevalent in black athletes compared with white
athletes (48% vs 26% of deaths; P = 0.01), and malformations involving
anomalous coronary artery origin (17 athletes, 13%). Of 115 athletes who
had a standard preparticipation medical evaluation, only 4 (3%) were
suspected of having cardiovascular disease, and the cardiovascular
anomaly responsible for sudden death was correctly identified in only 1
athlete (0.9%).

In a series of 387 young athletes who died suddenly, Maron (2003) found
that hypertrophic cardiomyopathy was the cause in 102 (26.4%). Coronary
artery anomalies had accounted for 53 (13.7%) and ruptured aortic
aneurysm of Marfan syndrome for 12 (3.1%). Arrhythmogenic right
ventricular cardiomyopathy was found in 11 (2.8%) and long QT syndrome
in 3 (0.8%).

Cannon (2003) tabulated the features of hypertrophic cardiomyopathy that
increase the risk of cardiovascular events. These included family
history of sudden death, recurrent syncope, ventricular tachycardia on
monitoring, extreme left ventricular hypertrophy (more than 3 cm), left
ventricular outflow pressure gradient of more than 30 mm Hg, and fall in
blood pressure during exercise.

INHERITANCE

In the family reported by Horlick et al. (1966), 10 persons in 4
generations were thought to have been affected. Pare et al. (1961)
described this disorder in 30 out of 87 members of a French Canadian
kindred. The genealogic survey was carried back to the original emigrant
from France in the 1600s. The pattern of occurrence over 5 generations
and 160 years since the death of the man believed to be the first
instance of the heart disease indicated autosomal dominant inheritance.
Elevated paternal age of sporadic (possible fresh mutation) cases was
observed by Jorgensen (1968). The family study of Clark et al. (1973),
using echocardiography, indicated that 28 of 30 probands (93%) had an
affected parent. This agrees well with estimates of the extent to which
this disorder, on the average, reduces reproductive fitness.

Greaves et al. (1987) performed echocardiographic studies of 193
first-degree relatives of 50 patients with hypertrophic cardiomyopathy.
More males than females were affected. In 28 of 50 families, familial
occurrence was observed. In 15 families the pattern of inheritance was
consistent with autosomal dominant inheritance; in the other 13 the
affected members were in a single generation and the pattern of
inheritance could not be determined.

The family reported by Yamaguchi et al. (1979) suggested X-linked
recessive inheritance. Burn (1985) felt that the existence of a
recessive form of hypertrophic cardiomyopathy (Emanuel et al., 1971;
Branzi et al., 1985) could neither be established nor disproved at the
time of his writing. Branzi et al. (1985) claimed the existence of an
autosomal recessive form because of a family they found with 2 affected
sisters and both parents normal by careful study. Formal segregation
analysis supported the existence of 2 classes: one with a segregation
ratio close to 50% and one with a value close to 25%.

MAPPING

Darsee et al. (1979) found a lod score of 7.7 for linkage between ASH
and HLA. They concluded that, in addition to the hereditary form linked
to HLA, a sporadic unlinked form is associated with severe systemic
hypertension. White patients with ASH were B12; black patients were B5.
This presumably strong evidence placing a gene for hypertrophic
subaortic stenosis on 6p by linkage to HLA was invalidated when the
infamous John R. Darsee confessed fabrication of the data. Nutter also
published a retraction. Motulsky (1979) wrote a laudatory editorial to
accompany the original article.

In his retraction letter, Darsee stated: 'The lod scores were
calculated, in part, by one of the journal referees who felt they should
be included, and partly by my own calculations. The biometrist I
consulted at Emory regarding these calculations was not familiar with
lod scores and unable to provide assistance.' Before Darsee confessed,
Darsee and Heymsfield (1981) wrote: 'It is the pinhole through which we
are forced to view this disease or these diseases that has helped confer
a degree of homogeneity. The pinhole is the limited collection of tools
we have to study hypertrophic cardiomyopathy--the angiogram, the
echocardiogram, and the autopsy table. It is a common practice of even
the most perspicacious and critical investigators to conclude that
diseases that look the same on canvas were painted with the same brush.'
Although these words are true in general terms and are a fine statement
of the principle of genetic heterogeneity, the falsified data do not
support them, of course.

Jarcho et al. (1989) did studies with DNA markers in the Canadian family
originally reported by Pare et al. (1961). At the time of the study,
hypertrophic cardiomyopathy had occurred in 20 surviving and 24 deceased
family members. With a polymorphic DNA probe with the trivial name
CRI-L436, which identified a DNA segment designated D14S26, they found
no recombination (lod score = 9.37 at theta = 0). This probe had been
assigned to chromosome 14 on the basis of somatic cell hybrid analysis
(Donis-Keller et al., 1987). The gene encoding the alpha chain of the
T-cell receptor (see 186880) was located approximately 20 cM from D14S26
(Mitchell et al., 1989). Solomon et al. (1990) mapped the probe CRI-L436
to 14q11-q12 by in situ hybridization. Because the cardiac myosin heavy
chain genes (MYH6, 160710; MYH7) map to the same chromosomal band, they
determined the genetic distance between the gene for the beta heavy
chain of cardiac myosin, D14S26, and the CMH1 locus. They presented data
indicating that these 3 loci are linked within 5 cM of each other. The
data were consistent with the possibility that the CMH1 mutation is in
either the alpha or the beta gene.

Hejtmancik et al. (1991) found that the gene for familial hypertrophic
cardiomyopathy was located at 14q1 in 8 unrelated families of varied
ethnic origins. Of 5 families with hypertrophic cardiomyopathy, Epstein
et al. (1992) found linkage to chromosome 14 markers in one and
suggestive linkage in a second. However, linkage to chromosome 14
markers was excluded in the other 3 kindreds. Ko et al. (1992) excluded
linkage to D14S26 in a Chinese family, likewise indicating genetic
heterogeneity.

MOLECULAR GENETICS

In affected members of the large French Canadian kindred originally
reported by Pare et al. (1961) and shown to have linkage to markers on
the proximal portion of 14q, Geisterfer-Lowrance et al. (1990)
identified heterozygosity for a missense mutation in the MYH7 gene
(R403Q; 160760.0001). Ross and Knowlton (1992) reviewed this discovery
beginning with the patients first seen by Pare in the 1950s.

Using a ribonuclease protection assay, Watkins et al. (1992) screened
the beta cardiac myosin heavy-chain genes of probands from 25 unrelated
families with familial hypertrophic cardiomyopathy and identified 7
different missense mutations in 12 of the 25 families (see, e.g.,
160760.0003-160760.0007).

Atiga et al. (2000) studied 36 patients with CMH1 using beat-to-beat QT
variability analysis. This technique quantifies the beat-to-beat
fluctuations in ventricular repolarization reflected in the QT interval.
Seven mutations were found in this group: 9 patients had the 'severe'
arg403-to-gln mutation (160760.0001) and 8 had the more benign
leu908-to-val mutation (160760.0010). Atiga et al. (2000) found higher
QT variability indices in patients with CMH1 compared with controls, and
the greatest abnormality was observed in patients with the arg403-to-gln
mutation. CMH1 patients therefore exhibited labile ventricular
repolarization and were considered to be at higher risk of sudden death
from ventricular arrhythmias, particularly those with a 'severe'
mutation.

Blair et al. (2001) studied a family with familial hypertrophic
cardiomyopathy in which 2 individuals suffered early sudden death and a
third individual died suddenly at the age of 60 years with autopsy
evidence of familial hypertrophic cardiomyopathy. A val606-to-met
(V606M) mutation was observed in the MYH7 gene (160760.0005). This
mutation had previously been proposed to give rise to a benign phenotype
(see Abchee and Marian, (1997)). A second ala728-to-val (A728V) mutation
(160760.0025) was found in cis with the V606M mutation. Blair et al.
(2001) suggested that this second mutation in cis explained the more
severe phenotype seen in this family.

