RBCC Red Blood Cell Collection

MYBPC3 [Confidence: low (only semi-automatic identification from reviews)]
Myosin-binding protein C, cardiac-type; Cardiac MyBP-C (C-protein, cardiac muscle isoform)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q14896
ID MYPC3_HUMAN Reviewed; 1274 AA.
AC Q14896; A5PL00; Q16410; Q6R2F7; Q9UE27; Q9UM53;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
read moreDT 28-NOV-2012, sequence version 4.
DT 22-JAN-2014, entry version 146.
DE RecName: Full=Myosin-binding protein C, cardiac-type;
DE Short=Cardiac MyBP-C;
DE AltName: Full=C-protein, cardiac muscle isoform;
GN Name=MYBPC3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT CMH4 GLN-820.
RC TISSUE=Heart;
RX PubMed=7744002;
RA Gautel M., Zuffardi O., Freiburg A., Labeit S.;
RT "Phosphorylation switches specific for the cardiac isoform of myosin
RT binding protein-C: a modulator of cardiac contraction?";
RL EMBO J. 14:1952-1960(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS CMH4 GLN-542 AND
RP GLN-820.
RX PubMed=9048664;
RA Carrier L., Bonne G., Bahrend E., Yu B., Richard P., Niel F.,
RA Hainque B., Cruaud C., Gary F., Labeit S., Bouhour J.-B., Dubourg O.,
RA Desnos M., Hagege A.A., Trent R.J., Komajda M., Fiszman M.,
RA Schwartz K.;
RT "Organization and sequence of human cardiac myosin binding protein C
RT gene (MYBPC3) and identification of mutations predicted to produce
RT truncated proteins in familial hypertrophic cardiomyopathy.";
RL Circ. Res. 80:427-434(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS CMH4 GLN-451; GLN-495
RP AND GLN-502.
RX PubMed=9562578; DOI=10.1056/NEJM199804303381802;
RA Niimura H., Bachinski L.L., Sangwatanaroj S., Watkins H.,
RA Chudley A.E., McKenna W., Kristinsson A., Roberts R., Sole M.,
RA Maron B.J., Seidman J.G., Seidman C.E.;
RT "Mutations in the gene for cardiac myosin-binding protein C and late-
RT onset familial hypertrophic cardiomyopathy.";
RL N. Engl. J. Med. 338:1248-1257(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS MET-158; ILE-189;
RP GLY-236; GLN-281; TRP-382; VAL-383; THR-522; VAL-833; GLU-998 AND
RP CYS-1048.
RG NIEHS SNPs program;
RL Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Rieder M.J., Bertucci C., Stanaway I.B., Johnson E.J., Swanson J.E.,
RA Siegel D.L., da Ponte S.H., Igartua C., Patterson K., Nickerson D.A.;
RL Submitted (NOV-2009) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F.,
RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
RA Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
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 [MRNA] OF 640-694.
RX PubMed=7493026; DOI=10.1038/ng1295-438;
RA Bonne G., Carrier L., Bercovici J., Cruaud C., Richard P., Hainque B.,
RA Gautel M., Labeit S., James M., Beckmann J., Weissenbach J.,
RA Vosberg H.-P., Fiszman M., Komajda M., Schwartz K.;
RT "Cardiac myosin binding protein-C gene splice acceptor site mutation
RT is associated with familial hypertrophic cardiomyopathy.";
RL Nat. Genet. 11:438-440(1995).
RN [9]
RP STRUCTURE BY NMR OF 641-770, AND CHARACTERIZATION OF VARIANTS HIS-654
RP AND LYS-755.
RX PubMed=12787675; DOI=10.1016/S0022-2836(03)00425-X;
RA Idowu S.M., Gautel M., Perkins S.J., Pfuhl M.;
RT "Structure, stability and dynamics of the central domain of cardiac
RT myosin binding protein C (MyBP-C): implications for multidomain
RT assembly and causes for cardiomyopathy.";
RL J. Mol. Biol. 329:745-761(2003).
RN [10]
RP STRUCTURE BY NMR OF 358-450, AND POTENTIAL DISULFIDE BOND.
RX PubMed=15213454; DOI=10.1023/B:JNMR.0000032510.03606.63;
RA Ababou A., Zhou L., Gautel M., Pfuhl M.;
RT "Sequence specific assignment of domain C1 of the N-terminal myosin-
RT binding site of human cardiac myosin binding protein C (MyBP-C).";
RL J. Biomol. NMR 29:431-432(2004).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (1.3 ANGSTROMS) OF 151-258.
RX PubMed=18560154; DOI=10.1107/S0907444908008792;
RA Fisher S.J., Helliwell J.R., Khurshid S., Govada L., Redwood C.,
RA Squire J.M., Chayen N.E.;
RT "An investigation into the protonation states of the C1 domain of
RT cardiac myosin-binding protein C.";
RL Acta Crystallogr. D 64:658-664(2008).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 151-258.
RX PubMed=18374358; DOI=10.1016/j.jmb.2008.02.044;
RA Govada L., Carpenter L., da Fonseca P.C., Helliwell J.R.,
RA Rizkallah P., Flashman E., Chayen N.E., Redwood C., Squire J.M.;
RT "Crystal structure of the C1 domain of cardiac myosin binding protein-
RT C: implications for hypertrophic cardiomyopathy.";
RL J. Mol. Biol. 378:387-397(2008).
RN [13]
RP STRUCTURE BY NMR OF 151-260, AND ZINC-BINDING SITE.
RX PubMed=18926831; DOI=10.1016/j.jmb.2008.09.065;
RA Ababou A., Rostkova E., Mistry S., Le Masurier C., Gautel M.,
RA Pfuhl M.;
RT "Myosin binding protein C positioned to play a key role in regulation
RT of muscle contraction: structure and interactions of domain C1.";
RL J. Mol. Biol. 384:615-630(2008).
RN [14]
RP VARIANT CMH4 LYS-755.
RX PubMed=9541104;
RA Yu B., French J.A., Carrier L., Jeremy R.W., McTaggart D.R.,
RA Nicholson M.R., Hambly B., Semsarian C., Richmond D.R., Schwartz K.,
RA Trent R.J.;
RT "Molecular pathology of familial hypertrophic cardiomyopathy caused by
RT mutations in the cardiac myosin binding protein C gene.";
RL J. Med. Genet. 35:205-210(1998).
RN [15]
RP VARIANT CMH4 HIS-654.
RX PubMed=9541115;
RA Moolman-Smook J.C., Mayosi B., Brink P., Corfield V.A.;
RT "Identification of a new missense mutation in MyBP-C associated with
RT hypertrophic cardiomyopathy.";
RL J. Med. Genet. 35:253-254(1998).
RN [16]
RP VARIANT MET-896.
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 [17]
RP VARIANT CMH4 GLN-495, AND VARIANT GLN-326.
RX PubMed=11499718; DOI=10.1016/S0735-1097(01)01386-9;
RA Maron B.J., Niimura H., Casey S.A., Soper M.K., Wright G.B.,
RA Seidman J.G., Seidman C.E.;
RT "Development of left ventricular hypertrophy in adults in hypertrophic
RT cardiomyopathy caused by cardiac myosin-binding protein C gene
RT mutations.";
RL J. Am. Coll. Cardiol. 38:315-321(2001).
RN [18]
RP VARIANTS CMH4 TRP-282; ARG-507; ARG-566 AND ILE-1115.
RX PubMed=11499719; DOI=10.1016/S0735-1097(01)01387-0;
RA Erdmann J., Raible J., Maki-Abadi J., Hummel M., Hammann J.,
RA Wollnik B., Frantz E., Fleck E., Hetzer R., Regitz-Zagrosek V.;
RT "Spectrum of clinical phenotypes and gene variants in cardiac myosin-
RT binding protein C mutation carriers with hypertrophic
RT cardiomyopathy.";
RL J. Am. Coll. Cardiol. 38:322-330(2001).
RN [19]
RP VARIANT CMH4 THR-948, AND VARIANTS GLY-236 AND GLN-326.
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 [20]
RP VARIANTS CMH4 ALA-59 AND GLN-1002, AND VARIANT GLN-326.
RX PubMed=11815426; DOI=10.1161/hc0402.102990;
RA Niimura H., Patton K.K., McKenna W.J., Soults J., Maron B.J.,
RA Seidman J.G., Seidman C.E.;
RT "Sarcomere protein gene mutations in hypertrophic cardiomyopathy of
RT the elderly.";
RL Circulation 105:446-451(2002).
RN [21]
RP VARIANTS CMH4 LYS-258; HIS-810; GLN-820 AND HIS-873.
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 [22]
RP VARIANTS CMH4 PRO-257; LYS-258; GLU-278; ALA-279; PRO-352; TRP-502;
RP LYS-504 DEL; GLN-542; ARG-811; VAL-833; THR-1194 AND THR-1255, AND
RP VARIANTS GLN-326 AND MET-896.
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 [23]
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 [24]
RP VARIANTS CMH4 LYS-258; TRP-282; ARG-507; TRP-523; ARG-566; PRO-668;
RP VAL-833 AND ILE-1115, AND VARIANTS GLY-236 AND GLN-326.
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 [25]
RP VARIANTS CMH4 SER-161; LYS-258; ASN-605; THR-833; TRP-834 AND
RP THR-1131.
RX PubMed=14563344; DOI=10.1016/S0195-668X(03)00466-4;
RA Alders M., Jongbloed R., Deelen W., van den Wijngaard A.,
RA Doevendans P., Ten Cate F., Regitz-Zagrosek V., Vosberg H.-P.,
RA van Langen I., Wilde A., Dooijes D., Mannens M.;
RT "The 2373insG mutation in the MYBPC3 gene is a founder mutation, which
RT accounts for nearly one-fourth of the HCM cases in the Netherlands.";
RL Eur. Heart J. 24:1848-1853(2003).
RN [26]
RP VARIANT CMH4 GLN-820.
RX PubMed=12628722; DOI=10.1016/S0735-1097(02)02957-1;
RA Konno T., Shimizu M., Ino H., Matsuyama T., Yamaguchi M., Terai H.,
RA Hayashi K., Mabuchi T., Kiyama M., Sakata K., Hayashi T., Inoue M.,
RA Kaneda T., Mabuchi H.;
RT "A novel missense mutation in the myosin binding protein-C gene is
RT responsible for hypertrophic cardiomyopathy with left ventricular
RT dysfunction and dilation in elderly patients.";
RL J. Am. Coll. Cardiol. 41:781-786(2003).
RN [27]
RP VARIANTS CMH4 SER-237; HIS-668 AND THR-833, AND VARIANTS GLN-326 AND
RP MET-896.
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 [28]
RP VARIANTS CMH4 ASN-228; LYS-258; LYS-813 DEL AND THR-833.
RX PubMed=15114369; DOI=10.1038/sj.ejhg.5201190;
RA Andersen P.S., Havndrup O., Bundgaard H., Larsen L.A., Vuust J.,
RA Pedersen A.K., Kjeldsen K., Christiansen M.;
RT "Genetic and phenotypic characterization of mutations in myosin-
RT binding protein C (MYBPC3) in 81 families with familial hypertrophic
RT cardiomyopathy: total or partial haploinsufficiency.";
RL Eur. J. Hum. Genet. 12:673-677(2004).
RN [29]
RP VARIANTS CMH4 ARG-5; LEU-219; ILE-256; LYS-258; HIS-458; ARG-490;
RP GLN-495; TRP-502; GLN-542; VAL-604; ASN-605; LEU-608; CYS-733;
RP ASN-770; ARG-792; HIS-810; LYS-811 DEL; THR-833; GLU-998; ARG-998;
RP ILE-1113 AND THR-1131, AND VARIANTS MET-158; GLY-236; GLN-326;
RP TRP-382; SER-416; ARG-507; MET-545 AND MET-896.
RX PubMed=15519027; DOI=10.1016/j.jacc.2004.07.045;
RA Van Driest S.L., Vasile V.C., Ommen S.R., Will M.L., Tajik A.J.,
RA Gersh B.J., Ackerman M.J.;
RT "Myosin binding protein C mutations and compound heterozygosity in
RT hypertrophic cardiomyopathy.";
RL J. Am. Coll. Cardiol. 44:1903-1910(2004).
RN [30]
RP VARIANT GLY-236.
RX PubMed=15582318; DOI=10.1016/j.jacc.2004.08.058;
RA Hayashi T., Arimura T., Itoh-Satoh M., Ueda K., Hohda S., Inagaki N.,
RA Takahashi M., Hori H., Yasunami M., Nishi H., Koga Y., Nakamura H.,
RA Matsuzaki M., Choi B.Y., Bae S.W., You C.W., Han K.H., Park J.E.,
RA Knoell R., Hoshijima M., Chien K.R., Kimura A.;
RT "Tcap gene mutations in hypertrophic cardiomyopathy and dilated
RT cardiomyopathy.";
RL J. Am. Coll. Cardiol. 44:2192-2201(2004).
RN [31]
RP VARIANTS CMH4 LYS-258; ARG-263; SER-417; HIS-669 AND ASP-759.
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 [32]
RP VARIANTS CMH4 HIS-273; TRP-502 AND GLN-542, AND VARIANT GLN-326.
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 [33]
RP VARIANTS CMH4 GLU-278; ARG-490; GLY-495; GLN-502; TRP-502; ASN-605;
RP SER-1028 AND ARG-1248, AND VARIANTS MET-158; GLY-236; GLN-326; MET-896
RP AND TRP-1002.
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).
CC -!- FUNCTION: Thick filament-associated protein located in the
CC crossbridge region of vertebrate striated muscle a bands. In vitro
CC it binds MHC, F-actin and native thin filaments, and modifies the
CC activity of actin-activated myosin ATPase. It may modulate muscle
CC contraction or may play a more structural role.
CC -!- INTERACTION:
CC Self; NbExp=2; IntAct=EBI-704176, EBI-704176;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q14896-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q14896-2; Sequence=VSP_047141;
CC -!- PTM: Substrate for phosphorylation by PKA and PKC. Reversible
CC phosphorylation appears to modulate contraction (By similarity).
CC -!- DISEASE: Cardiomyopathy, familial hypertrophic 4 (CMH4)
CC [MIM:115197]: 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 -!- SIMILARITY: Belongs to the immunoglobulin superfamily. MyBP
CC family.
CC -!- SIMILARITY: Contains 3 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 7 Ig-like C2-type (immunoglobulin-like)
CC domains.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MYBPC3";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/mybpc3/";
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DR EMBL; X84075; CAA58882.1; -; mRNA.
DR EMBL; Y10129; CAA71216.1; -; Genomic_DNA.