Arad et al. (2005) identified 2 different MYH7 missense mutations in 2
probands with apical hypertrophy from families in which the mutations
also caused other CMH morphologies (see 160760.0038 and 160760.0039,
respectively). Another MYH7 mutation (R243H; 160760.0040) was identified
in a sporadic patient with apical hypertrophy; the same R243H mutation
was later found by Klaassen et al. (2008) in a family segregating
isolated left ventricular noncompaction (LVNC5; see 613426).

In a Japanese proband with CMH (CMH17; 613873), Matsushita et al. (2007)
identified heterozygosity for a missense mutation in the JPH2 gene
(605267.0004); subsequent analysis of 15 known CMH-associated genes
revealed that the proband also carried 2 mutations in MYH7 (see, e.g.,
160760.0016). The authors suggested that mutations in both JPH2 and MYH7
could be associated with the pathogenesis of CMH in this proband.

In a 32-year-old African American woman with severe hypertrophic
cardiomyopathy (see CMH7, 613690) and a family history of CMH and sudden
cardiac death, Frazier et al. (2008) identified a heterozygous mutation
in the TNNI3 gene (P82S; 191044.0003) and a heterozygous mutation in the
MYH7 gene (R453S; 160760.0043). Frazier et al. (2008) suggested that the
P82S variant, which they found in 3% of healthy African Americans, is a
disease-modifying mutation in severely affected individuals, and that
carriers of the variant might be at increased risk of late-onset cardiac
hypertrophy.

- Skeletal Muscle Involvement

Fananapazir et al. (1993) demonstrated by biopsy of the soleus muscle
the presence of central core disease of skeletal muscle (117000) in
association with hypertrophic cardiomyopathy due to any of 4 different
mutations in the MYH7 gene. Soleus muscle samples from patients in 4
kindreds in which hypertrophic cardiomyopathy was not linked to the MYH7
locus showed no myopathy or central core disease. In 1 family with the
leu908-to-val mutation of the MYH7 gene (160760.0010), central core
disease was demonstrated on soleus muscle biopsy, although cardiac
hypertrophy was absent on echocardiogram in 2 adults and 3 children.
Almost all patients had no significant muscle weakness, despite the
histologic changes. The histologic hallmark of CCD was the absence of
mitochondria in the center of many type I fibers as revealed by light
microscopic examination of NADH-stained fresh-frozen skeletal muscle
sections. McKenna (1993), who stated that he had never seen clinical
evidence of skeletal myopathy in CMH1, doubted the significance of the
findings.

In a 44-year-old male with hypertrophic cardiomyopathy and respiratory
failure, born of second-cousin British parents, Tajsharghi et al. (2007)
identified homozygosity for a missense mutation in the MYH7 gene
(E1883K; 160760.0035). The proband had 2 similarly affected sibs, a
sister who had died at 57 years of age in cardiorespiratory failure and
a brother who died at age 32 years from cardiac failure. Muscle biopsies
from all 3 sibs showed findings typical for myosin storage myopathy
(608358) with hyaline bodies seen in type 1 fibers. The sister had
progressive muscle weakness and was wheelchair dependent by age 45,
whereas the 2 brothers had milder proximal muscle weakness. The
unaffected parents were presumed heterozygous carriers of the mutation,
and another sib was unaffected. There was no family history of muscle
weakness.

In a mother with myosin storage myopathy, who later developed CMH, and
in her daughter, who had early-symptomatic left ventricular
noncompaction (LVNC5; see 613426), Uro-Coste et al. (2009) identified
heterozygosity for the L1793P mutation in MYH7 (160760.0037). The mother
presented at age 30 years with proximal muscle weakness, which
progressed to the point of her being wheelchair-bound by 48 years of
age. At age 51, CMH was diagnosed; echocardiography revealed no atrial
or ventricular dilatation, and no abnormal appearance of the ventricular
walls. Skeletal muscle biopsy at 53 years of age showed subsarcolemmal
accumulation of hyaline material in type 1 fibers. Her 24-year-old
daughter presented with heart failure at 3 months of age and was
diagnosed with early-onset cardiomyopathy. Angiography revealed a
less-contractile, irregular 'spongiotic' wall in the inferior left
ventricle, and echocardiography confirmed the diagnosis of LVNC. The
daughter did not complain of muscle weakness, but clinical examination
revealed bilateral wasting of the distal leg anterior compartment and
she had some difficulty with heel-walking.

HETEROGENEITY

In affected members of an Italian family, Ferraro et al. (1990) found
that 7 affected members and none of 3 unaffected members showed a
fragile site on 16q (FRA16B).

Hengstenberg et al. (1993, 1994) studied a family with familial
hypertrophic cardiomyopathy in which preliminary haplotype analyses
excluded linkage to chromosomes 14q1, 1q3, 11p13-q13, and 15q2,
suggesting the existence of another locus, designated CMH5, for this
disorder. Further studies in this family by Richard et al. (1999)
demonstrated that of 8 affected family members, 4 had a mutation in the
MYH7 gene (160760.0033), 2 had a mutation in the MYBPC3 gene
(600958.0014), and 2 were doubly heterozygous for the 2 mutations. The
doubly heterozygous patients exhibited marked left ventricular
hypertrophy, which was significantly greater than that in the other
affected individuals.

Seidman and Seidman (2001) reviewed the genetic and clinical
heterogeneity of hypertrophic cardiomyopathy.

Arad et al. (2002) reviewed the clinical spectrum of hypertrophic
cardiomyopathy in the context of genetic heterogeneity, as well as
animal models of hypertrophic cardiomyopathy.

In 108 consecutive patients with hypertrophic cardiomyopathy diagnosed
by echocardiography, angiography, or findings after myectomy, Erdmann et
al. (2003) screened for mutations in 6 sarcomeric genes. They identified
34 different mutations: 18 in the MYBPC3 gene in 20 patients, with 2
mutations identified twice; 13 missense mutations in the MYH7 gene in 14
patients, with 1 mutation identified twice; and 1 amino acid change each
in the TPM1, TNNT2, and TNNI3 genes. No disease-causing mutation was
identified in TNNC1 (191040). In only 8 of the 37 mutation carriers was
the mutation sporadic. Thus, systematic mutation screening in a large
sample of patients with hypertrophic cardiomyopathy led to a genetic
diagnosis in approximately 30% of unrelated index patients and in
approximately 57% of patients with a positive family history.

In 197 unrelated probands with familial or sporadic hypertrophic
cardiomyopathy, Richard et al. (2003) screened for mutations in 9 genes
and identified mutations in 124 (63%) of 197 probands. The MYBPC3 and
MYH7 genes accounted for 82% of families with identified mutations (42%
and 40%, respectively). A mutation was identified in 15 (60%) of 25
sporadic patients.

In 80 unrelated Australian probands with CMH, Chiu et al. (2007)
screened 7 CMH genes, including MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, MYL2,
and MYL3. Twenty-four different mutations were identified in 23 (29%) of
80 families, with 19 probands having a single mutation (11 in MYH7, 4 in
MYPBC3, 3 in TNNI3, and 1 in TNNT2). Multiple gene mutations were
identified in 4 probands: 1 was doubly heterozygous, with 1 mutation in
MYH7 and 1 in MYBPC3, whereas the other 3 were compound heterozygous for
mutations in MYBPC3 (see, e.g., 600958.0021 and 600958.0022). Six (43%)
of 14 affected individuals from multiple mutation families experienced
sudden cardiac death, compared with 10 (18%) of 55 affected members from
single mutation families (p = 0.05). Septal wall thickness was increased
in patients with multiple mutations (mean thickness, 30.7 mm vs 24.4 mm;
p less than 0.05). Ingles et al. (2005) concluded that multiple gene
mutations occurring in CMH families may result in a more severe clinical
phenotype because of a 'double-dose' effect, and emphasized the
importance of screening the entire panel of CMH genes even after a
single mutation has been identified.