DR EMBL; U91629; AAC04620.1; -; Genomic_DNA.
DR EMBL; AY518390; AAR89909.1; -; Genomic_DNA.
DR EMBL; GU324918; ADL14489.1; -; Genomic_DNA.
DR EMBL; AC090582; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC136543; AAI36544.1; -; mRNA.
DR EMBL; BC136546; AAI36547.1; -; mRNA.
DR EMBL; BC142685; AAI42686.1; -; mRNA.
DR EMBL; BC151211; AAI51212.1; -; mRNA.
DR EMBL; S80778; AAB35662.1; -; mRNA.
DR PIR; S55050; S55050.
DR RefSeq; NP_000247.2; NM_000256.3.
DR UniGene; Hs.524906; -.
DR PDB; 1GXE; NMR; -; A=641-770.
DR PDB; 1PD6; NMR; -; A=358-451.
DR PDB; 2AVG; NMR; -; A=151-260.
DR PDB; 2K1M; NMR; -; A=2-96.
DR PDB; 2V6H; X-ray; 1.55 A; A=151-258.
DR PDB; 3CX2; X-ray; 1.30 A; A=151-258.
DR PDBsum; 1GXE; -.
DR PDBsum; 1PD6; -.
DR PDBsum; 2AVG; -.
DR PDBsum; 2K1M; -.
DR PDBsum; 2V6H; -.
DR PDBsum; 3CX2; -.
DR ProteinModelPortal; Q14896; -.
DR SMR; Q14896; 2-96, 151-258, 319-353, 358-1168, 1181-1271.
DR IntAct; Q14896; 3.
DR MINT; MINT-6174801; -.
DR STRING; 9606.ENSP00000382193; -.
DR PhosphoSite; Q14896; -.
DR DMDM; 116242668; -.
DR UCD-2DPAGE; Q14896; -.
DR PaxDb; Q14896; -.
DR PRIDE; Q14896; -.
DR Ensembl; ENST00000256993; ENSP00000256993; ENSG00000134571.
DR Ensembl; ENST00000545968; ENSP00000442795; ENSG00000134571.
DR GeneID; 4607; -.
DR KEGG; hsa:4607; -.
DR UCSC; uc021qir.1; human.
DR CTD; 4607; -.
DR GeneCards; GC11M048799; -.
DR HGNC; HGNC:7551; MYBPC3.
DR HPA; HPA040147; -.
DR HPA; HPA043898; -.
DR MIM; 115197; phenotype.
DR MIM; 600958; gene.
DR neXtProt; NX_Q14896; -.
DR Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR Orphanet; 155; Familial isolated hypertrophic cardiomyopathy.
DR Orphanet; 54260; Left ventricular noncompaction.
DR PharmGKB; PA31351; -.
DR eggNOG; NOG12793; -.
DR HOGENOM; HOG000220906; -.
DR HOVERGEN; HBG052560; -.
DR KO; K12568; -.
DR OMA; EIQMSGS; -.
DR OrthoDB; EOG7WX07H; -.
DR Reactome; REACT_17044; Muscle contraction.
DR ChiTaRS; MYBPC3; human.
DR EvolutionaryTrace; Q14896; -.
DR GeneWiki; Myosin_binding_protein_C,_cardiac; -.
DR GenomeRNAi; 4607; -.
DR NextBio; 17732; -.
DR PRO; PR:Q14896; -.
DR ArrayExpress; Q14896; -.
DR Bgee; Q14896; -.
DR CleanEx; HS_MYBPC3; -.
DR Genevestigator; Q14896; -.
DR GO; GO:0014705; C:C zone; NAS:BHF-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005863; C:striated muscle myosin thick filament; IDA:BHF-UCL.
DR GO; GO:0001671; F:ATPase activator activity; ISS:BHF-UCL.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0017022; F:myosin binding; IDA:BHF-UCL.
DR GO; GO:0008307; F:structural constituent of muscle; IMP:BHF-UCL.
DR GO; GO:0031432; F:titin binding; NAS:BHF-UCL.
DR GO; GO:0060048; P:cardiac muscle contraction; ISS:BHF-UCL.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0030049; P:muscle filament sliding; TAS:Reactome.
DR GO; GO:0031034; P:myosin filament assembly; IEA:Ensembl.
DR GO; GO:0002027; P:regulation of heart rate; IEA:Ensembl.
DR GO; GO:0032971; P:regulation of muscle filament sliding; ISS:BHF-UCL.
DR GO; GO:0006942; P:regulation of striated muscle contraction; ISS:BHF-UCL.
DR GO; GO:0045214; P:sarcomere organization; IEA:Ensembl.
DR GO; GO:0055010; P:ventricular cardiac muscle tissue morphogenesis; IMP:BHF-UCL.
DR Gene3D; 2.60.40.10; -; 11.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013098; Ig_I-set.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR Pfam; PF00041; fn3; 3.
DR Pfam; PF07679; I-set; 8.
DR SMART; SM00060; FN3; 3.
DR SMART; SM00409; IG; 7.
DR SMART; SM00408; IGc2; 1.
DR SUPFAM; SSF49265; SSF49265; 2.
DR PROSITE; PS50853; FN3; 3.
DR PROSITE; PS50835; IG_LIKE; 6.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Actin-binding; Alternative splicing;
KW Cardiomyopathy; Cell adhesion; Complete proteome; Disease mutation;
KW Disulfide bond; Immunoglobulin domain; Metal-binding; Muscle protein;
KW Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW Thick filament; Zinc.
FT CHAIN 1 1274 Myosin-binding protein C, cardiac-type.
FT /FTId=PRO_0000072693.
FT DOMAIN 153 256 Ig-like C2-type 1.
FT DOMAIN 362 452 Ig-like C2-type 2.
FT DOMAIN 453 543 Ig-like C2-type 3.
FT DOMAIN 544 633 Ig-like C2-type 4.
FT DOMAIN 645 771 Ig-like C2-type 5.
FT DOMAIN 774 870 Fibronectin type-III 1.
FT DOMAIN 872 967 Fibronectin type-III 2.
FT DOMAIN 971 1065 Ig-like C2-type 6.
FT DOMAIN 1068 1163 Fibronectin type-III 3.
FT DOMAIN 1181 1274 Ig-like C2-type 7.
FT COMPBIAS 102 152 Pro-rich.
FT METAL 208 208 Zinc.
FT METAL 210 210 Zinc.
FT METAL 223 223 Zinc.
FT METAL 225 225 Zinc.
FT MOD_RES 1 1 N-acetylmethionine (By similarity).
FT MOD_RES 275 275 Phosphoserine; by PKA and PKC (By
FT similarity).
FT MOD_RES 284 284 Phosphoserine; by PKA and PKC (By
FT similarity).
FT MOD_RES 304 304 Phosphoserine; by PKA and PKC (By
FT similarity).
FT DISULFID 436 443 Potential.
FT VAR_SEQ 408 409 SK -> R (in isoform 2).
FT /FTId=VSP_047141.
FT VARIANT 5 5 G -> R (in CMH4).
FT /FTId=VAR_029390.
FT VARIANT 59 59 T -> A (in CMH4).
FT /FTId=VAR_029391.
FT VARIANT 158 158 V -> M (in dbSNP:rs3729986).
FT /FTId=VAR_020085.
FT VARIANT 161 161 P -> S (in CMH4).
FT /FTId=VAR_029392.
FT VARIANT 189 189 V -> I (in dbSNP:rs11570052).
FT /FTId=VAR_020568.
FT VARIANT 219 219 V -> L (in CMH4).
FT /FTId=VAR_029393.
FT VARIANT 228 228 D -> N (in CMH4).
FT /FTId=VAR_029394.
FT VARIANT 236 236 S -> G (in dbSNP:rs3729989).
FT /FTId=VAR_020086.
FT VARIANT 237 237 Y -> S (in CMH4).
FT /FTId=VAR_029395.
FT VARIANT 256 256 V -> I (in CMH4).
FT /FTId=VAR_029396.
FT VARIANT 257 257 H -> P (in CMH4).
FT /FTId=VAR_019889.
FT VARIANT 258 258 E -> K (in CMH4).
FT /FTId=VAR_019890.
FT VARIANT 263 263 G -> R (in CMH4).
FT /FTId=VAR_042740.
FT VARIANT 273 273 R -> H (in CMH4).
FT /FTId=VAR_042741.
FT VARIANT 278 278 G -> E (in CMH4; dbSNP:rs147315081).
FT /FTId=VAR_019891.
FT VARIANT 279 279 G -> A (in CMH4).
FT /FTId=VAR_019892.
FT VARIANT 281 281 R -> Q (in dbSNP:rs11570060).
FT /FTId=VAR_020569.
FT VARIANT 282 282 R -> W (in CMH4).
FT /FTId=VAR_029397.
FT VARIANT 326 326 R -> Q (in dbSNP:rs34580776).
FT /FTId=VAR_019893.
FT VARIANT 352 352 L -> P (in CMH4).
FT /FTId=VAR_019894.
FT VARIANT 382 382 R -> W (in dbSNP:rs11570076).
FT /FTId=VAR_020570.
FT VARIANT 383 383 L -> V (in dbSNP:rs11570077).
FT /FTId=VAR_020571.
FT VARIANT 416 416 G -> S.
FT /FTId=VAR_029398.
FT VARIANT 417 417 A -> S (in CMH4).
FT /FTId=VAR_042742.
FT VARIANT 451 451 E -> Q (in CMH4).
FT /FTId=VAR_027879.
FT VARIANT 458 458 R -> H (in CMH4).
FT /FTId=VAR_029399.
FT VARIANT 490 490 G -> R (in CMH4).
FT /FTId=VAR_029400.
FT VARIANT 495 495 R -> G (in CMH4).
FT /FTId=VAR_045929.
FT VARIANT 495 495 R -> Q (in CMH4).
FT /FTId=VAR_027880.
FT VARIANT 502 502 R -> Q (in CMH4).
FT /FTId=VAR_027881.
FT VARIANT 502 502 R -> W (in CMH4).
FT /FTId=VAR_019895.
FT VARIANT 504 504 Missing (in CMH4).
FT /FTId=VAR_019896.
FT VARIANT 507 507 G -> R (in CMH4; dbSNP:rs35736435).
FT /FTId=VAR_029401.
FT VARIANT 522 522 A -> T (in dbSNP:rs11570082).
FT /FTId=VAR_020573.
FT VARIANT 523 523 G -> W (in CMH4).
FT /FTId=VAR_029402.
FT VARIANT 542 542 E -> Q (in CMH4).
FT /FTId=VAR_003917.
FT VARIANT 545 545 L -> M.
FT /FTId=VAR_029403.
FT VARIANT 566 566 C -> R (in CMH4).
FT /FTId=VAR_029404.
FT VARIANT 604 604 D -> V (in CMH4).
FT /FTId=VAR_029405.
FT VARIANT 605 605 D -> N (in CMH4; pathogenicity remains to
FT be determined).
FT /FTId=VAR_029406.
FT VARIANT 608 608 P -> L (in CMH4).
FT /FTId=VAR_029407.
FT VARIANT 654 654 R -> H (in CMH4; as well folded and
FT stable as the wild-type;
FT dbSNP:rs1800565).
FT /FTId=VAR_003918.
FT VARIANT 668 668 R -> H (in CMH4).
FT /FTId=VAR_029408.
FT VARIANT 668 668 R -> P (in CMH4).
FT /FTId=VAR_029409.
FT VARIANT 669 669 L -> H (in CMH4).
FT /FTId=VAR_042743.
FT VARIANT 733 733 R -> C (in CMH4).
FT /FTId=VAR_029410.
FT VARIANT 755 755 N -> K (in CMH4; destabilizes the
FT structure of Ig-like C2-type domain 5).
FT /FTId=VAR_003919.
FT VARIANT 759 759 E -> D (in CMH4).
FT /FTId=VAR_042744.
FT VARIANT 770 770 D -> N (in CMH4; dbSNP:rs36211723).
FT /FTId=VAR_029411.
FT VARIANT 792 792 W -> R (in CMH4).
FT /FTId=VAR_029412.
FT VARIANT 810 810 R -> H (in CMH4).
FT /FTId=VAR_029413.
FT VARIANT 811 811 K -> R (in CMH4).
FT /FTId=VAR_019897.
FT VARIANT 811 811 Missing (in CMH4).
FT /FTId=VAR_029414.
FT VARIANT 813 813 Missing (in CMH4).
FT /FTId=VAR_029415.
FT VARIANT 820 820 R -> Q (in CMH4; dbSNP:rs2856655).
FT /FTId=VAR_029416.
FT VARIANT 833 833 A -> T (in CMH4; pathogenicity is
FT uncertain).
FT /FTId=VAR_029417.
FT VARIANT 833 833 A -> V (in CMH4; dbSNP:rs3729952).
FT /FTId=VAR_019898.
FT VARIANT 834 834 R -> T (in CMH4).
FT /FTId=VAR_029418.
FT VARIANT 834 834 R -> W (in CMH4; pathogenicity is
FT uncertain).
FT /FTId=VAR_029419.
FT VARIANT 873 873 P -> H (in CMH4).
FT /FTId=VAR_029420.
FT VARIANT 896 896 V -> M (may act as a phenotype modifier
FT in cardiomyopathy patients;
FT dbSNP:rs35078470).
FT /FTId=VAR_019899.
FT VARIANT 948 948 N -> T (in CMH4).
FT /FTId=VAR_029421.
FT VARIANT 998 998 Q -> E (in CMH4; dbNP:11570112;
FT dbSNP:rs11570112).
FT /FTId=VAR_020574.
FT VARIANT 998 998 Q -> R (in CMH4).
FT /FTId=VAR_029422.
FT VARIANT 1002 1002 R -> Q (in CMH4).
FT /FTId=VAR_029423.
FT VARIANT 1002 1002 R -> W (in dbSNP:rs3729799).
FT /FTId=VAR_029424.
FT VARIANT 1003 1003 P -> Q (in CMH4).
FT /FTId=VAR_029425.
FT VARIANT 1028 1028 T -> S (in CMH4).
FT /FTId=VAR_045930.
FT VARIANT 1048 1048 R -> C (in dbSNP:rs11570113).
FT /FTId=VAR_020575.
FT VARIANT 1113 1113 F -> I (in CMH4).
FT /FTId=VAR_029426.
FT VARIANT 1115 1115 V -> I (in CMH4).
FT /FTId=VAR_029427.
FT VARIANT 1131 1131 I -> T (in CMH4; pathogenicity is
FT uncertain).
FT /FTId=VAR_029428.
FT VARIANT 1155 1155 Missing (in CMH4).
FT /FTId=VAR_029429.
FT VARIANT 1194 1194 A -> T (in CMH4).
FT /FTId=VAR_019900.
FT VARIANT 1248 1248 G -> R (in CMH4).
FT /FTId=VAR_045931.
FT VARIANT 1255 1255 A -> T (in CMH4).
FT /FTId=VAR_019901.
FT CONFLICT 248 248 D -> E (in Ref. 1 and 2).
FT CONFLICT 302 303 RD -> SS (in Ref. 4; AAR89909).
FT CONFLICT 536 536 A -> R (in Ref. 1; CAA58882).
FT STRAND 19 22
FT STRAND 27 32
FT STRAND 34 37
FT STRAND 41 43
FT STRAND 45 49
FT STRAND 56 60
FT STRAND 63 70
FT STRAND 77 83
FT STRAND 86 95
FT STRAND 156 159
FT STRAND 164 167
FT STRAND 172 179
FT STRAND 184 186
FT STRAND 188 193
FT TURN 194 196
FT HELIX 199 202
FT STRAND 207 214
FT TURN 215 218
FT STRAND 219 226
FT HELIX 231 233
FT STRAND 235 242
FT STRAND 247 257
FT STRAND 650 652
FT STRAND 658 665
FT STRAND 670 672
FT STRAND 675 677
FT STRAND 680 686
FT STRAND 722 724
FT STRAND 726 730
FT STRAND 733 737
FT TURN 743 745
FT STRAND 747 754
FT STRAND 759 768
SQ SEQUENCE 1274 AA; 140762 MW; 4E5385C40085B796 CRC64;
MPEPGKKPVS AFSKKPRSVE VAAGSPAVFE AETERAGVKV RWQRGGSDIS ASNKYGLATE
GTRHTLTVRE VGPADQGSYA VIAGSSKVKF DLKVIEAEKA EPMLAPAPAP AEATGAPGEA
PAPAAELGES APSPKGSSSA ALNGPTPGAP DDPIGLFVMR PQDGEVTVGG SITFSARVAG
ASLLKPPVVK WFKGKWVDLS SKVGQHLQLH DSYDRASKVY LFELHITDAQ PAFTGSYRCE
VSTKDKFDCS NFNLTVHEAM GTGDLDLLSA FRRTSLAGGG RRISDSHEDT GILDFSSLLK
KRDSFRTPRD SKLEAPAEED VWEILRQAPP SEYERIAFQY GVTDLRGMLK RLKGMRRDEK
KSTAFQKKLE PAYQVSKGHK IRLTVELADH DAEVKWLKNG QEIQMSGSKY IFESIGAKRT
LTISQCSLAD DAAYQCVVGG EKCSTELFVK EPPVLITRPL EDQLVMVGQR VEFECEVSEE
GAQVKWLKDG VELTREETFK YRFKKDGQRH HLIINEAMLE DAGHYALCTS GGQALAELIV
QEKKLEVYQS IADLMVGAKD QAVFKCEVSD ENVRGVWLKN GKELVPDSRI KVSHIGRVHK
LTIDDVTPAD EADYSFVPEG FACNLSAKLH FMEVKIDFVP RQEPPKIHLD CPGRIPDTIV
VVAGNKLRLD VPISGDPAPT VIWQKAITQG NKAPARPAPD APEDTGDSDE WVFDKKLLCE
TEGRVRVETT KDRSIFTVEG AEKEDEGVYT VTVKNPVGED QVNLTVKVID VPDAPAAPKI
SNVGEDSCTV QWEPPAYDGG QPILGYILER KKKKSYRWMR LNFDLIQELS HEARRMIEGV
VYEMRVYAVN AIGMSRPSPA SQPFMPIGPP SEPTHLAVED VSDTTVSLKW RPPERVGAGG
LDGYSVEYCP EGCSEWVAAL QGLTEHTSIL VKDLPTGARL LFRVRAHNMA GPGAPVTTTE
PVTVQEILQR PRLQLPRHLR QTIQKKVGEP VNLLIPFQGK PRPQVTWTKE GQPLAGEEVS
IRNSPTDTIL FIRAARRVHS GTYQVTVRIE NMEDKATLVL QVVDKPSPPQ DLRVTDAWGL
NVALEWKPPQ DVGNTELWGY TVQKADKKTM EWFTVLEHYR RTHCVVPELI IGNGYYFRVF
SQNMVGFSDR AATTKEPVFI PRPGITYEPP NYKALDFSEA PSFTQPLVNR SVIAGYTAML
CCAVRGSPKP KISWFKNGLD LGEDARFRMF SKQGVLTLEI RKPCPFDGGI YVCRATNLQG
EARCECRLEV RVPQ
//