Van Driest et al. (2004) analyzed the MYBPC3 gene in a cohort of 389 CMH
probands who had previously been genotyped for mutation in genes
encoding the sarcomeric proteins comprising the thick filament (MYH7 and
the regulatory and essential light chains, MYL2 and MYL3) and the thin
filament (TNNT2, TNNI3, TPM1, and ACTC). Overall, 63 (16.2%) of the
patients had a single mutation in the MYBPC3 gene, 54 (13.8%) in MYH7, 7
(1.8%) in MYL2, 6 (1.5%) in TNNT2, 4 (1.0%) in TNNI3, 2 (0.5%) in TPM1,
and 1 (0.3%) in ACTC. The 10 patients with multiple mutations (2.6%) had
the most severe disease presentation: they were significantly younger at
diagnosis than any other subgroup, had the most hypertrophy, and had the
highest incidence of myectomy and placement of implantable
cardioverter-defibrillators.

DIAGNOSIS

To screen for mutations that cause familial hypertrophic cardiomyopathy,
Rosenzweig et al. (1991) capitalized on the fact that 'ectopic' or
'illegitimate' transcription of beta cardiac myosin heavy chain gene can
be detected in blood lymphocytes. Preclinical or prenatal screening will
make it possible to study the disorder longitudinally and to develop
preventive interventions. The findings again illustrate the important
application of PCR. Clarke and Harper (1992) suggested that 'the
parallels between this cardiomyopathy and Huntington's disease are
sufficiently striking that we would be very cautious about testing for
it in childhood. The emotional consequences of being brought up under a
cloud of doom may be damaging, and the lack of any uncertainty in
identifying gene carriers by mutation analysis might paradoxically make
this worse.' Watkins et al. (1992) countered this view, saying that
children with the condition face a 4 to 6% risk of sudden death each
year. Genetic diagnosis will allow evaluation of prophylactic use of
antiarrhythmic agents or implantable defibrillator devices. It will also
provide parents and physicians an appropriate basis on which to make
decisions regarding the participation of children in competitive sports.
They suggested that in their experience '...any perception of a cloud of
doom comes as much from a lack of knowledge of and research into this
inherited cardiomyopathy as from anything else.'

To provide a method of genetic diagnosis of cardiomyopathy, Mogensen et
al. (2001) developed a method of linkage analysis using multiplex PCR of
markers covering 9 loci associated with familial hypertrophic
cardiomyopathy. They evaluated this method in 3 families. In all 3
families the locus showing the highest lod score was subsequently found
by mutation analysis to be the locus at which the disease-causing gene
was found. Mogensen et al. (2001) emphasized the importance of stringent
phenotypic definitions in the diagnostic process.

Ingles et al. (2013) studied the clinical predictors of genetic testing
outcomes for hypertrophic cardiomyopathy. The authors studied 265
unrelated individuals with hypertrophic cardiomyopathy over a 10-year
period in specialized cardiac genetic clinics across Australia. Of the
265 individuals studied, 138 (52%) had at least 1 mutation identified.
The mutation detection rate was significantly higher in probands with
hypertrophic cardiomyopathy with an established family history of
disease (72% vs 29%, p less than 0.0001), and a positive family history
of sudden cardiac death further increased the detection rate (89% vs
59%, p less than 0.0001). Multivariate analysis identified female
gender, increased left ventricular wall thickness, family history of
hypertrophic cardiomyopathy, and family history of sudden cardiac death
as being associated with greatest chance of identifying a gene mutation.
Multiple mutation carriers (n = 16, 6%) were more likely to have
suffered an out-of-hospital cardiac arrest or sudden cardiac death (31%
vs 7%, p = 0.012). Ingles et al. (2013) concluded that family history is
a key clinical predictor of a positive genetic diagnosis and has direct
clinical relevance, particularly in the pretest genetic counseling
setting.

PATHOGENESIS

Wagner et al. (1989) investigated a possible role of adrenergic
innervation or of cellular calcium regulation in pathogenesis, as
suggested by the presence of hyperdynamic left ventricular function and
by the clinical and symptomatic improvement seen in patients treated
with beta-receptor antagonists or calcium antagonists. They found that
calcium-antagonist binding sites, measured as the amount of
dihydropyridine bound to atrial tissue, were increased by 33% in
patients with hypertrophic cardiomyopathy. The densities of
saxitoxin-binding sites on voltage-sensitive sodium channels and
beta-adrenoceptors did not differ from controls. Wagner et al. (1989)
interpreted the findings as suggesting that abnormal calcium fluxes
through voltage-sensitive calcium channels may play a pathophysiologic
role in the disease.

There is evidence that 'myocardial bridging' with compression of an
epicardial coronary artery, such as the left anterior descending
coronary artery, can cause myocardial ischemia and sudden death. Yetman
et al. (1998) performed angiographic studies of 36 children with
hypertrophic cardiomyopathy to determine whether myocardial bridging was
present and, if so, to assess the characteristics of systolic narrowing
of the left anterior descending coronary artery caused by myocardial
bridging and the duration of residual diastolic compression. Myocardial
bridging was present in 10 (28%) of the patients. As compared with
patients without bridging, patients with bridging had a greater
incidence of chest pain, cardiac arrest with subsequent resuscitation,
and ventricular tachycardia. On average, the patients with bridging had
a reduction in systolic blood pressure with exercise, as compared with
an elevation in those without bridging. Patients with bridging also had
greater ST-segment depression with exercise and a shorter duration of
exercise. Kaplan-Meier estimates of the proportions of patients who had
not died or had cardiac arrest with subsequent resuscitation 5 years
after the diagnosis of hypertrophic cardiomyopathy were 67% among
patients with bridging and 94% among those without bridging. No
statement concerning the family history or other information relevant to
a etiology in these patients was provided.

Using pharmacologic models of cardiac hypertrophy in mice, Friddle et
al. (2000) performed expression profiling with fragments of more than
4,000 genes to characterize and contrast expression changes during
induction and regression of hypertrophy. Administration of angiotensin
II and isoproterenol by osmotic minipump produced increases in cardiac
weight (15% and 45%, respectively) that returned to preinduction size
after drug withdrawal. From multiple expression analyses of left
ventricular RNA isolated at daily time points during cardiac hypertrophy
and regression, Friddle et al. (2000) identified sets of genes whose
expression was altered at specific stages of this process. While
confirming the participation of 25 genes or pathways previously shown to
be altered by hypertrophy, a larger set of 30 genes was identified whose
expression had not previously been associated with cardiac hypertrophy
or regression. Of the 55 genes that showed reproducible changes during
the time course of induction and regression, 32 were altered only during
induction, and 8 were altered only during regression. Thus, cardiac
remodeling during regression uses a set of genes that are distinct from
those used during induction of hypertrophy.

Tsybouleva et al. (2004) observed that myocardial aldosterone and
aldosterone synthase (CYP11B2; 124080) mRNA levels were elevated by 4-
to 6-fold in patients with hypertrophic cardiomyopathy compared to
controls. In studies in rat cardiomyocytes, they found that aldosterone
increased expression of several hypertrophic markers via protein kinase
D (PRKCM; 605435) and increased collagens and TGFB1 (190180) via
PI3K-delta (PIK3CD; 602839). Inhibition of PRKCM and PIK3CD abrogated
the hypertrophic and profibrotic effects, respectively, as did the
mineralocorticoid receptor antagonist spironolactone. In a mouse model
of hypertrophic cardiomyopathy, spironolactone reversed interstitial
fibrosis, decreased myocyte disarray, and improved diastolic function.
Tsybouleva et al. (2004) concluded that aldosterone is a major link
between sarcomeric mutations and cardiac phenotype in CMH.