MIM 115197
*RECORD*
*FIELD* NO
115197
*FIELD* TI
#115197 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4; CMH4
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4, SUSCEPTIBILITY TO, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because familial hypertrophic
cardiomyopathy-4 (CMH4) is caused by heterozygous, homozygous, or
compound heterozygous mutation in the gene encoding cardiac
myosin-binding protein C (MYBPC3; 600958) on chromosome 11p11.

For a phenotypic description and a discussion of genetic heterogeneity
of familial hypertrophic cardiomyopathy, see CMH1 (192600).

CLINICAL FEATURES

Xin et al. (2007) studied 23 Old Order Amish infants with severe
neonatal hypertrophic cardiomyopathy, 20 from the Geauga County
settlement in Ohio, 1 from the Holmes County settlement in Ohio, and 2
from a settlement in New York. All of the infants presented with signs
and symptoms of congestive heart failure during the first 3 weeks of
life and had hypertrophic nonobstructive cardiomyopathy on
echocardiography (ECG); life span averaged 3 to 4 months, and all died
before 1 year of age except for 2 children who underwent cardiac
transplantation.

Kimura et al. (1997) stated that they identified a 2-bp deletion at
codon 945 in the MYBPC3 gene in a patient with hypertrophic
cardiomyopathy who also displayed Wolff-Parkinson-White ventricular
preexcitation (WPW; 194200); they also detected the same mutation in 3
additional CMH patients without WPW. Kimura et al. (1997) noted that
although a locus for 'CMH with WPW' had been mapped to chromosome 7q3
(CMH6; 600858), their findings indicated that more than 1 form of CMH is
associated with WPW syndrome.

Wang et al. (2013) studied a consanguineous Chinese family in which the
21-year-old proband was referred for cardiac evaluation after the sudden
cardiac death of his 23-year-old brother, who had been diagnosed with
CMH but was not offered an implantable cardioverter-defibrillator due to
the lack of clinical symptoms. The proband had a 2-year history of mild
chest pain after intense physical exertion, and diffuse repolarization
changes with inverted T waves on ECG. Echocardiography showed mid to
distal interventricular septal hypertrophy, and cardiac magnetic
resonance imaging (CMR) revealed hypertrophy of the mid to distal
interventricular septum and the inferior ventricular wall. The proband's
younger brother, who was asymptomatic, had similar findings on ECG and
echocardiography, with isolated hypertrophic septum and inferior
ventricular wall on CMR. Both brothers had preserved cardiac function
with left ventricular ejection fractions of 66% and 71%, respectively,
normal atrial and ventricular chamber dimensions, no left ventricular
outflow tract obstruction at rest or after exercise, and negative late
gadolinium enhancement.

MAPPING

Carrier et al. (1993) found evidence of a locus on chromosome 11
responsible for familial hypertrophic cardiomyopathy. In a French
pedigree in which the disease was not linked to the MYH7 gene (160760),
they found linkage to several microsatellite (CA)n repeats located on
chromosome 11. They concluded that the gene could be localized to a
17-cM region in 11p13-q13. Kullmann et al. (1993) reported the case of a
patient with Holt-Oram syndrome (142900) who had atrial septal defect
and developed hypertrophic cardiomyopathy during the first year of life.
A reciprocal translocation was found in this patient between 1p13 and
11q13.

Ko et al. (1996) reported results of linkage analysis in a Chinese
family with apical hypertrophic cardiomyopathy. Apical hypertrophic
cardiomyopathy (Japanese type) appears to be a distinct subtype of
hypertrophic cardiomyopathy. It is characterized by giant negative T
waves on EKG and left ventricular hypertrophy localized to the apex. The
authors reported a maximal lod score of 3.38 at theta = 0.00 between the
disease gene and the microsatellite markers D11S905, D11S987, and
D11S913, which had been mapped to 11p13-q13.

Bonne et al. (1995) concluded that the COX8 gene (123870) that encodes
cytochrome c oxidase subunit XIII is probably not the site of the
mutation in CMH4, since in affected members of a family with chromosome
11-linked CMH, no deletions or insertions were found in COX8 cDNA or
mRNA and no abnormality was detected in the COX8 sequence.

Xin et al. (2007) performed genomewide mapping analysis in 3 Old Order
Amish infants from 3 different consanguineous families with severe
neonatal hypertrophic cardiomyopathy and identified a 4.6-Mb block of
homozygosity on chromosome 11p11.2-p11.12, encompassing the MYBPC3 gene
(600958).

MOLECULAR GENETICS

Both Watkins et al. (1995) and Bonne et al. (1995) demonstrated
mutations in the MYBPC gene that cause CMH4 (600958.0001, 600958.0002,
600958.0003).

Niimura et al. (1998) identified 12 novel mutations in the MYBPC3 gene
in probands from 16 families with CMH. The clinical expression of these
mutations was similar to that observed for other genetic causes of
hypertrophic cardiomyopathy, but the age at onset of the disease
differed markedly. Only 58% of adults under the age of 50 years who had
a mutation in the MYBPC3 gene (68 of 117 patients) had cardiac
hypertrophy; disease penetrance remained incomplete through the age of
60 years. Survival was generally better than that observed among
patients with hypertrophic cardiomyopathy caused by mutations in other
genes for sarcomere proteins. Most deaths due to cardiac causes in these
families occurred suddenly. Niimura et al. (1998) pointed out that
delayed expression of cardiac hypertrophy and a favorable clinical
course may hinder recognition of the heritable nature of mutations in
the MYBPC3 gene. Clinical screening in adult life may be warranted for
members of families characterized by hypertrophic cardiomyopathy.

Hengstenberg et al. (1993, 1994) studied a family with familial
hypertrophic cardiomyopathy in which preliminary haplotype analyses
excluded linkage to previously identified CMH loci at 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.

In a 28-year-old Australian man with CMH who had previously been studied
by Ingles et al. (2005) and found to be compound heterozygous for
missense mutations in the MYBPC3 gene (600958.0021 and 600958.0022),
Chiu et al. (2007) also identified a heterozygous R73Q substitution in
the CALR3 gene (611414). The proband was diagnosed at 18 years of age
and had severe asymmetric septal hypertrophy on echocardiography (ECG).
His father and 1 brother also had CMH, but declined to participate in
the study. Chiu et al. (2007) suggested that calreticulin may be
involved in both disease pathogenesis and modification.

Lekanne Deprez et al. (2006) reported 2 unrelated Dutch infants with
severe hypertrophic cardiomyopathy in whom they identified compound
heterozygosity for truncating mutations in the MYBPC3 gene (see, e.g.,
600958.0023). The infants died at 5 and 6 weeks of age. The
nonconsanguineous asymptomatic parents were heterozygous carriers of 1
of the mutations in each case; 1 of the fathers was found to have mild
hypertrophic cardiomyopathy on cardiac MRI.

In 23 Old Order Amish infants with severe neonatal hypertrophic
cardiomyopathy, 20 of whom were from the Geauga County settlement in
Ohio, Xin et al. (2007) identified homozygosity for a splice site
mutation in the MYBPC3 gene (3330+2T-G; 600958.0020). In addition, DNA
analysis of a Mennonite couple with a child who died of CMH revealed
that both parents were heterozygous for the 3330+2T-C mutation. The
authors calculated the heterozygous carrier frequency in the Geauga
County settlement to be approximately 10%. Noting the many reports of
cardiac symptoms, including sudden death, among these probands' parents
and relatives, and the close similarity between this mutation and the
3330+5G-C mutation (600958.0001) previously documented by Watkins et al.
(1995) as the cause of CMH in heterozygous carriers, Xin et al. (2007)
suggested that heterozygotes for the 3330+2T-G mutation may also be at
risk for CMH.

In 250 unrelated patients with CMH, Frank-Hansen et al. (2008) used SSCP
analysis and sequence confirmation of the MYBPC3 gene to determine
whether intronic variation flanking the 3 MYBPC3 microexons is
disease-causing. Functional studies and segregation analysis indicated
that 4 of the 7 mutations they identified are associated with CMH (see,
e.g., 600958.0016 and 600958.0017): all 4 mutations result in premature
termination codons, suggesting that haploinsufficiency is a pathogenic
mechanism of this type of mutation. In 1 family, a second mutation in
the MYBPC3 gene was also identified (V1125M; 600958.0018). None of the
mutations were found in DNA samples from 192 Caucasian controls.

Waldmuller et al. (2003) identified a 25-bp deletion in intron 32 of the
MYBPC3 gene (600958.0019) in 2 CMH families, 1 of which was also known
to carry a mutation in the MYH7 gene (160760). The authors stated that
the relationship to disease was 'not unequivocal' and suggested that the
deletion may represent a modifier polymorphism that may enhance the
phenotypes of mutations responsible for disease. Dhandapany et al.
(2009) analyzed the 25-bp deletion in the MYBPC3 gene in Indian patients
with hypertrophic, dilated, and restrictive cardiomyopathies found an
association with familial cardiomyopathy and an increased risk of heart
failure (overall odds ratio, 6.99; p = 4 x 10(-11)). Analysis of RNA and
protein from endomyocardial biopsies of 2 heterozygous individuals
revealed 2 transcript structures, a normal transcript and a mutated
allele with skipping of the associated exon, but the altered protein was
not detected in tissue samples. Expression of mutant and wildtype
protein in neonatal rat cardiomyocytes demonstrated a highly
disorganized and diffuse pattern of sarcomeric architecture as a result
of aberrant incorporation of the mutant protein. The authors concluded
that the 25-bp MYBPC3 deletion is associated with a lifelong increased
risk of heart failure. Dhandapany et al. (2009) tested 63 world
population samples, comprising 2,085 individuals from 26 countries, for
the 25-bp deletion, and they identified samples heterozygous for the
deletion from Pakistan, Sri Lanka, Indonesia, and Malaysia but not in
other samples. Haplotype analysis determined that the common 25-bp
deletion likely arose approximately 33,000 years ago on the Indian
subcontinent.

Ehlermann et al. (2008) screened the MYBPC3 gene in 87 patients with
hypertrophic cardiomyopathy and 71 patients with CMD and identified
heterozygous mutations in 16 (18.4%) of the CMH patients and in 2 (2.8%)
of the CMD patients. However, in the first CMD family, 3 additional
carriers of the MYBPC3 missense mutation had no certain pathologic
findings, and the authors noted that in the index patient, hypertensive
heart disease could not be ruled out as the cause of his CMD phenotype.
In the second CMD family, the 2 oldest carriers of the splice site
mutation displayed CMD, whereas 4 younger mutation carriers showed CMH;
the authors stated that it was mostly likely that the 2 older patients
suffered from end-stage CMH with progression to a CMD phenotype.
Screening the cohort for variation in 5 additional
cardiomyopathy-associated genes (MYH7, 160760; TNNT2, 191045; TNNI3,
191044; ACTC1, 102540; and TPM1, 191010) revealed no further mutations.
Of a total of 45 affected individuals, from 12 families and 6 sporadic
patients, 23 (51%) suffered an adverse event such as progression to
severe heart failure, transient ischemic attack, stroke, or sudden
death.

Tajsharghi et al. (2010) reported a female infant with fatal
cardiomyopathy and skeletal myopathy who was homozygous for a nonsense
mutation in the MYBPC3 gene (R943X; 600958.0023). Skeletal muscle biopsy
at 2 months of age showed pronounced myopathic changes with numerous
small fibers, which all expressed slow/beta-cardiac myosin heavy chain
protein (MYH7; 160760). Electron microscopy revealed disorganization of
the sarcomeres and partial depletion of thick filaments in the small
fibers; immunohistochemical staining showed the presence of cardiac
MYBPC in the small abnormal fibers. RT-PCR and sequencing demonstrated
the R943X mutation in transcripts of skeletal muscle. Tajsharghi et al.
(2010) noted that cardiac MYBPC is not normally expressed in skeletal
muscle and stated that the reason for the ectopic expression of cardiac
MYBPC remained unknown. The R943X mutation had previously been reported
in compound heterozygosity with other truncating MYBPC3 mutations in 2
unrelated Dutch infants with fatal hypertrophic cardiomyopathy (Lekanne
Deprez et al., 2006); skeletal myopathy was not mentioned in that
report.

In a 21-year-old man from a consanguineous Chinese family with
hypertrophic cardiomyopathy, Wang et al. (2013) screened 26 CMH-related
genes and identified a homozygous missense mutation in the MYBPC3 gene
(G490V; 600958.0029). His affected younger brother was also homozygous
for the mutation; 6 other relatives, including their unaffected parents,
were heterozygous for the mutation. None of the heterozygous carriers
had any of the typical clinical manifestations of CMH, including the 2
oldest carriers at ages 62 years and 71 years, and none showed
abnormalities on electrocardiography or left ventricular hypertrophy on
echocardiography. CMR of 3 heterozygous individuals showed no structural
abnormalities or cardiac fibrosis. Family members who did not carry the
mutation all had normal electrocardiograms (ECGs) and echocardiograms
except for the maternal grandfather, who had a more than 20-year history
of uncontrolled hypertension and showed concentric hypertrophy on
echocardiography without abnormal T or Q waves or arrhythmia on ECG.

ANIMAL MODEL

Meurs et al. (2005) identified a reduction in Mybpc3 protein in
myocardium from Maine Coon cats with hypertrophic cardiomyopathy in
comparison to control cats (P less than 0.001). In affected cats, the
authors identified a G-C transversion in exon 3 of the feline Mybpc3
gene, resulting in an ala31-to-pro (A31P) substitution in the linker
region between the C0 and C1 domains. The mutation was predicted to
alter protein conformation and result in sarcomeric disorganization.
Affected cats had some variability of phenotype from mildly affected to
severe hypertrophy. Some cats developed congestive heart failure, and
others died suddenly.

Pohlmann et al. (2007) found that cardiac myocytes from 6-week-old
Mybpc3-null mice exhibited mild hypertrophy that became more pronounced
by 30 weeks of age. Isolated Mybpc3-null myocytes showed markedly lower
diastolic sarcomere length without change in diastolic Ca(2+). This
reduced sarcomere length was partially abolished by inhibition of
actin-myosin ATPase, indicating residual actin-myosin interaction in
diastole. Mybpc3-null myocytes started to contract at lower Ca(2+)
concentration, and both sarcomere shortening and Ca(2+) transients were
prolonged in Mybpc3-null cells. Isolated Mybpc3-null left atria
exhibited a marked increase in sensitivity to external Ca(2+) and, in
contrast to wildtype, continued to develop twitch force at low
micromolar Ca(2+) concentration. Pohlmann et al. (2007) concluded that
MYBPC3 functions as a restraint on myosin-actin interaction at low
Ca(2+) concentrations and short sarcomere length to allow complete
relaxation during diastole.

*FIELD* RF
1. Bonne, G.; Carrier, L.; Bercovici, J.; Cruaud, C.; Richard, P.;
Hainque, B.; Gautel, M.; Labeit, S.; James, M.; Beckmann, J.; Weissenbach,
J.; Vosberg, H.-P.; Fiszman, M.; Komajda, M.; Schwartz, K.: Cardiac
myosin binding protein-C gene splice acceptor site mutation is associated
with familial hypertrophic cardiomyopathy. Nature Genet. 11: 438-440,
1995.

2. Bonne, G.; Carrier, L.; Schwartz, K.; Komajda, M.: The COX8 gene
is not the disease gene of the CMH4 locus in familial hypertrophic
cardiomyopathy.(Letter) J. Med. Genet. 32: 670-671, 1995.

3. Carrier, L.; Hengstenberg, C.; Beckmann, J. S.; Guicheney, P.;
Dufour, C.; Bercovici, J.; Dausse, E.; Berebbi-Bertrand, I.; Wisnewsky,
C.; Pulvenis, D.; Fetler, L.; Vignal, A.; Weissenbach, J.; Hillaire,
D.; Feingold, J.; Bouhour, J.-B.; Hagege, A.; Desnos, M.; Isnard,
R.; Dubourg, O.; Komajda, M.; Schwartz, K.: Mapping of a novel gene
for familial hypertrophic cardiomyopathy to chromosome 11. Nature
Genet. 4: 311-313, 1993.

4. Chiu, C.; Tebo, M.; Ingles, J.; Yeates, L.; Arthur, J. W.; Lind,
J. M.; Semsarian, C.: Genetic screening of calcium regulation genes
in familial hypertrophic cardiomyopathy. J. Molec. Cell. Cardiol. 43:
337-343, 2007.

5. Dhandapany, P. S.; Sadayappan, S.; Xue, Y.; Powell, G. T.; Rani,
D. S.; Nallari, P.; Rai, T. S.; Khullar, M.; Soares, P.; Bahl, A.;
Tharkan, J. M.; Vaideeswar, P.; and 13 others: A common MYBPC3
(cardiac myosin binding protein C) variant associated with cardiomyopathies
in South Asia. Nature Genet. 41: 187-191, 2009.

6. Ehlermann, P.; Weichenhan, D.; Zehelein, J.; Steen, H.; Pribe,
R.; Zeller, R.; Lehrke, S.; Zugck, C.; Ivandic, B. T.; Katus, H. A.
: Adverse events in families with hypertrophic or dilated cardiomyopathy
and mutations in the MYBPC3 gene. BMC Med. Genet. 9: 95, 2008. Note:
Electronic Article.

7. Frank-Hansen, R.; Page, S. P.; Syrris, P.; McKenna, W. J.; Christiansen,
M.; Andersen, P. S.: Micro-exons of the cardiac myosin binding protein
C gene: flanking introns contain a disproportionately large number
of hypertrophic cardiomyopathy mutations. Europ. J. Hum. Genet. 16:
1062-1069, 2008.

8. Hengstenberg, C.; Charron, P.; Beckmann, J. S.; Weissenbach, J.;
Isnard, R.; Komajda, M.; Schwartz, K.: Evidence for the existence
of a fifth gene causing familial hypertrophic cardiomyopathy. (Abstract) Am.
J. Hum. Genet. 53 (suppl.): A1013 only, 1993.

9. Hengstenberg, C.; Charron, P.; Isnard, R.; Beckmann, J. S.; Fetler,
L.; Desnos, M.; Hagege, A.; Bouhour, J. B.; Souriant, G.; Dubourg,
O.; Schwartz, K.; Komajda, M.: Mise en evidence d'un cinquieme locus
implique dans les cardiomyopathies hypertrophiques familiales. Arch.
Mal. Coeur. 87: 1655-1662, 1994.

10. Ingles, J.; Doolan, A.; Chiu, C.; Seidman, J.; Seidman, C.; Semsarian,
C.: Compound and double mutations in patients with hypertrophic cardiomyopathy:
implications for genetic testing and counselling. J. Med. Genet. 42:
e59, 2005. Note: Electronic Article.

11. Kimura, A.; Harada, H.; Park, J.-E.; Nishi, H.; Satoh, M.; Takahashi,
M.; Hiroi, S.; Sasaoka, T.; Ohbuchi, N.; Nakamura, T.; Koyanagi, T.;
Hwang, T.-H.; Choo, J.; Chung, K.-S.; Hasegawa, A.; Nagai, R.; Okazaki,
O.; Nakamura, H.; Matsuzaki, M.; Sakamoto, T.; Toshima, H.; Koga,
Y.; Imaizumi, T.; Sasazuki, T.: Mutations in the cardiac troponin
I gene associated with hypertrophic cardiomyopathy. Nature Genet. 16:
379-382, 1997.

12. Ko, Y.-L.; Chen, J.-J.; Tang, T.-K.; Teng, M.-S.; Lin, S.-Y.;
Kuan, P.; Wu, C.-W.; Lien, W.-P.; Liew, C.-C.: Mapping the locus
for familial hypertrophic cardiomyopathy to chromosome 11 in a family
with a case of apical hypertrophic cardiomyopathy of the Japanese
type. Hum. Genet. 97: 457-461, 1996.