CLINICAL MANAGEMENT

Wilson et al. (1983) observed marked improvement in the manifestations
of familial hypertrophic cardiomyopathy when affected persons with
hyperthyroidism were treated for the latter condition. This prompted
them to suggest that antithyroid therapy 'should be considered in this
form of cardiomyopathy.'

In discussing the management of hypertrophic cardiomyopathy, Spirito et
al. (1997) reviewed heterogeneity of clinical and genetic features and
stated that 'the diverse clinical and genetic features of hypertrophic
cardiomyopathy make it impossible to define precise guidelines for
management.' The treatment of symptoms to improve quality of life and
the identification of patients who are at high risk for sudden death and
require aggressive therapy are 2 distinct issues that must be addressed
by largely independent strategies. The stratification of risk and the
prevention of sudden death were discussed.

Ventricular tachycardia or fibrillation is thought to be the principal
mechanism of sudden death in patients with hypertrophic cardiomyopathy.
Maron et al. (2000) conducted a retrospective study, the results of
which indicated that in high-risk patients with hypertrophic
cardiomyopathy, implantable defibrillators are highly effective in
terminating such arrhythmias, indicating that these devices have a role
in the prevention of sudden death. In comments on the study of Maron et
al. (2000), Watkins (2000) stated that for most patients with
hypertrophic cardiomyopathy, the risk is not high enough to offset the
adverse effects of an implantable defibrillator. He suggested the
creation of an international registry to document discharge rates after
implantation for each of the indicators of risk. Ideally, the data
should include molecular genetic information, since the underlying
mutation will itself be predictive. He cited the cohort studies of
McKenna et al. (1985) in which patients with hypertrophic cardiomyopathy
who were treated with low-dose amiodarone compared with untreated
historical controls suggested that long-term treatment was partially
protective; and the work of Ostman-Smith et al. (1999), indicating that
high doses of beta-blockers may also confer protection. Since there has
been an excess rate of sudden death during or shortly after exercise,
most physicians recommend that patients with hypertrophic cardiomyopathy
avoid competitive sports or intensive exertion.

In a study of 480 consecutive patients with hypertrophic cardiomyopathy,
Spirito et al. (2000) found that the magnitude of hypertrophy is
directly related to the risk of sudden death and then is a strong and
independent predictor of prognosis. Young patients with extreme
hypertrophy, even those with few or no symptoms, appeared to be at
substantial long-term risk and thus were considered for interventions to
prevent sudden death. Most patients with mild hypertrophy were at low
risk and were reassured regarding their prognosis.

Ho et al. (2002) studied confirmed MYH7 mutation heterozygotes using
echocardiography, including Doppler tissue imaging. Left ventricular
ejection fraction was significantly higher in mutation carriers than in
normal controls. Mean early diastolic myocardial velocities were
significantly lower in mutation carriers, irrespective of whether
hypertrophy was already present. Overall the authors concluded that
abnormalities of diastolic function were detectable before the onset of
myocardial hypertrophy in mutation carriers, providing a mechanism for
predicting affected individuals.

POPULATION GENETICS

In a discussion of hypertrophic cardiomyopathy, Maron et al. (1987)
stated that approximately 45% of cases are sporadic. New mutations
cannot be the explanation for all of the sporadic cases; hence, there
may be other etiologically distinct disorders represented in the group
of hypertrophic cardiomyopathies. Systematic echocardiographic surveys
of families of patients with hypertrophic cardiomyopathy have identified
relatives older than 50 years of age with mild and localized left
ventricular hypertrophy. Thus, the true proportion of sporadic cases may
not be as high as 45%.

*FIELD* SA
Bingle et al. (1975); Bulkley et al. (1977); Criley et al. (1965);
Gardin et al. (1982); Goodwin and Krikler (1976); Hardarson et al.
(1973); Haugland et al. (1986); Henry et al. (1973); Jeschke et al.
(1998); Manchester (1963); Masuya et al. (1982); Powell et al. (1973);
Smith et al. (1976); Solomon et al. (1990); Taylor et al. (2003);
Wei et al. (1980); Wood et al. (1962)
*FIELD* RF
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83. Uro-Coste, E.; Arne-Bes, M.-C.; Pellissier, J.-F.; Richard, P.;
Levade, T.; Heitz, F.; Figarella-Branger, D.; Delisle, M.-B.: Striking
phenotypic variability in two familial cases of myosin storage myopathy
with a MYH7 leu1793pro mutation. Neuromusc. Disord. 19: 163-166,
2009.

84. Van Driest, S. L.; Vasile, V. C.; Ommen, S. R.; Will, M. L.; Tajik,
A. J.; Gersh, B. J.; Ackerman, M. J.: Myosin binding protein C mutations
and compound heterozygosity in hypertrophic cardiomyopathy. J. Am.
Coll. Cardiol. 44: 1903-1910, 2004.

85. Wagner, J. A.; Sax, F. L.; Weisman, H. F.; Porterfield, J.; McIntosh,
C.; Weisfeldt, M. L.; Snyder, S. H.; Epstein, S. E.: Calcium-antagonist
receptors in the atrial tissue of patients with hypertrophic cardiomyopathy. New
Eng. J. Med. 320: 755-761, 1989.

86. Watkins, H.: Sudden death in hypertrophic cardiomyopathy. (Editorial) New
Eng. J. Med. 342: 422-424, 2000.

87. Watkins, H.; Rosenzweig, A.; Hwang, D.-S.; Levi, T.; McKenna,
W.; Seidman, C. E.; Seidman, J. G.: Characteristics and prognostic
implications of myosin missense mutations in familial hypertrophic
cardiomyopathy. New Eng. J. Med. 326: 1108-1114, 1992.

88. Watkins, H.; Seidman, J. G.; Seidman, C. E.: Genetic testing
for hypertrophic cardiomyopathy. (Letter) New Eng. J. Med. 327:
1176, 1992.

89. Wei, J. Y.; Weiss, J. L.; Bulkley, B. H.: The heterogeneity of
hypertrophic cardiomyopathy: an autopsy and one dimensional echocardiographic
study. Am. J. Cardiol. 45: 24-32, 1980.

90. Wilson, R.; Gibson, T. C.; Terrien, C. M., Jr.; Levy, A. M.:
Hyperthyroidism and familial hypertrophic cardiomyopathy. Arch. Intern.
Med. 143: 378-380, 1983.

91. Wood, R. S.; Taylor, W. J.; Wheat, M. W.; Schiebler, G. L.: Muscular
subaortic stenosis in childhood: report of occurrence in three siblings. Pediatrics 30:
749-758, 1962.

92. Yamaguchi, H.; Ishimura, T.; Nishiyama, S.; Nagasaki, F.; Nakanishi,
S.; Takatsu, F.; Nishijo, T.; Umeda, T.; Machii, K.: Hypertrophic
nonobstructive cardiomyopathy with giant negative T waves (apical
hypertrophy): ventriculographic and echocardiographic features in
30 patients. Am. J. Cardiol. 44: 401-412, 1979.