13. Kullmann, F.; Koch, R.; Feichtinger, W.; Giesen, H.; Schmid, M.;
Grimm, T.: Holt-Oram syndrom in kombination mit reziproker translokation,
lungenhypoplasie und kardiomyopathie. Klin. Padiat. 205: 185-189,
1993.

14. Lekanne Deprez, R. H.; Muurling-Vlietman, J. J.; Hruda, J.; Baars,
M. J. H.; Wijnaendts, L. C. D.; Stolte-Dijkstra, I.; Alders, M.; van
Hagen, J. M.: Two cases of severe neonatal hypertrophic cardiomyopathy
caused by compound heterozygous mutations in the MYBPC3 gene. (Letter) J.
Med. Genet. 43: 829-832, 2006.

15. Meurs, K. M.; Sanchez, X.; David, R. M.; Bowles, N. E.; Towbin,
J. A.; Reiser, P. J.; Kittleson, J. A.; Munro, M. J.; Dryburgh, K.;
MacDonald, K. A.; Kittleson, M. D.: A cardiac myosin binding protein
C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy. Hum.
Molec. Genet. 14: 3587-3593, 2005.

16. Niimura, H.; Bachinski, L. L.; Sangwatanaroj, S.; Watkins, H.;
Chudley, A. E.; McKenna, W.; Kristinsson, A.; Roberts, R.; Sole, M.;
Maron, B. J.; Seidman, J. G.; Seidman, C. E.: Mutations in the gene
for cardiac myosin-binding protein C and late-onset familial hypertrophic
cardiomyopathy. New Eng. J. Med. 338: 1248-1257, 1998.

17. Pohlmann, L.; Kroger, I.; Vignier, N.; Schlossarek, S.; Kramer,
E.; Coirault, C.; Sultan, K. R.; El-Armouche, A.; Winegrad, S.; Eschenhagen,
T.; Carrier, L.: Cardiac myosin-binding protein C is required for
complete relaxation in intact myocytes. Circ. Res. 101: 928-938,
2007.

18. Richard, P.; Isnard, R.; Carrier, L.; Dubourg, O.; Donatien, Y.;
Mathieu, B.; Bonne, G.; Gary, F.; Charron, P.; Hagege, A.; Komajda,
M.; Schwartz, K.; Hainque, B.: Double heterozygosity for mutations
in the beta-myosin heavy chain and in the cardiac myosin binding protein
C genes in a family with hypertrophic cardiomyopathy. J. Med. Genet. 36:
542-545, 1999.

19. Tajsharghi, H.; Leren, T. P.; Abdul-Hussein, S.; Tulinius, M.;
Brunvand, L.; Dahl, H. M.; Oldfors, A.: Unexpected myopathy associated
with a mutation in MYBPC3 and misplacement of the cardiac myosin binding
protein C. J. Med. Genet. 47: 575-577, 2010.

20. Waldmuller, S.; Sakthivel, S.; Saadi, A. V.; Selignow, C.; Rakesh,
P. G.; Golubenko, M.; Joseph, P. K.; Padmakumar, R.; Richard, P.;
Schwartz, K.; Tharakan, J. M.; Rajamanickam, C.; Vosberg, H.-P.:
Novel deletions in MYH7 and MYBPC3 identified in Indian families with
familial hypertrophic cardiomyopathy. J. Molec. Cell. Cardiol. 35:
623-636, 2003.

21. Wang, Y.; Wang, Z.; Yang, Q.; Zou, Y.; Zhang, H.; Yan, C.; Feng,
X.; Chen, Y.; Zhang, Y.; Wang, J.; Zhou, X.; Ahmad, F.; Hui, R.; Song,
L.: Autosomal recessive transmission of MYBPC3 mutation results in
malignant phenotype of hypertrophic cardiomyopathy. PLoS One 6:
e67087, 2013. Note: Electronic Article.

22. Watkins, H.; Conner, D.; Thierfelder, L.; Jarcho, J. A.; MacRae,
C.; McKenna, W. J.; Maron, B. J.; Seidman, J. G.; Seidman, C. E.:
Mutations in the cardiac myosin binding protein-C gene on chromosome
11 cause familial hypertrophic cardiomyopathy. Nature Genet. 11:
434-437, 1995.

23. Xin, B.; Puffenberger, E.; Tumbush, J.; Bockoven, J. R.; Wang,
H.: Homozygosity for a novel splice site mutation in the cardiac
myosin-binding protein C gene causes severe neonatal hypertrophic
cardiomyopathy. Am. J. Med. Genet. 143A: 2662-2667, 2007.

*FIELD* CS

Cardiac:
Hypertrophic cardiomyopathy

Inheritance:
Autosomal dominant (11p13-q13);
other forms at loci on chromosomes 1, 14, 15 and at least one other
locus

*FIELD* CN
Marla J. F. O'Neill - updated: 9/3/2013
Marla J. F. O'Neill - updated: 9/5/2012
Marla J. F. O'Neill - updated: 4/7/2011
Marla J. F. O'Neill - updated: 3/25/2010
Marla J. F. O'Neill - updated: 8/5/2009
George E. Tiller - updated: 5/13/2009
Marla J. F. O'Neill - updated: 2/20/2009
Marla J. F. O'Neill - updated: 2/2/2009
Marla J. F. O'Neill - updated: 1/12/2007
Carol A. Bocchini - updated: 8/12/2005
Victor A. McKusick - updated: 5/8/1998
Moyra Smith - updated: 3/13/1996

*FIELD* CD
Victor A. McKusick: 5/21/1993

*FIELD* ED
carol: 10/15/2013
carol: 9/4/2013
carol: 9/3/2013
carol: 9/6/2012
terry: 9/5/2012
wwang: 4/8/2011
terry: 4/7/2011
carol: 3/25/2010
carol: 3/24/2010
wwang: 9/1/2009
terry: 8/5/2009
wwang: 5/13/2009
wwang: 2/23/2009
terry: 2/20/2009
wwang: 2/10/2009
terry: 2/2/2009
carol: 1/17/2007
terry: 1/12/2007
carol: 8/12/2005
carol: 5/11/1998
terry: 5/8/1998
mark: 3/21/1996
mark: 3/13/1996
terry: 3/13/1996
mark: 3/13/1996
mark: 12/13/1995
terry: 12/5/1995
terry: 12/4/1995
mark: 9/22/1995
mimadm: 6/25/1994
carol: 9/23/1993
carol: 5/21/1993

MIM 600958
*RECORD*
*FIELD* NO
600958
*FIELD* TI
*600958 MYOSIN-BINDING PROTEIN C, CARDIAC; MYBPC3
*FIELD* TX

DESCRIPTION

Cardiac myosin-binding protein C (MYBPC3) is arrayed transversely in
read moresarcomere A-bands and binds myosin heavy chain (see 160710) in thick
filaments and titin (188840) in elastic filaments. Phosphorylation of
this protein appears to modulate contraction.

GENE STRUCTURE

Carrier et al. (1997) reported that the MYBPC3 gene spans more than 21
kb and contains 35 exons. Two exons are unusually small, 3 bp each.

Klaassen (2013) noted that the MYBPC3 gene contains a noncoding exon 1.
Some authors (e.g., Probst et al., 2011) have used this noncoding exon
in the numbering of the exons in the gene.

GENE FUNCTION

Using single-particle fluorescence imaging techniques, transgenic
protein expression, proteomics, and modeling, Previs et al. (2012) found
that cMyBP-C slows actomyosin motion generation in native cardiac thick
filaments. This mechanical effect was localized to where cMyBP-C resides
within the thick filament (i.e., the C-zones) and was modulated by
phosphorylation and site-specific proteolytic degradation. Previs et al.
(2012) concluded that their results provided molecular insight into why
cMyBP-C should be considered a member of a tripartite complex with actin
and myosin that allows fine tuning of cardiac muscle contraction.

MAPPING

Gautel et al. (1995) mapped the MYBPC3 gene to 11p11.2 by fluorescence
in situ hybridization and proposed it as a candidate for the site of the
mutation in familial hypertrophic cardiomyopathy-4 (CMH4; 115197), which
maps to the same region.

MOLECULAR GENETICS

Watkins et al. (1995) found that the MYBPC3 gene was linked to CMH4 and
demonstrated a splice donor mutation (600958.0001) in 1 family with
familial hypertrophic cardiomyopathy and a duplication mutation
(600958.0002) in a second. Both mutations were predicted to disrupt the
high-affinity, C-terminal myosin-binding domain of cardiac MyBP-C.
Again, findings demonstrated that as in the case of the 3 forms that had
been defined in molecular terms previously, familial hypertrophic
cardiomyopathy is a disease of the sarcomere.

In 2 unrelated French families with familial hypertrophic cardiomyopathy
of the CMH4 type (as indicated by linkage), Bonne et al. (1995) found a
mutation in a splice acceptor site of the MYBPC3 gene which caused
skipping of the associated exon and was predicted to produce a truncated
gene product. The 2 families shared a common haplotype in a region of 2
cM around the MYBPC gene, suggesting that they may be distantly related.

Carrier et al. (1997) found 6 novel mutations in the CYBPC3 gene that
were associated with familial hypertrophic cardiomyopathy in 7 unrelated
French families. Four of these mutations were predicted to produce
truncated cardiac myosin-binding protein C polypeptides (e.g.,
600958.0007). The 2 others produced aberrant proteins, 1 truncated
(600985.0005) and 1 mutated (600958.0006).

Mutations in the gene for cardiac myosin-binding protein C account for
approximately 15% of cases of familial hypertrophic cardiomyopathy.
Niimura et al. (1998) studied the spectrum of disease-causing mutations
and the associated clinical features of these gene defects. Among 16
families studied, 12 novel mutations were identified: 4 missense
mutations and 8 defects (insertions, deletions, and splice mutations)
predicted to truncate cardiac myosin-binding protein C. The clinical
expression of either missense or truncation mutations was similar to
that observed for other genetic causes of hypertrophic cardiomyopathy,
but the age at onset of the disease differed markedly. Only 58% of
adults under the age of 50 years who had a mutation in the MYBPC3 gene
(68 of 117 patients) had cardiac hypertrophy; disease penetrance
remained incomplete through the age of 60 years. Survival was generally
better than that observed among patients with hypertrophic
cardiomyopathy caused by mutations in other genes for sarcomere
proteins. Most deaths due to cardiac causes in these families occurred
suddenly.

In 46 young patients with dilated cardiomyopathy (CMD1MM; 615396),
Daehmlow et al. (2002) performed mutation screening of 4 sarcomeric
protein genes. They identified 2 mutations in the MYH7 gene
(160760.0026-160760.0027) and 1 mutation in the MYBPC3 gene
(asn948-to-thr; 600958.0013). Daehmlow et al. (2002) noted that they
could not confirm the disease-causing nature of these variants because
family members for the calculation of 2-point lod scores could not be
obtained for further investigation.

Konno et al. (2003) analyzed the MYBPC3 gene in 250 unrelated probands
with CMH and 90 with CMD and identified a missense mutation (R820Q;
600958.0015) in 16 individuals from families with CMH and in a
71-year-old man with a clinical diagnosis of CMD. The authors suggested
that the patient diagnosed with CMD may actually have been in the
'burnt-out' phase of hypertrophic cardiomyopathy.

Lekanne Deprez et al. (2006) reported 2 unrelated Dutch infants with
severe hypertrophic cardiomyopathy in whom they identified compound
heterozygosity for truncating mutations in the MYBPC3 gene (see, e.g.,
600958.0023). The infants died at 5 and 6 weeks of age. The
nonconsanguineous asymptomatic parents were heterozygous carriers of 1
of the mutations in each case; 1 of the fathers was found to have mild
hypertrophic cardiomyopathy on cardiac MRI.

Wang et al. (2005) observed that patients with hypertrophic
cardiomyopathy carrying identical mutations can have different left
ventricular thicknesses, suggesting the presence of modifying variants.
They genotyped 226 patients with CMH and 226 age- and sex-matched
controls for 3 MYBPC3 polymorphisms, and found that the GG genotype at
nucleotide 18443 in exon 30 was associated with a significantly thicker
left ventricular wall in patients, compared to the AA and AG genotypes
(p less than 0.001). GG was not associated with left ventricular wall
thickness in normal controls, and there was no difference in genotype
distribution between patients and controls. Wang et al. (2005) concluded
that the MYBPC3 polymorphism is a modifier for expression of cardiac
hypertrophy in patients with CMH.

In a 12-month-old girl with restrictive cardiomyopathy (RCM3; 612422),
Peddy et al. (2006) performed direct sequencing of the 8 genes most
commonly implicated in hypertrophic cardiomyopathy and identified a de
novo 3-bp deletion in the TNNT2 gene (191045.0011). The girl also
carried a known MYBPC3 (600958) polymorphism, V896M, which was also
found in her unaffected father; the authors suggested that the V896M
variant may have acted as a modifier, exacerbating the phenotypic
expression of the TNNT2 mutation and causing an unusually early onset of
RMC.

In 23 Old Order Amish infants with severe neonatal hypertrophic
cardiomyopathy, Xin et al. (2007) identified homozygosity for a splice
site mutation in the MYBPC3 gene (3330+2T-G; 600958.0020). Noting the
many reports of cardiac symptoms, including sudden death, among these
probands' parents and relatives, and the close similarity between this
mutation and the 3330+5G-C mutation (600958.0001) previously documented
by Watkins et al. (1995) as the cause of CMH in heterozygous carriers,
Xin et al. (2007) suggested that heterozygotes for the 3330+2T-G
mutation may also be at risk for CMH.

Frank-Hansen et al. (2008) used SSCP analysis and sequence confirmation
in 250 unrelated patients with CMH to determine whether intronic
variation flanking the 3 microexons in the MYBPC3 gene is
disease-causing. Functional studies and segregation analysis indicated
that 4 of the 7 mutations they identified are associated with CMH (see,
e.g., 600958.0016 and 600958.0017): all 4 mutations result in premature
termination codons, suggesting that haploinsufficiency is a pathogenic
mechanism of this type of mutation. In 1 family, a second mutation in
the MYBPC3 gene was also identified (V1125M; 600958.0018).

Ehlermann et al. (2008) screened the MYBPC3 gene in 87 patients with
hypertrophic cardiomyopathy and 71 patients with CMD and identified
heterozygous mutations in 16 (18.4%) of the CMH patients and in 2 (2.8%)
of the CMD patients. However, in the first CMD family, 3 additional
carriers of the MYBPC3 missense mutation had no certain pathologic
findings, and the authors noted that in the index patient, hypertensive
heart disease could not be ruled out as the cause of his CMD phenotype.
In the second CMD family, the 2 oldest carriers of the splice site
mutation displayed CMD, whereas 4 younger mutation carriers showed CMH;
the authors stated that it was mostly likely that the 2 older patients
suffered from end-stage CMH with progression to a CMD phenotype.
Screening the cohort for variation in 5 additional
cardiomyopathy-associated genes (MYH7, 160760; TNNT2, 191045; TNNI3,
191044; ACTC1, 102540; and TPM1, 191010) revealed no further mutations.
Of a total of 45 affected individuals, from 12 families and 6 sporadic
patients, 23 (51%) suffered an adverse event such as progression to
severe heart failure, transient ischemic attack, stroke, or sudden
death.

Waldmuller et al. (2003) identified a 25-bp deletion in intron 32 of the
MYBPC3 gene (600958.0019) in 2 south Indian families with CMH, 1 of
which was also known to carry a mutation in the MYH7 gene (160760). The
polymorphism was detected in 16 of 229 unrelated healthy Indian
individuals but not in western European individuals, and the authors
considered that it represents a regional polymorphism restricted to
southern India. Waldmuller et al. (2003) stated that the relationship to
disease was 'not unequivocal' and suggested that the deletion may
represent a modifier polymorphism that may enhance the phenotypes of
mutations responsible for disease. Dhandapany et al. (2009) analyzed the
25-bp deletion in the MYBPC3 gene in Indian patients with hypertrophic,
dilated, and restrictive cardiomyopathies and identified an association
with familial cardiomyopathy and an increased risk of heart failure
(overall odds ratio, 6.99; p = 4 x 10(-11)).

After typing 811 genomewide short-tandem repeat markers in 100 members
of a CMH family originally reported by Niimura et al. (1998), 36 of whom
carried the MYBPC3 791insG mutation (600958.0011), Daw et al. (2007)
performed oligogenic simultaneous segregation and linkage analyses using
Markov chain Monte Carlo methods and detected the strongest signals on
chromosomes 10p13 and 17q24, with log of the posterior placement
probability ratio (LOP) scores of 4.86 and 4.17, respectively. The
effect size of the MYBPC3 mutation on left ventricular mass was
significantly decreased when modifier loci were included in the
analysis, suggesting an interaction between the causal mutation and
modifier genes.

In a 28-year-old Australian man who was diagnosed at age 18 years with
severe CMH, Ingles et al. (2005) detected compound heterozygous missense
mutations in the MYBPC3 gene (600958.0021 and 600958.0022). Chiu et al.
(2007) also identified a heterozygous R73Q substitution in the CALR3
gene (611414) in this patient. Chiu et al. (2007) suggested that
calreticulin may be involved in both disease pathogenesis and
modification.

In a female infant with fatal cardiomyopathy who also showed evidence of
skeletal myopathy, Tajsharghi et al. (2010) identified homozygosity for
a nonsense mutation in the MYBPC3 gene (R943X; 600958.0023). Skeletal
muscle biopsy at 2 months of age showed pronounced myopathic changes
with numerous small fibers; immunohistochemical staining showed the
presence of cardiac MYBPC in the small abnormal fibers, and RT-PCR and
sequencing demonstrated the mutation in transcripts of skeletal muscle.
Tajsharghi et al. (2010) noted that cardiac MYBPC is not normally
expressed in skeletal muscle and stated that the reason for the ectopic
expression of cardiac MYBPC remained unknown.

Hershberger et al. (2010) screened 5 cardiomyopathy-associated genes in
312 patients with CMD, who had previously been studied by Hershberger et
al. (2008), and identified 12 MYBPC3 variants in 13 (4.2%) of the
probands, of which 2 were considered to be 'likely' disease-causing
mutations: A833T (600958.0024) and C1264F (600958.0025). The A833T
change was identified in affected individuals from 3 families; haplotype
analysis suggested a founder mutation. Hershberger et al. (2010) noted
that the A833T mutation had previously been identified in a family with
CMH (Morner et al., 2003).

In a cohort of 63 unrelated white patients of western European descent
with left ventricular noncompaction (LVNC10; see 615396), Probst et al.
(2011) analyzed 8 sarcomere genes and identified 5 probands with 4
different heterozygous mutations in the MYBPC3 gene (see, e.g.,
600958.0026-600958.0028). In a 21-year-old man from a consanguineous
Chinese family with hypertrophic cardiomyopathy, Wang et al. (2013)
screened the coding sequence and flanking regions of 26 CMH-related
genes and identified a homozygous missense mutation in the MYBPC3 gene
(G490V; 600958.0029). His affected younger brother was also homozygous
for the mutation; 6 other relatives, including their unaffected parents,
were heterozygous for the mutation. None of the heterozygous carriers
had any of the typical clinical manifestations of CMH, including the 2
oldest carriers at ages 62 years and 71 years, and none showed
abnormalities on electrocardiography or left ventricular hypertrophy on
echocardiography. CMR of 3 heterozygous individuals showed no structural
abnormalities or cardiac fibrosis. Wang et al. (2013) noted that a
different mutation at the same residue, G490R (600958.0026), had
previously been reported to cause disease in heterozygosity; they
proposed that the difference in inheritance pattern might stem from the
fact that G490R produces a more prominent structural change by
substituting a small side chain for a bulky one and changing the
polarity from neutral to basic, whereas G490V keeps the side chain small
and polarity neutral.

GENOTYPE/PHENOTYPE CORRELATIONS

Charron et al. (1998) studied clinical features of 76 individuals
heterozygous for disease-causing mutations in the MYBPC3 gene. Little
phenotypic variation was noted among the 7 MYBPC3 mutations described.
Compared to 52 individuals with familial hypertrophic cardiomyopathy due
to myosin heavy chain gene mutations, prognosis was significantly better
in patients with CMH due to MYBPC3 mutations. In patients with MYBPC3
mutations, the mean age of onset was higher and penetrance below the age
of 30 was lower, leading to a milder phenotype with less hypertrophy and
fewer T-wave abnormalities. No deaths occurred below the age of 40
regardless of the mutation involved. Cause of death was sudden death in
4 of 9 individuals, refractory heart failure in 3 of 9 individuals, and
stroke in 2 of 9 individuals.

To test the hypothesis that some cardiac hypertrophy of the elderly
might be attributable to sarcomere protein gene mutations, Niimura et
al. (2002) conducted a genetic analysis of 31 individuals with
late-onset hypertrophic cardiomyopathy and no other family history. Five
individuals with pathogenic mutations in MYBPC were identified. The mean
age of symptom development in this group was 56 +/- 13.2 with a mean age
at diagnosis of 60.2 +/- 8.9. The reported mutations in the MYBPC3 gene
included missense mutations, truncating mutations, and splice mutations.
The authors highlighted the importance of these findings for counseling
relatives of individuals with elderly-onset hypertrophic cardiomyopathy.

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.

Verweij and Hamel (2002) discussed the moral dilemma when there are
unexpected findings in identifiable stored blood samples collected for
an unrelated study and not carrying consent for other use. The case in
point was that of a woman in a family with triphalangeal
thumb-polysyndactyly syndrome (174500) in which the disorder was mapped
to 7q36 (Tsukurov et al., 1994). The samples were used to study genes
involved in hypertrophic cardiomyopathy, and a mutation in the MYBPC3
gene was found. Verweij and Hamel (2002) discussed the benefits and
harmful consequences of disclosure, including the uncertainty of the
functional significance of the particular mutation.

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). Forty-six different MYBPC3
mutations were identified in 71 (18%) of the patients. Patients with
MYBPC3 mutations did not differ significantly from patients with thick
filament-CMH, thin filament-CMH, or genotype-negative CMH with respect
to age at diagnosis, degree of hypertrophy, incidence of myectomy, or
family history of CMH or sudden death. The 10 patients with multiple
mutations (2.6% of the total cohort) had the most severe disease
presentation.

ANIMAL MODEL

Yang et al. (1998) created transgenic mice in which varying amounts of a
mutated MYBPC gene, lacking the myosin and titin binding domains, were
expressed in the heart. The transgenically encoded, truncated protein
was stable but was not incorporated efficiently into the sarcomere. The
transgenic muscle fibers showed a leftward shift in the calcium-force
curve and their power output was reduced. Additionally, expression of
the mutant protein led to decreased levels of endogenous myosin-binding
protein C, resulting in a striking pattern of sarcomere disorganization
and dysgenesis.

Yang et al. (1999) generated a second series of transgenic mice
containing a mutant MYBPC gene lacking only the myosin binding site. In
contrast to this group's previous mouse model (see Yang et al. (1998)),
expression of mutant protein was reduced in the heterozygote transgenic
mouse myocardium. Immunofluorescence studies demonstrated correct
incorporation of the mutant protein into the sarcomere, but transmission
electron microscopy revealed marked disorganization of sarcomeric
ultrastructure. Gross cardiac morphology in transgenic mice was also
abnormal, with a globular heart and mild thickening of the left
ventricular free wall and papillary muscle. Functional analysis of
skinned papillary fibers demonstrated reductions in unloaded shortening
velocity, maximum shortening velocity, and relative maximal power
output. This mutant polypeptide appeared to behave in a
dominant-negative fashion.

Meurs et al. (2005) identified a reduction in Mybpc3 protein in
myocardium from Maine Coon cats with hypertrophic cardiomyopathy in
comparison to control cats (P less than 0.001). In affected cats, the
authors identified a G-C transversion in exon 3 of the feline Mybpc3
gene, resulting in an ala31-to-pro (A31P) substitution in the linker
region between the C0 and C1 domains. The mutation was predicted to
alter protein conformation and result in sarcomeric disorganization.
Affected cats had some variability of phenotype from mildly affected to
severe hypertrophy. Some cats developed congestive heart failure, and
others died suddenly.

Pohlmann et al. (2007) found that cardiac myocytes from 6-week-old
Mybpc3-null mice exhibited mild hypertrophy that became more pronounced
by 30 weeks of age. Isolated Mybpc3-null myocytes showed markedly lower
diastolic sarcomere length without change in diastolic Ca(2+). This
reduced sarcomere length was partially abolished by inhibition of
actin-myosin ATPase, indicating residual actin-myosin interaction in
diastole. Mybpc3-null myocytes started to contract at lower Ca(2+)
concentration, and both sarcomere shortening and Ca(2+) transients were
prolonged in Mybpc3-null cells. Isolated Mybpc3-null left atria
exhibited a marked increase in sensitivity to external Ca(2+) and, in
contrast to wildtype, continued to develop twitch force at low
micromolar Ca(2+) concentration. Pohlmann et al. (2007) concluded that
MYBPC3 functions as a restraint on myosin-actin interaction at low
Ca(2+) concentrations and short sarcomere length to allow complete
relaxation during diastole.

*FIELD* AV
.0001
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, IVS, G-C, +5

To determine if mutation of the cardiac MYBPC gene caused CMH in
chromosome 11-linked families (115197), Watkins et al. (1995) amplified
lymphocyte RNA by reverse-transcription and nested PCR. An abnormally
short cDNA in one patient was found to be the result of a G-to-C
transversion at position 5 of the 5-prime splice donor sequence GTGAGC
in the following intron. The G-to-C transversion created a new BstEII
site, allowing independent confirmation of the mutation which was
present in all clinically affected members and not present in unaffected
members (except for 2, who carried a disease-associated haplotype).

.0002
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, 18-BP DUP

In a family with chromosome 11-linked familial hypertrophic
cardiomyopathy (115197), Watkins et al. (1995) demonstrated an 18-bp
tandem duplication of nucleotide residues 3774-3791. Sequencing of the
genomic product confirmed the duplication, which occurred in the
penultimate exon of the coding sequence (denoted exon P). The
duplication was demonstrated in all affected members of the family and
also in a presumed nonpenetrant 16-year-old member. It was not present
in the other unaffected family members or in 200 chromosomes from
unrelated, unaffected individuals.