93. Yetman, A. T.; McCrindle, B. W.; MacDonald, C.; Freedom, R. M.;
Gow, R.: Myocardial bridging in children with hypertrophic cardiomyopathy--a
risk factor for sudden death. New Eng. J. Med. 339: 1201-1209, 1998.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Asymmetric septal hypertrophy;
Apical hypertrophy (in some patients);
Subaortic stenosis;
Hypertrophic cardiomyopathy;
Presystolic gallop;
Palpitation;
Arrhythmia;
Congestive heart failure;
Sudden death

MUSCLE, SOFT TISSUE:
Myosin storage myopathy (in some patients)

MOLECULAR BASIS:
Caused by mutation in the myosin, heavy polypeptide-7, cardiac muscle,
beta gene (MYH7, 160760.0001)

*FIELD* CN
Marla J. F. O'Neill - revised: 06/26/2012

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

*FIELD* ED
joanna: 06/26/2012

*FIELD* CN
Ada Hamosh - updated: 01/08/2014
Marla J. F. O'Neill - updated: 9/4/2013
Marla J. F. O'Neill - updated: 4/6/2011
Marla J. F. O'Neill - updated: 3/25/2011
Marla J. F. O'Neill - updated: 6/7/2010
Marla J. F. O'Neill - updated: 5/11/2010
Marla J. F. O'Neill - updated: 6/24/2008
Marla J. F. O'Neill - updated: 6/4/2008
Marla J. F. O'Neill - updated: 12/4/2007
Marla J. F. O'Neill - updated: 1/18/2006
Carol A. Bocchini - updated: 8/12/2005
Marla J. F. O'Neill - updated: 7/8/2004
George E. Tiller - updated: 12/10/2003
Victor A. McKusick - updated: 11/18/2003
Victor A. McKusick - updated: 11/4/2003
Victor A. McKusick - updated: 5/9/2003
Victor A. McKusick - updated: 3/19/2003
Victor A. McKusick - updated: 11/7/2002
Victor A. McKusick - updated: 8/22/2002
Paul Brennan - updated: 8/7/2002
Michael J. Wright - updated: 7/26/2002
Michael J. Wright - updated: 6/28/2002
Victor A. McKusick - updated: 8/7/2000
Victor A. McKusick - updated: 7/14/2000
Paul Brennan - updated: 4/10/2000
Victor A. McKusick - updated: 2/15/2000
Victor A. McKusick - updated: 12/2/1998
Victor A. McKusick - updated: 5/9/1997

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

*FIELD* ED
alopez: 01/08/2014
carol: 10/8/2013
mgross: 10/4/2013
carol: 9/4/2013
carol: 5/24/2013
carol: 2/14/2013
carol: 6/6/2012
terry: 4/26/2011
terry: 4/25/2011
carol: 4/22/2011
wwang: 4/8/2011
terry: 4/7/2011
terry: 4/6/2011
carol: 3/25/2011
terry: 3/25/2011
alopez: 1/14/2011
carol: 6/8/2010
carol: 6/7/2010
carol: 6/3/2010
wwang: 5/17/2010
wwang: 5/12/2010
terry: 5/11/2010
wwang: 2/16/2010
wwang: 2/15/2010
carol: 2/4/2010
wwang: 2/3/2010
wwang: 6/25/2009
terry: 6/3/2009
terry: 2/10/2009
carol: 9/8/2008
wwang: 7/14/2008
wwang: 6/24/2008
carol: 6/4/2008
terry: 6/4/2008
carol: 12/4/2007
terry: 12/4/2007
joanna: 2/24/2006
alopez: 2/16/2006
terry: 2/15/2006
wwang: 1/18/2006
carol: 8/12/2005
carol: 5/9/2005
joanna: 3/14/2005
carol: 7/8/2004
terry: 7/8/2004
carol: 6/16/2004
carol: 3/30/2004
mgross: 12/10/2003
alopez: 11/18/2003
terry: 11/11/2003
tkritzer: 11/10/2003
tkritzer: 11/6/2003
terry: 11/4/2003
carol: 5/9/2003
terry: 5/9/2003
terry: 3/19/2003
joanna: 3/4/2003
carol: 11/8/2002
terry: 11/7/2002
carol: 8/23/2002
terry: 8/22/2002
alopez: 8/7/2002
tkritzer: 8/2/2002
tkritzer: 8/1/2002
terry: 7/26/2002
alopez: 6/28/2002
terry: 6/28/2002
alopez: 3/12/2002
alopez: 3/11/2002
mcapotos: 8/28/2000
mcapotos: 8/11/2000
terry: 8/7/2000
carol: 7/14/2000
terry: 7/14/2000
alopez: 4/12/2000
alopez: 4/10/2000
alopez: 3/22/2000
mcapotos: 2/18/2000
terry: 2/15/2000
mgross: 12/6/1999
mgross: 11/24/1999
terry: 12/11/1998
carol: 12/8/1998
terry: 12/2/1998
terry: 11/11/1997
terry: 11/10/1997
mark: 7/9/1997
alopez: 6/27/1997
alopez: 6/3/1997
alopez: 5/9/1997
alopez: 5/7/1997
jamie: 2/26/1997
jamie: 2/18/1997
mark: 8/15/1996
mark: 4/29/1996
terry: 4/24/1996
John: 11/14/1995
mimadm: 6/7/1995
pfoster: 3/30/1995
davew: 8/16/1994
carol: 5/11/1994
warfield: 3/29/1994

MIM 608358
*RECORD*
*FIELD* NO
608358
*FIELD* TI
#608358 MYOPATHY, MYOSIN STORAGE
;;MYOPATHY, HYALINE BODY, AUTOSOMAL DOMINANT
*FIELD* TX
read moreA number sign (#) is used with this entry because myosin storage
myopathy is caused by mutation in the gene encoding the beta cardiac
myosin heavy chain (MYH7; 160760).

Other disorders caused by mutation in the MYH7 gene include Laing distal
myopathy (MPD1; 160500) and familial hypertrophic cardiomyopathy (CMH;
192600).

An autosomal recessive form of hyaline body myopathy (255160) has been
mapped to chromosome 3p.

CLINICAL FEATURES

Hyaline body myopathy is a rare congenital myopathy characterized by
subsarcolemmal hyalinized bodies in type I muscle fibers.

Cancilla et al. (1971) described a brother and sister with a congenital
myopathy in which they noted probable lysis of type I myofibrils. A fine
granular material that stained intensely with the myosin ATPase reaction
had accumulated within the fibers. Dye et al. (2006) stated that the
disease progressed over the years in the patients reported by Cancilla
et al. (1971). The sister developed joint contractures of her limbs,
severe scoliosis, and required ventilatory assistance. She died at age
25 years from bronchopneumonia after exploratory abdominal surgery for
appendicitis. Her younger brother had scoliosis with fusion rod and
tracheotomy at the age of 30 years.

Sahgal and Sahgal (1977) reported a patient with sporadic nonprogressive
congenital myopathy with weakness and atrophy of the scapuloperoneal
muscles. Muscle biopsy showed preferential atrophy of type I muscle
fibers and subsarcolemmal bodies composed of an acid protein with ATPase
activity.

Goebel et al. (1981) reported a 15-year-old girl with proximal muscle
weakness since infancy. Milder distal muscle weakness was also present.
Quadriceps muscle biopsy showed a predominance of type I muscle fibers
with 'cytoplasmic bodies.' There was no family history.

Ceuterick et al. (1993) reported a 10-year-old boy with nonprogressive
myopathy. Muscle biopsy showed hyaline bodies in type I fibers that
stained with the myosin ATPase reaction at pH 4.2 and with polyclonal
antiskeletal myosin. Immunoreactive deposits to antidesmin were observed
at the border of some hyaline bodies. Ultrastructurally, the hyaline
bodies were not surrounded by a limiting membrane and were only
localized in subsarcolemmal areas. Periodic acid Schiff (PAS) staining
for polysaccharides was negative.

Barohn et al. (1994) reported 2 patients with sporadic hyaline body
myopathy since infancy: a 40-year-old male and a 3-year-old female. Both
had numerous subsarcolemmal glassy, hyaline bodies in 20 to 30% of type
I muscle fibers. The hyaline bodies stained negative for PAS and
oxidative enzymes, contained amorphous granular material, but were not
contained within a membrane.

Masuzugawa et al. (1997) reported a family in which 7 members over 4
generations developed slowly progressive scapuloperoneal muscle weakness
and atrophy with an age at onset ranging from the first to fifth decade.
Muscle biopsy of 2 patients showed subsarcolemmal hyaline bodies in
approximately 20% of type I fibers. The hyaline bodies showed
myofibrillar ATPase activity and stained intensely with antibodies to
slow myosin heavy chain. Ultrastructurally, the hyaline bodies consisted
of granules in linear array, filaments, or amorphous materials.