.0003
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, IVS, A-G

In 2 French kindreds with chromosome 11-linked hypertrophic
cardiomyopathy (115197), Bonne et al. (1995) found 2 cDNAs of different
lengths, 336 bp and 196 bp, in affected individuals. Direct sequencing
of the 336 nucleotide product gave 2 different sequences; the normal
cDNA and a cDNA with an 11-bp deletion between nucleotides 1960 and
1970. Sequencing of the 196-bp product gave a cDNA with a 140-bp
deletion between positions 1960 and 2099. Both deletions resulted in a
frameshift followed by a premature stop codon. Studies of genomic DNA
revealed an A-to-G transition at a 3-prime splice acceptor site in
affected individuals. This mutation accounted for both aberrant
transcripts since the 140-bp deletion resulted from skipping the exon
that spans positions 1060 to 2099, while the 11-bp deletion resulted
from the use of a cryptic splice site downstream from the normal splice
site that had been inactivated. The A-to-G transition mutation
introduced a new NlaIV restriction site which was used to screen
affected and unaffected individuals.

.0004
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, IVS, G-A, +1

In a family with hypertrophic cardiomyopathy linked to polymorphic
markers on chromosome 11 (115197), Rottbauer et al. (1997) found a
mutation of a splice donor site of the MYBPC gene. The mutation, a
G-to-A transition at position +1 of the donor splice site of exon N,
caused skipping of the associated exon in mRNA from lymphocytes and
myocardium. The skipping of the exon with a consecutive reading
frameshift led to premature termination of translation and was expected
to produce a truncated cardiac myosin-binding protein-C. Western blot
analysis of endomyocardial biopsies from histologically affected left
ventricular myocardium failed to show the expected truncated protein.
The absence of a mutant protein and of significantly reduced amounts of
wildtype protein in the presence of the mutated mRNA argued against the
'poison protein' and the 'null allele' hypotheses and suggested yet
unknown mechanisms relevant to the genesis of chromosome 11-associated
familial hypertrophic cardiomyopathy.

.0005
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, IVS7, G-A, +5

One of the 6 new mutations associated with CMH (115197) discovered by
Carrier et al. (1997) in 7 unrelated French families was a G-to-A
transition at position +5 in intron 7. The G residue is highly conserved
at this position in the splice donor consensus sequence. The mutation
resulted in skipping of the 49-bp exon 7 and a frameshift. The aberrant
cDNA encoded 258 normal residues, followed by 25 new amino acids and a
premature termination of translation. This was predicted to produce a
large truncated protein, missing approximately 80% of the normal protein
and lacking the motif containing the phosphorylation sites and the titin
(188840) and myosin (160710)-binding sites.

.0006
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, GLU542GLN

The second of the 6 new mutations discovered by Carrier et al. (1997) in
7 unrelated French CMH (115197) families was a G-to-C transversion at
position 1656 in exon 17 of the MYBPC3 gene. This was found in 2
families and produced the missense change glu542gln in the C3 domain. In
addition, the mutation affected the last nucleotide of the exon, which
is part of the consensus splicing site. A common feature in human
exon/intron boundaries is that 80% of exons finish with a guanine; this
proportion is 85% in MYBPC3. As a result exon 17 was skipped. The
aberrant cDNA encoded 486 normal residues, leading to a truncated
protein that lacked about 62%, including the titin (188840) and myosin
(160710)-binding sites.

.0007
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, IVS23, G-A, +1

The third of 6 new mutations discovered by Carrier et al. (1997) in
French CMH (115197) families was a G-to-A transition at position +1 in
the splice donor site of intron 23 that inactivated the splicing site
and produced skipping of the 160-bp exon 23. The mutated cDNA encoded
717 normal residues and then 51 novel amino acids, followed by premature
termination of the translation in the C5 domain. The resulting protein
was predicted to be truncated with a loss of 44%, including the titin
(188840) and myosin (160710)-binding domains.

.0008
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, BRANCH POINT, IVS23, A-G, TGAT-TGGT

The fourth of the 6 novel mutations discovered by Carrier et al. (1997)
in French CMH (115197) families involved a change from TGAT to TGGT in
intron 23. This A-to-G transition inactivated a potential branch point
consensus sequence (URAY). Although 3 potential branch points existed
upstream from the mutation they did not seem to be used, since analysis
of the transcripts in lymphocytes indicated the existence of 2 aberrant
cDNAs. One corresponded to skipping of the 105-bp exon 24 without
frameshift and encoded a polypeptide depleted of 35 amino acids in the
C6 domain. The other cDNA retained the 724-bp intron 23. The mutant cDNA
was associated with a frameshift; it encoded 770 normal residues and
then 100 novel amino acids, followed by a stop codon, and the
corresponding truncated protein was predicted to be missing 40% of its
structure and should not react with either titin (188840) or myosin
(160710).

.0009
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, 5-BP DEL, EX25

The fifth the of 6 novel mutations in the MYBPC3 gene discovered by
Carrier et al. (1997) in French CMH (115197) families was a 5-bp
deletion (-GCGTC) in exon 25. The deletion produced a frameshift; the
aberrant cDNA identified in lymphocytes encoded 845 normal residues and
then 35 novel amino acids, followed by premature stop codon in domain C6
that should produce a truncated protein missing 34% and loosing the
C-terminal region containing both the titin (188840)- and myosin
(160710)-binding sites.

.0010
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, 12-BP DUP/4-BP DEL, EX33

One of the 6 novel mutations in the MYBPC3 gene discovered by Carrier et
al. (1997) in French CMH (115197) families was a 12-bp duplication and a
4-bp deletion in exon 33. This modification introduced a frameshift at
position 3691 that led to 1,220 normal MyBPC residues and then 19 novel
amino acids, followed by a premature stop codon in the last third of the
C10 domain. The predicted truncated protein, lacking 4%, should lose
part of its myosin (160710) binding site.

.0011
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, 1-BP INS, 2405G

In 115 members of 3 families with hypertrophic cardiomyopathy, Niimura
et al. (1998) identified a 1-bp insertion in codon 791 (791insG, or
2405insG) in exon 25 of the MYBPC3 gene. Of mutation-positive
individuals who underwent examination, only 1 of 19 less than 20 years
of age had cardiac hypertrophy, whereas 44 of 72 mutation-positive
individuals 20 years old or older had cardiac hypertrophy.

Moolman et al. (2000) reported a large family with hypertrophic
cardiomyopathy (CMH4; 115197) with a single base insertion (G) in exon
25 of the MYBPC3 gene. This created a 5-prime splice donor site
(AGGTGGG). Moolman et al. (2000) demonstrated that this mutation
resulted in the loss of 40 basepairs at the 3-prime end of exon 25 in
mRNA extracted from affected myocardium. This in turn led to a premature
translation stop and a truncated protein in which the C-terminal binding
sites for myosin heavy chain and titin were lost. This study also
examined the phenotypic consequences of this mutation in 27 carriers
within the same family. Overall, only 15 (56%) showed features of
hypertrophic cardiomyopathy. Age of onset of symptoms varied from 29 to
68, with most individuals developing their first symptoms from the
fourth decade onwards. The Kaplan-Meier survival curve for this group
was similar to that of carriers of the asp175-to-asn tropomyosin-1
mutation (191010.0002) and significantly better than that of carriers of
cardiac troponin T2 (191045) or cardiac beta-myosin heavy chain (160760)
mutations. Twelve mutation carriers were entirely asymptomatic and had
no changes on echocardiography or ECG at the time of the study. This
mutation was therefore considered to have considerably reduced
penetrance and delayed onset.

.0012
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, THR59ALA

In a study of late-onset hypertrophic cardiomyopathy (115197), Niimura
et al. (2002) reported an individual with an A-to-G transition at
nucleotide 206 of the MYBPC3 gene that was predicted to replace the
normal, conserved hydrophilic polar threonine with a hydrophobic
nonpolar alanine at amino acid residue 59 (T59A). The individual had no
family history of hypertrophic cardiomyopathy.

.0013
CARDIOMYOPATHY, DILATED, 1MM
MYBPC3, ASN948THR

In a 40-year-old man diagnosed at the age of 36 years with dilated
cardiomyopathy (CMD1MM; see 615396), Daehmlow et al. (2002) found
heterozygosity for an A-to-C transversion at nucleotide 16575 in exon 27
of the MYBPC3 gene, resulting in an asn948-to-thr (N948T) substitution
at a highly conserved residue. Daehmlow et al. (2002) noted that they
could not confirm the disease-causing nature of this variant because
family members for the calculation of 2-point lod scores could not be
obtained for further investigation.

.0014
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, GLU1096TER

In a family with hypertrophic cardiomyopathy (115197) previously
reported by Hengstenberg et al. (1993, 1994), Richard et al. (1999)
found that of 8 affected members, 2 had a G-to-T mutation at codon 1096
of the MYBPC3 gene, leading to a TAA termination codon (E1096X); 4 had a
G-to-A transition in exon 15 of the MYH7 gene (160760.0033) and 2 were
doubly heterozygous for the 2 mutations. The E1096X mutation was
predicted to produce a truncated protein without the C-terminal domain,
which binds to titin and myosin.

.0015
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, ARG820GLN

In 16 affected members of 7 families with hypertrophic cardiomyopathy
(115197) and in a 71-year-old man with a clinical diagnosis of dilated
cardiomyopathy (see 115200), Konno et al. (2003) identified
heterozygosity for a G-A transition in exon 25 of the MYBPC3 gene,
resulting in an arg820-to-gln (R820Q) substitution at a conserved
residue. The mutation was not found in 6 clinically unaffected family
members or in 100 controls. The authors suggested that the elderly man
with a clinical diagnosis of CMD was in the 'burnt-out' phase of
hypertrophic cardiomyopathy; cardiac biopsy showed mild fibrosis, no
myocardial hypertrophy, and no myofibrillar disarray. In a follow-up
study of this patient, Shimizu et al. (2005) stated that it was unclear
whether this patient had 'burnt-out' CMH or had had CMD from the outset.

.0016
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, IVS13AS, G-A, -19

In a 32-year-old man of Greek Cypriot descent who had mild cardiac
hypertrophy (CMH4; 115197) and severe left ventricular outflow tract
obstruction treated with left ventricular myectomy, Frank-Hansen et al.
(2008) identified heterozygosity for a splice site transition
(1224-19G-A) near exon 14 of the MYBPC3 gene. RT-PCR analysis of
peripheral blood leukocytes from the patient revealed that the mutation
produced a de novo acceptor splice site and extended the transcript by
17 nucleotides, thus introducing a frameshift and premature termination
codon in exon 15. The mutation was also identified in 2 other unrelated
probands, 1 Indian and 1 British, with mild hypertrophic cardiomyopathy,
and was not found in DNA samples from 192 Caucasian controls.

.0017
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, IVS9, G-C, -1

In a 57-year-old woman with hypertrophic cardiomyopathy (CMH4; 115197)
involving asymmetric septal hypertrophy with systolic anterior motion,
Frank-Hansen et al. (2008) identified compound heterozygosity for a
splice site mutation (906-1G-C) near exon 10 of the MYBPC3 gene and a
val1125-to-met (V1125M) substitution (600958.0018). RT-PCR analysis of
peripheral blood leukocytes from the patient revealed that the 906-1G-C
transition disrupted the existing 3-prime splice site and activated a
neighboring cryptic 3-prime splice site positioned 2 nucleotides
downstream, resulting in exclusion of the first 2 bases of exon 10,
producing a frameshift and premature termination codon in exon 12. The
proband's 64-year-old older sister also carried both mutations, and had
asymmetrical septal hypertrophy, right bundle branch block, and left
atrium dilatation; her son, the proband's nephew, who had a borderline
diagnosis of cardiac hypertrophy, was found to carry only the V1125M
mutation. The proband's mother and son carried only the 906-1G-C
mutation; her 94-year-old mother had a borderline diagnosis with T wave
inversion in the lateral leads and abnormal Q waves in the high lateral
leads on electrocardiogram, but a normal echocardiogram; the 26-year-old
son was unaffected, with normal electrocardiogram and echocardiogram.
Neither mutation was found in DNA samples from 192 Caucasian controls.

.0018
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, VAL1125MET

See 600958.0017 and Frank-Hansen et al. (2008).

.0019
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4, SUSCEPTIBILITY TO
MYBPC3, IVS32, 25-BP DEL

In a south Indian family with mild hypertrophic cardiomyopathy (CMH4;
115197) and another south Indian family with CMH1 (192600) due to
mutation in the MYH7 gene (160760), Waldmuller et al. (2003) identified
a 25-bp deletion (nt21348-21372) in intron 32 of the MYBPC3 gene,
predicted to cause loss of the splicing branch point. Exon 33 sequences
in processed mRNA were significantly reduced in COS-1 cells and neonatal
rat cardiomyocytes transfected with the deletion but not in cells
transfected with wildtype; however, residual normal splicing was
observed. Noting that the 25-bp deletion was observed in 16 of 229
unrelated Indian controls from Kerala and Tamil Nadu but not in 270
Caucasians from Russia and western Europe, Waldmuller et al. (2003)
suggested that the deletion may represent a regional polymorphism of
southern India and may be a modifier enhancing the phenotypes of
mutations responsible for disease.