Bohlega et al. (2003) reported a Saudi Arabian kindred in which 11
members, including a mother, her father, and 8 of her 13 children, were
affected with hyaline body myopathy inherited in an autosomal dominant
pattern. Muscle biopsies showed subsarcolemmal hyaline bodies in type I
fibers that were positive for ATPase and heavy chain slow myosin.
Ultrastucturally, the hyaline bodies were granular and filamentous or
amorphous, surrounded by disorganized sarcomeres. There were also many
signs of myopathy, including fiber-type grouping, angulated fibers,
fiber necrosis, fibrosis, and central nucleation. Bohlega et al. (2003)
noted 2 distinct disease patterns in the family: a nonprogressive
minimal generalized muscle wasting and weakness since childhood, and a
relentlessly progressive weakness starting at age 2 years with proximal
arm and hand weakness, scapular winging, and severe functional
impairment resulting in loss of ambulation around age 20 years.

Goebel and Warlo (2001) suggested that hyaline body myopathy may be
related to a surplus of proteins present in a granular or filamentous
form.

Tajsharghi et al. (2003) reported a patient with slowly progressive
muscle weakness since childhood, when his gait was affected by hip
weakness, but he was able to climb stairs and even run. He also had
shoulder girdle weakness, bilateral winging of the scapulae, and
pseudohypertrophy of the calves. By age 71 years, he was severely weak
in the proximal muscles and moderately weak in the distal muscles. Lung
vital capacity was 57% of normal, serum creatine kinase was elevated,
and EMG findings were consistent with a myopathy. There were no signs of
cardiomyopathy clinically or by imaging, although he did have atrial
fibrillation. His mother had had similar symptoms, with hip and shoulder
girdle weakness, as well as atrial fibrillation. One of 3 children (a
daughter) of the proband was also affected. Tajsharghi et al. (2003)
also reported an unrelated 33-year-old woman with a similar phenotype,
including waddling gait, winging of the scapulae, pseudohypertrophy of
the calves, and normal cardiac findings. None of her family members was
affected. Muscle biopsy in the proband of the first family showed type 1
fiber predominance and increased interstitial fat and connective tissue.
Inclusion bodies consisting of the beta cardiac myosin heavy chain were
present in the majority of type 1 fibers, but not in type 2 fibers. The
authors termed the disorder 'myosin storage myopathy.'

MOLECULAR GENETICS

In affected members of a family and in an unrelated patient with myosin
storage myopathy, Tajsharghi et al. (2003) identified a heterozygous
mutation in the MYH7 gene (160760.0028).

In affected members of a Saudi Arabian family with autosomal dominant
hyaline body myopathy reported by Bohlega et al. (2003), Bohlega et al.
(2004) identified a mutation in the MYH7 gene (160760.0031).

In a Belgian patient with myosin storage myopathy originally reported by
Ceuterick et al. (1993), Laing et al. (2005) identified a mutation in
the MYH7 gene (160760.0028).

In 1 of the affected sibs originally reported by Cancilla et al. (1971),
Dye et al. (2006) identified a heterozygous mutation in the MYH7 gene
(L1793P; 160760.0037), confirming that the disease in that family was
autosomal dominant myosin storage myopathy. Dye et al. (2006) noted that
contact with the family had been lost and DNA studies were performed on
archival postmortem sections from the affected sister who died at age 25
years. The sibs presumably had the disease because of gonadal mosaicism
in 1 of the unaffected parents, although this could not be confirmed.

In a mother with myosin storage myopathy, who later developed
hypertrophic cardiomyopathy (CMH1; 192600), and in her daughter, who had
early-symptomatic left ventricular noncompaction (LVNC5; 613426),
Uro-Coste et al. (2009) identified heterozygosity for the L1793P
mutation in MYH7. The mother presented at age 30 years with proximal
muscle weakness, which progressed to the point of her being
wheelchair-bound by 48 years of age. At age 51, CMH was diagnosed.
Skeletal muscle biopsy at 53 years of age showed subsarcolemmal
accumulation of hyaline material in type 1 fibers. Her 24-year-old
daughter presented with heart failure at 3 months of age and was
diagnosed with early-onset cardiomyopathy. Angiography revealed a
less-contractile, irregular 'spongiotic' wall in the inferior left
ventricle, and echocardiography confirmed the diagnosis of LVNC. The
daughter did not complain of muscle weakness, but clinical examination
revealed bilateral wasting of the distal leg anterior compartment and
she had some difficulty with heel-walking.

PATHOGENESIS

Armel and Leinwand (2009) analyzed the functional effects of 4 different
MYH7 mutations in the rod or tail domain that were found to be
responsible for myosin storage myopathy: R1845W (160760.0028), H1901L
(160760.0031), E1886K (160760.0035), and L1793P (160760.0037). None of
the mutations altered the secondary structure of the protein, but L1793P
and H1901L showed decreased thermodynamic stability. All mutations
decreased the extent of self-assembly of the light meromyosin rod (less
than 50 to 60%) compared to the wildtype protein. R1845W and H1901L
showed formation of more stable and larger filaments, whereas L1793P and
E1886K showed more rapid filament degradation. Armel and Leinwand (2009)
noted that the assembly of muscle filaments is a multistep process that
involves both the proper folding of alpha-helices into coiled-coils, and
the assembly of these coiled-coils, in proper register, into filaments,
and concluded that defects in any one of these steps can result in
improper filament formation leading to muscle disease.

*FIELD* RF
1. Armel, T. Z.; Leinwand, L. A.: Mutations in the alpha-myosin rod
cause myosin storage myopathy via multiple mechanisms. Proc. Nat.
Acad. Sci. 106: 6291-6296, 2009.

2. Barohn, R. J.; Brumback, R. A.; Mendell, J. R.: Hyaline body myopathy. Neuromusc.
Disord. 4: 257-262, 1994.

3. Bohlega, S.; Abu-Amero, S. N.; Wakil, S. M.; Carroll, P.; Al-Amr,
R.; Lach, B.; Al-Sayed, Y.; Cupler, E. J.; Meyer, B. F.: Mutation
of the slow myosin heavy chain rod domain underlies hyaline body myopathy. Neurology 62:
1518-1521, 2004.

4. Bohlega, S.; Lach, B.; Meyer, B. F.; Al Said, Y.; Kambouris, M.;
Al Homsi, M.; Cupler, E. J.: Autosomal dominant hyaline body myopathy:
clinical variability and pathologic findings. Neurology 61: 1519-1523,
2003.

5. Cancilla, P. A.; Kalyanaraman, K.; Verity, M. A.; Munsat, T.; Pearson,
C. M.: Familial myopathy with probable lysis of myofibrils in type
1 fibers. Neurology 21: 579-585, 1971.

6. Ceuterick, C.; Martin, J. J.; Martens, C.: Hyaline bodies in skeletal
muscle of a patient with a mild chronic nonprogressive congenital
myopathy. Clin. Neuropath. 12: 79-83, 1993.

7. Dye, D. E.; Azzarelli, B.; Goebel, H. H.; Laing, N. G.: Novel
slow-skeletal myosin (MYH7) mutation in the original myosin storage
myopathy kindred. Neuromusc. Disord. 16: 357-360, 2006.

8. Goebel, H. H.; Schloon, H.; Lenard, H. G.: Congenital myopathy
with cytoplasmic bodies. Neuropediatrics 12: 166-180, 1981.

9. Goebel, H. H.; Warlo, I. A. P.: Surplus protein myopathies. Neuromusc.
Disord. 11: 3-6, 2001.

10. Laing, N. G.; Ceuterick-de Groote, C.; Dye, D. E.; Liyanage, K.;
Duff, R. M.; Dubois, B.; Robberecht, W.; Sciot, R.; Martin, J.-J.;
Goebel, H. H.: Myosin storage myopathy: slow skeletal myosin (MYH7)
mutation in two isolated cases. Neurology 64: 527-529, 2005.

11. Masuzugawa, S.; Kuzuhara, S.; Narita, Y.; Naito, Y.; Taniguchi,
A.; Ibi, T.: Autosomal dominant hyaline body myopathy presenting
as scapuloperoneal syndrome: clinical features and muscle pathology. Neurology 48:
253-257, 1997.

12. Sahgal, V.; Sahgal, S.: A new congenital myopathy. Acta Neuropath. 37:
225-230, 1977.

13. Tajsharghi, H.; Thornell, L.-E.; Lindberg, C.; Lindvall, B.; Henriksson,
K.-G.; Oldfors, A.: Myosin storage myopathy associated with a heterozygous
missense mutation in MYH7. Ann. Neurol. 54: 494-500, 2003.

14. Uro-Coste, E.; Arne-Bes, M.-C.; Pellissier, J.-F.; Richard, P.;
Levade, T.; Heitz, F.; Figarella-Branger, D.; Delisle, M.-B.: Striking
phenotypic variability in two familial cases of myosin storage myopathy
with a MYH7 leu1793pro mutation. Neuromusc. Disord. 19: 163-166,
2009.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
No hypertrophic cardiomyopathy

RESPIRATORY:
[Lung];
Reduced vital capacity due to muscle weakness

CHEST:
[Ribs, sternum, clavicle, and scapulae];
Scapular winging

MUSCLE, SOFT TISSUE:
Scapuloperoneal weakness;
Scapuloperoneal atrophy;
Generalized muscle weakness, proximal and distal;
Generalized muscle atrophy, proximal and distal;
'Waddling' gait;
Pseudohypertrophy of the calves;
EMG shows myopathy;
Muscle biopsy shows type 1 fiber predominance;
Subsarcolemmal hyaline bodies in type 1 fibers only;
Type 1 fibers with inclusions containing MYH7 protein aggregates;
Centralized nuclei;
Positive staining for ATPase activity at pH of 4.3

LABORATORY ABNORMALITIES:
Increased serum creatine kinase

MISCELLANEOUS:
Onset ranges from childhood to adulthood;
Slowly progressive;
Clinical variability;
Non-progressive and more severe progressive forms;
See 255160 for an autosomal recessive form;
Allelic disorder to familial hypertrophic cardiomyopathy (CMH, 192600)
and Laing distal myopathy (160500)

MOLECULAR BASIS:
Caused by mutation in the beta cardiac myosin heavy chain gene (MYH7,
160760.0028)

*FIELD* CN
Cassandra L. Kniffin - updated: 7/16/2004

*FIELD* CD
Cassandra L. Kniffin: 12/29/2003

*FIELD* ED
ckniffin: 10/19/2010
joanna: 3/19/2008
ckniffin: 7/16/2004
ckniffin: 12/29/2003

*FIELD* CN
Marla J. F. O'Neill - updated: 6/7/2010
Cassandra L. Kniffin - updated: 10/14/2009
Cassandra L. Kniffin - updated: 6/9/2005
Cassandra L. Kniffin - updated: 1/25/2005

*FIELD* CD
Cassandra L. Kniffin: 12/22/2003

*FIELD* ED
ckniffin: 11/08/2010
carol: 6/7/2010
wwang: 10/26/2009
ckniffin: 10/14/2009
carol: 3/6/2009
terry: 12/21/2005
ckniffin: 6/30/2005
wwang: 6/14/2005
ckniffin: 6/9/2005
ckniffin: 1/25/2005
ckniffin: 7/16/2004
tkritzer: 12/31/2003
ckniffin: 12/24/2003

MIM 613426
*RECORD*
*FIELD* NO
613426
*FIELD* TI
#613426 CARDIOMYOPATHY, DILATED, 1S; CMD1S
LEFT VENTRICULAR NONCOMPACTION 5, INCLUDED; LVNC5, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because dilated
cardiomyopathy-1S (CMD1S) is caused by heterozygous mutation in the MYH7
gene (160760) on chromosome 14q12.

Mutation in the MYH7 gene has also been associated with left ventricular
noncompaction (LVNC5), hypertrophic cardiomyopathy (CMH1; 192600), and
myosin storage myopathy (608358).

For a general phenotypic description and a discussion of genetic
heterogeneity of dilated cardiomyopathy, see CMD1A (115200); for a
similar discussion of left ventricular noncompaction, see LVNC1
(604169).

CLINICAL FEATURES

Kamisago et al. (2000) studied affected members of a large 4-generation
family segregating autosomal dominant dilated cardiomyopathy (CMD).
Seventeen family members had dilated cardiomyopathy without conduction
system disease, skeletal muscle dysfunction, or other phenotypes. The
authors noted that previous clinical studies of 12 affected individuals
showed no evidence of ventricular hypertrophy. In many family members,
the onset of disease occurred early in life: one patient was
hospitalized with heart failure at 2 years of age; another developed
heart failure followed by sudden death at 20 years of age; and another
underwent cardiac transplantation for end-stage heart failure at 23
years of age. Histopathologic study of the explanted heart from the last
patient showed mildly increased interstitial fibrosis without myocyte or
myofibrillar disarray.

- Left Ventricular Noncompaction 5

Sasse-Klaassen et al. (2003) studied a family (designated 'INVM-101')
segregating autosomal dominant left ventricular noncompaction (LVNC), in
which there were 5 affected individuals over 2 generations. The proband
underwent diagnostic evaluation because of inverted T waves seen on
routine electrocardiogram at 60 years of age, and was found to have
marked noncompaction confined to the left ventricular apex and an
enlarged left ventricle with a left ventricle end-diastolic diameter
(LVEDD) of 66 mm and reduced systolic function (left ventricle
fractional shortening, 14%; left ventricle ejection fraction, 27%). Two
asymptomatic daughters with LVNC were identified at 40 and 23 years of
age, respectively. Sasse-Klaassen et al. (2003) also studied 2 brothers
with LVNC ('family INVM-107'). The probands from both families were
originally characterized by Oechslin et al. (2000).

Klaassen et al. (2008) provided follow-up on families INVM-101 and
INVM-107, stating that clinical evaluation of family 101 was remarkable
for the very pronounced morphology of LVNC. The proband, who had
suffered a stroke and systemic peripheral emboli, had an affected
brother who initially presented with decompensated heart failure and
pulmonary emboli; both patients remained stable over a period of 8
years. Other affected members of family INVM-101 fulfilled morphologic
LVNC criteria but were clinically asymptomatic. The 4 affected
individuals in family INVM-107 all had noncompaction involving the apex
and mid-left ventricular wall, and the right ventricle was involved as
well in 2 patients. The 25-year-old male proband, who had been diagnosed
with LVNC after developing cardiogenic shock and pulmonary and systemic
peripheral emboli, received a cardiac transplant at age 26 years. His
32-year-old affected brother also carried the mutation, as did their
65-year-old mother, who had typical LVNC morphology but remained
clinically asymptomatic. The brother's son fulfilled criteria for LVNC
at 2 years of age.

Uro-Coste et al. (2009) studied a family in which the mother had myosin
storage myopathy (608358) and later developed hypertrophic
cardiomyopathy (CMH1; 192600), whereas the daughter had early
symptomatic LVNC. The mother presented at age 30 years with proximal
muscle weakness, which progressed to the point of her being
wheelchair-bound by age 48 years. At age 51, hypertrophic cardiomyopathy
was diagnosed; echocardiography revealed no atrial or ventricular
dilatation, and no abnormal appearance of the ventricular walls.
Skeletal muscle biopsy at age 53 years showed subsarcolemmal
accumulation of hyaline material in type 1 fibers. Her 24-year-old
daughter presented with heart failure at 3 months of age and was
diagnosed with early-onset cardiomyopathy. Angiography revealed a
less-contractile, irregular 'spongiotic' wall in the inferior left
ventricle; on echocardiography, the left ventricle was dilated and
fulfilled the criteria for LVNC, with a severely thickened, 2-layered
myocardium and numerous prominent trabeculations and deep
intertrabecular recesses. The daughter did not complain of muscle
weakness, but clinical examination revealed bilateral wasting of the
distal leg anterior compartment and she had some difficulty with
heel-walking.