Dhandapany et al. (2009) analyzed the 25-bp MYBPC3 deletion in 354
Indian patients with cardiomyopathy and 238 healthy controls and found
an association with cardiomyopathy (odds ratio, 5.3; p = 2 x 10(-6)).
The findings were replicated in 446 cases and 466 controls from 6
independent Indian cohorts (combined odds ratio, 6.99; p = 4 x 10(-11)).
Analysis of RNA and protein from endomyocardial biopsies of 2
heterozygous individuals revealed 2 transcript structures, a normal
transcript and a mutated allele with skipping of the associated exon,
but the altered protein was not detected in tissue samples. Expression
of mutant and wildtype protein in neonatal rat cardiomyocytes
demonstrated a highly disorganized and diffuse pattern of sarcomeric
architecture as a result of aberrant incorporation of the mutant
protein. Dhandapany et al. (2009) concluded that the 25-bp MYBPC3
deletion is associated with a lifelong increased risk of heart failure.

Dhandapany et al. (2009) tested 63 world population samples, comprising
2,085 individuals from 26 countries, for the 25-bp deletion, and they
identified samples heterozygous for the deletion from Pakistan, Sri
Lanka, Indonesia, and Malaysia but not in other samples. Haplotype
analysis determined that the common 25-bp deletion likely arose
approximately 33,000 years ago on the Indian subcontinent.

.0020
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, IVS30DS, T-G, +2

In 23 Old Order Amish infants with severe neonatal hypertrophic
cardiomyopathy (CMH4; 115197), 20 of whom were from the Geauga County
settlement in Ohio, Xin et al. (2007) identified homozygosity for a
3330+2T-G transition in the splice donor site of intron 30 of the MYBPC3
gene, resulting in skipping of the 140-bp exon 30 and causing a
frameshift and premature termination in exon 31. The mutation was found
in heterozygosity in parents. Heterozygous carrier frequency of this
mutation was calculated at 10% in the Geauga County settlement of Ohio.
DNA analysis of a Mennonite couple with a child who had died from CMH
revealed heterozygosity for the same 3330+2T-G mutation.

.0021
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, ARG745GLY

In a 28-year-old Australian man with familial hypertrophic
cardiomyopathy (CMH4; 115197), Ingles et al. (2005) identified compound
heterozygosity for an arg745-to-gly (R745G) substitution in exon 24 of
the MYBPC3 gene and a pro873-to-his (P873H; 600958.0022) substitution in
exon 27 of the MYBPC3 gene. The proband was diagnosed at 18 years of age
and had severe asymmetric septal hypertrophy on echocardiography and
received an implantable cardioverter-defibrillator (ICD). The proband's
13-year-old son also had severe hypertrophy requiring myectomy on 2
occasions and received an ICD. The proband's father and a brother also
had CMH, but declined to participate in the study. Chiu et al. (2007)
also identified heterozygosity for an R73Q substitution in the CALR3
gene (611414) in this patient and suggested that calreticulin may be
involved in both disease pathogenesis and modification.

.0022
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, PRO873HIS

See 600958.0021 and Ingles et al. (2005).

.0023
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, ARG943TER

In a female infant with fatal cardiomyopathy (CMH4; 115197) who also had
evidence of skeletal myopathy, Tajsharghi et al. (2010) identified
homozygosity for a 2827C-T transition, resulting in an arg943-to-ter
(R943X) substitution in the MYBPC3 gene. Skeletal muscle biopsy at 2
months of age showed pronounced myopathic changes with numerous small
fibers, which all expressed slow/beta-cardiac myosin heavy chain protein
(MYH7; 160760). Electron microscopy revealed disorganization of the
sarcomeres and partial depletion of thick filaments in the small fibers;
immunohistochemical staining showed the presence of cardiac MYBPC in the
small abnormal fibers. RT-PCR and sequencing demonstrated the mutation
in transcripts of skeletal muscle. Tajsharghi et al. (2010) noted that
cardiac MYBPC is not normally expressed in skeletal muscle, and stated
that the reason for the ectopic expression of cardiac MYBPC remained
unknown. The R943X mutation had previously been identified in compound
heterozygosity with other truncating MYBPC3 mutations in 2 unrelated
Dutch infants with fatal hypertrophic cardiomyopathy (Lekanne Deprez et
al., 2006); skeletal myopathy was not mentioned in that report.

.0024
CARDIOMYOPATHY, DILATED, 1MM
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4, INCLUDED
MYBPC3, ALA833THR

In 2 affected individuals from a family with dilated cardiomyopathy
(CMD1MM; 615396), Hershberger et al. (2010) identified heterozygosity
for a 17207G-A transition in exon 25 of the MYBPC3 gene (GenBank GENBANK
NM_000256.3), resulting in an ala833-to-thr (A833T) substitution at a
highly conserved residue. The mutation was also identified in 2
unrelated CMD probands, but was not found in 246 controls. Haplotype
sharing near the variant suggested a founder mutation. Hershberger et
al. (2010) noted that the A833T variant had previously been identified
in a family with hypertrophic cardiomyopathy (CMH4; 115197) by Morner et
al. (2003); the proband's brother and father had mild cardiac
hypertrophy.

.0025
CARDIOMYOPATHY, DILATED, 1MM
MYBPC3, CYS1264PHE

In 2 affected individuals from a family with dilated cardiomyopathy
(CMD1MM; 615396), Hershberger et al. (2010) identified heterozygosity
for a 22608G-T transversion in exon 33 of the MYBPC3 gene (GenBank
GENBANK NM_000256.3), resulting in a cys1264-to-phe (C1264F)
substitution at a conserved residue. The mutation was not found in 246
controls.

.0026
CARDIOMYOPATHY, DILATED, 1MM
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4, INCLUDED;;
LEFT VENTRICULAR NONCOMPACTION 10, INCLUDED
MYBPC3, GLY490ARG

In a patient with dilated cardiomyopathy (CMD1MM; 615396), Hershberger
et al. (2010) reported a heterozygous 11969G-A transition in exon 17 of
the MYBPC3 gene (GenBank GENBANK NM_000256.3), resulting in a
gly490-to-arg (G490R) substitution at a highly conserved residue. No
family members were available for segregation analysis. Hershberger et
al. (2010) noted that the MYBPC3 G490R mutation had previously been
associated with hypertrophic cardiomyopathy (CMH4; 115197) by Van Driest
et al. (2004) and Morita et al. (2008).

In 2 unrelated white probands of western European descent with left
ventricular noncompaction (LVNC10; see 615396), Probst et al. (2011)
identified heterozygosity for a c.1523G-A transition in exon 18 of the
MYBPC3 gene, resulting in the G490R substitution within the third
cardiac-specific Ig-like domain. One proband was a 70-year-old man who
presented with dyspnea; family screening revealed that his asymptomatic
32-year-old son was also affected. The other proband was a 24-year-old
woman who had been evaluated for syncopal episodes. All 3
mutation-positive individuals had noncompacted segments of the left
midventricular inferior and lateral wall on echocardiography.

.0027
LEFT VENTRICULAR NONCOMPACTION 10
MYBPC3, PRO873LEU

In a 37-year-old white man of western European descent with left
ventricular noncompaction (LVNC10; see 615396) who presented with
decompensated congestive heart failure, Probst et al. (2011) identified
heterozygosity for a c.2673C-T transition in exon 27 of the MYBPC3 gene,
resulting in a pro873-to-leu (P873L) substitution within the seventh
cardiac-specific Ig-like domain.

.0028
LEFT VENTRICULAR NONCOMPACTION 10
MYBPC3, 2-BP DEL, 2919CT

In a white woman of western European descent with left ventricular
noncompaction (LVNC10; see 615396), who had nonsustained ventricular
flutter and received an implantable cardioverter-defibrillator, Probst
et al. (2011) identified heterozygosity for a 2-bp deletion
(c.2919_2920delCT) in exon 28 of the MYBPC3 gene, causing a frameshift
predicted to result in a premature termination codon in exon 30
(Pro955ArgfsTer95). The mutation was also detected in her 14-year-old
unaffected daughter.

.0029
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
MYBPC3, GLY490VAL

In 2 brothers from a consanguineous Chinese family with hypertrophic
cardiomyopathy (CMH4; 115197), Wang et al. (2013) identified
homozygosity for a c.1469G-T transversion in exon 17 of the MYBPC3 gene,
resulting in a gly490-to-val (G490V) substitution at a highly conserved
residue. The mutation was present in heterozygosity in their unaffected
parents and 4 other unaffected relatives, none of whom had typical
clinical manifestations of CMH or any abnormalities on
electrocardiography or left ventricular hypertrophy on echocardiography.
The mutation was not found in 376 Chinese controls or in the dbSNP or
1000 Genomes public polymorphism databases. Wang et al. (2013) noted
that a different mutation at the same residue, G490R (600958.0026), had
previously been reported to cause disease in heterozygosity; they
proposed that the difference in inheritance pattern might stem from the
fact that G490R produces a more prominent structural change by
substituting a small side chain for a bulky one and changing the
polarity from neutral to basic, whereas G490V keeps the side chain small
and polarity neutral.

*FIELD* RF
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Hainque, B.; Gautel, M.; Labeit, S.; James, M.; Beckmann, J.; Weissenbach,
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myosin binding protein-C gene splice acceptor site mutation is associated
with familial hypertrophic cardiomyopathy. Nature Genet. 11: 438-440,
1995.

2. Carrier, L.; Bonne, G.; Bahrend, E.; Yu, B.; Richard, P.; Niel,
F.; Hainque, B.; Cruaud, C.; Gary, F.; Labeit, S.; Bouhour, J.-B.;
Dubourg, O.; Desnos, M.; Hagege, A. A.; Trent, R. J.; Komajda, M.;
Fiszman, M.; Schwartz, K.: Organization and sequence of human cardiac
myosin binding protein C gene (MYBPC3) and identification of mutations
predicted to produce truncated proteins in familial hypertrophic cardiomyopathy. Circ.
Res. 80: 427-434, 1997.

3. Charron, P.; Dubourg, O.; Desnos, M.; Bennaceur, M.; Carrier, L.;
Camproux, A.-C.; Isnard, R.; Hagege, A.; Langlard, J. M.; Bonne, G.;
Richard, P.; Hainque, B.; Bouhour, J.-B.; Schwartz, K.; Komajda, M.
: Clinical features and prognostic implications of familial hypertrophic
cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation 97:
2230-2236, 1998.

4. Chiu, C.; Tebo, M.; Ingles, J.; Yeates, L.; Arthur, J. W.; Lind,
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*FIELD* CN
Marla J. F. O'Neill - updated: 9/3/2013
Marla J. F. O'Neill - updated: 5/16/2013
Ada Hamosh - updated: 10/31/2012
Marla J. F. O'Neill - updated: 9/5/2012
Marla J. F. O'Neill - updated: 4/7/2011
Marla J. F. O'Neill - updated: 12/1/2009
Marla J. F. O'Neill - updated: 8/5/2009
George E. Tiller - updated: 4/23/2009
Marla J. F. O'Neill - updated: 2/20/2009
Marla J. F. O'Neill - updated: 2/2/2009
Marla J. F. O'Neill - updated: 11/20/2008
Marla J. F. O'Neill - updated: 11/19/2008
Patricia A. Hartz - updated: 9/23/2008
Marla J. F. O'Neill - updated: 3/7/2008
Marla J. F. O'Neill - updated: 1/12/2007
Carol A. Bocchini - updated: 8/12/2005
Victor A. McKusick - updated: 5/9/2003
Victor A. McKusick - updated: 11/5/2002
Victor A. McKusick - updated: 8/23/2002
Paul Brennan - updated: 3/11/2002
Paul Brennan - updated: 4/11/2000
Victor A. McKusick - updated: 10/19/1998
Paul Brennan - updated: 8/24/1998
Victor A. McKusick - updated: 5/8/1998
Victor A. McKusick - updated: 2/6/1998
Victor A. McKusick - updated: 9/3/1997

*FIELD* CD
Victor A. McKusick: 12/13/1995

*FIELD* ED
carol: 09/11/2013
carol: 9/4/2013
carol: 9/3/2013
tpirozzi: 6/28/2013
carol: 5/16/2013
alopez: 11/5/2012
terry: 10/31/2012
carol: 9/6/2012
terry: 9/5/2012
wwang: 4/8/2011
terry: 4/7/2011
carol: 3/25/2010
wwang: 12/17/2009
terry: 12/1/2009
wwang: 9/1/2009
terry: 8/5/2009
wwang: 5/13/2009
terry: 4/23/2009
wwang: 2/24/2009
wwang: 2/23/2009
terry: 2/20/2009
wwang: 2/10/2009
terry: 2/2/2009
carol: 11/25/2008
terry: 11/20/2008
carol: 11/19/2008
mgross: 9/23/2008
terry: 9/23/2008
carol: 3/7/2008
carol: 1/17/2007
carol: 1/12/2007
terry: 1/12/2007
carol: 2/23/2006
carol: 8/12/2005
carol: 5/9/2003
carol: 11/12/2002
tkritzer: 11/11/2002
terry: 11/5/2002
carol: 8/28/2002
tkritzer: 8/26/2002
terry: 8/23/2002
alopez: 3/11/2002
alopez: 3/8/2002
alopez: 4/11/2000
carol: 10/28/1999
alopez: 2/4/1999
carol: 10/28/1998
terry: 10/19/1998
alopez: 10/15/1998
terry: 10/14/1998
alopez: 8/24/1998
carol: 5/11/1998
terry: 5/8/1998
mark: 2/14/1998
terry: 2/6/1998
terry: 9/8/1997
terry: 9/3/1997
mark: 7/22/1996
mark: 2/19/1996
terry: 2/15/1996
mark: 12/13/1995