MAPPING

In a large 4-generation family segregating autosomal dominant dilated
cardiomyopathy (CMD), Kamisago et al. (2000) performed genomewide
linkage analysis and obtained a maximum lod score of 5.11 on chromosome
14q11.2-q13 at D14S990. Haplotype analysis defined a 14-cM critical
interval between D14S283 and D14S597.

MOLECULAR GENETICS

In a large 4-generation family segregating autosomal dominant dilated
cardiomyopathy mapping to chromosome 14q11.2-q13, Kamisago et al. (2000)
analyzed the candidate gene MYH7 (160760) and identified heterozygosity
for a missense mutation (S532P; 160760.0022). In an unrelated family
with CMD, in which a father and 2 daughters were affected, the authors
identified a different heterozygous missense mutation (F764L;
160760.0023).

In a series of 46 young patients with CMD, Daehmlow et al. (2002)
screened 4 sarcomere genes and identified 2 probands with heterozygous
missense mutations in the MYH7 gene: A223T (160760.0026) and S642L
(160760.0027). The patients were diagnosed at ages 35 years and 18
years, respectively.

Klaassen et al. (2008) analyzed 6 genes encoding sarcomere proteins in
63 unrelated adult probands with left ventricular noncompaction but no
other congenital heart anomalies. They identified 7 different
heterozygous mutations in the MYH7 gene in the probands from 4 families,
2 of which were previously studied by Sasse-Klaassen et al. (2003)
(families INVM-101 and INVM-107), and in 4 sporadic patients,
respectively (see, e.g., 160760.0040-160760.0042). Klaassen et al.
(2008) stated that the most frequent symptom at presentation for
patients with MYH7 mutations was dyspnea, followed by atypical chest
pain and palpitations. LVNC was always present in the ventricular apex,
and in all but 2 probands, the midventricular inferior and lateral walls
were involved, whereas there was sparing of the basal left ventricular
segments. Five of 8 probands had biventricular involvement. Left
ventricular end-diastolic dimensions were enlarged and systolic function
was impaired in 5 of 8 probands, and heart failure was present at
initial diagnosis or occurred during follow-up in all but 2 probands.
Stroke or pulmonary or systemic peripheral thromboemboli occurred in 4
of 8 probands.

In a mother with myosin storage myopathy (608358) and hypertrophic
cardiomyopathy (CMH1; 192600) and her daughter with early symptomatic
LVNC, Uro-Coste et al. (2009) identified heterozygosity for an L1793P
mutation in the MYH7 gene (160760.0037).

In an analysis of the MYH7 gene in 141 white probands of western
European descent diagnosed with Ebstein anomaly (see 224700), Postma et
al. (2011) identified heterozygous mutations in 8 (see, e.g.,
160760.0045 and 160760.0046). Of these 8 probands, LVNC was present in 7
and uncertain in 1, whereas none of the 133 mutation-negative probands
had LVNC. Evaluation of all available family members of
mutation-positive probands revealed 3 families in which additional
mutation-positive individuals had cardiomyopathy or congenital heart
malformations, including type II atrial septal defect, ventricular
septal defect, bicuspid aortic valve, aortic coarctation, and pulmonary
artery stenosis/hypoplasia.

*FIELD* RF
1. Daehmlow, S.; Erdmann, J.; Knueppel, T.; Gille, C.; Froemmel, C.;
Hummel, M.; Hetzer, R.; Regitz-Zagrosek, V.: Novel mutations in sarcomeric
protein genes in dilated cardiomyopathy. Biochem. Biophys. Res. Commun. 298:
116-120, 2002.

2. Kamisago, M.; Sharma, S. D.; DePalma, S. R.; Solomon, S.; Sharma,
P.; McDonough, B.; Smoot, L.; Mullen, M. P.; Woolf, P. K.; Wigle,
E. D.; Seidman, J. G.; Seidman, C. E.: Mutations in sarcomere protein
genes as a cause of dilated cardiomyopathy. New Eng. J. Med. 343:
1688-1696, 2000.

3. Klaassen, S.; Probst, S.; Oechslin, E.; Gerull, B.; Krings, G.;
Schuler, P.; Greutmann, M.; Hurlimann, D.; Yegibasi, M.; Pons, L.;
Gramlich, M.; Drenckhahn, J.-D.; Heuser, A.; Berger, F.; Jenni, R.;
Thierfelder, L.: Mutations in sarcomere protein genes in left ventricular
noncompaction. Circulation 117: 2893-2901, 2008.

4. Oechslin, E. N.; Attenhofer Jost, C. H.; Rojas, J. R.; Kaufmann,
P. A.; Jenni, R.: Long-term follow-up of 34 adults with isolated
left ventricular noncompaction: a distinct cardiomyopathy with poor
prognosis. J. Am. Coll. Cardiol. 36: 493-500, 2000.

5. Postma, A. V.; van Engelen, K.; van de Meerakker, J.; Rahman, T.;
Probst, S.; Baars, M. J. H.; Bauer, U.; Pickardt, T.; Sperling, S.
R.; Berger, F.; Moorman, A. F. M.; Mulder, B. J. M.; Thierfelder,
L.; Keavney, B.; Goodship, J.; Klaassen, S.: Mutations in the sarcomere
gene MYH7 in Ebstein anomaly. Circ. Cardiovasc. Genet. 4: 43-50,
2011.

6. Sasse-Klaassen, S.; Gerull, B.; Oechslin, E.; Jenni, R.; Thierfelder,
L.: Isolated noncompaction of the left ventricular myocardium in
the adult is an autosomal dominant disorder in the majority of patients. Am.
J. Med. Genet. 119A: 162-167, 2003.

7. Uro-Coste, E.; Arne-Bes, M.-C.; Pellissier, J.-F.; Richard, P.;
Levade, T.; Heitz, F.; Figarella-Branger, D.; Delisle, M.-B.: Striking
phenotypic variability in two familial cases of myosin storage myopathy
with a MYH7 leu1793pro mutation. Neuromusc. Disord. 19: 163-166,
2009.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Left ventricular dilation;
Congestive heart failure;
Left ventricular noncompaction (in some patients);
Ventricular arrhythmia (in some patients);
Ebstein anomaly (in some patients);
Tricuspid regurgitation (in some patients);
Atrial septal defect, secundum type (in some patients);
Bicuspid aortic valve (in some patients);
Aortic coarctation (in some patients);
[Vascular];
Emboli, pulmonary (in some patients);
Pulmonary artery hypoplasia (in some patients)

MOLECULAR BASIS:
Caused by mutation in the myosin, heavy polypeptide-7, cardiac muscle,
beta gene (MYH7, 160760.0022)

*FIELD* CN
Marla J. F. O'Neill - updated: 11/11/2013

*FIELD* CD
Marla J. F. O'Neill: 6/16/2010

*FIELD* ED
joanna: 11/11/2013
joanna: 6/26/2012

*FIELD* CN
Marla J. F. O'Neill - updated: 10/09/2013
Marla J. F. O'Neill - updated: 9/5/2013

*FIELD* CD
Marla J. F. O'Neill: 6/4/2010

*FIELD* ED
carol: 10/09/2013
carol: 10/8/2013
carol: 9/5/2013
carol: 9/4/2013
terry: 12/7/2010
terry: 9/8/2010
carol: 6/7/2010