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MYBPC3  -  myosin binding protein C, cardiac

Homo sapiens

 
 
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Disease relevance of MYBPC3

 

High impact information on MYBPC3

  • Cardiac MyBP-C is arrayed transversely in sarcomere A-bands and binds myosin heavy chain in thick filaments and titin in elastic filaments [6].
  • Two further FHC loci have been mapped to chromosomes 11p13-q13 (CMH4, ref. 6) and 7q3 (ref. 7). The gene encoding the cardiac isoform of myosin binding protein-C (cardiac MyBP-C) has recently been assigned to chromosome 11p11.2 and proposed as a candidate FHC gene [6].
  • Mutations in the cardiac MyBP-C gene likely cause chromosome 11-linked hypertrophic cardiomyopathy, further supporting the hypothesis that hypertrophic cardiomyopathy results from mutations in genes encoding contractile proteins [7].
  • Recently the human cardiac myosin binding protein-C (MyBP-C) gene was mapped to chromosome 11p11.2 (ref. 8), making this gene a good candidate for the fourth locus, CMH4 (ref. 5). Indeed, MyBP-C is a substantial component of the myofibrils that interacts with several proteins of the thick filament of the sarcomere [7].
  • The gene coding for cardiac MyBP-C has been assigned to the chromosomal location 11p11.2 in humans, and is therefore in a region of physical linkage to subsets of familial hypertrophic cardiomyopathy (FHC) [8].
 

Biological context of MYBPC3

 

Anatomical context of MYBPC3

  • Cardiac myosin binding protein-C (cardiac MyBP-C, cardiac C protein) belongs to a family of proteins implicated in both regulatory and structural functions of striated muscle [8].
  • Both FHC and NM mutant alpha-Tm proteins incorporated normally into the adult muscle sarcomere, similar to normal Tm but exerted differential "dominant-negative" effects on the contractile function of the muscle cell [12].
  • For this characterization, cDNA constructs (rat alpha-MyHC, full-length and truncated human cardiac MyBP-C) were transiently expressed singly or in pairwise combination in COS cells [13].
  • Heterozygous mice bearing a cardiac MHC missense mutation (alphaMHC(403/+) or a cardiac MyBP-C mutation (MyBP-C(t/+)) were constructed as murine FHC models using homologous recombination in embryonic stem cells [14].
 

Associations of MYBPC3 with chemical compounds

  • Triton skinned fibers were tested for maximal isometric force, Ca(2+)/force relation, rigor force, and stiffness in the absence and presence of the recombinant cardiac MyBP-C motif [15].
  • In order to determine the consequences of these mutations on myosin filament organization, we have characterized the effect of a 52-kDa NH2-terminal peptide of human cardiac MyBP-C on the alpha-myosin heavy chain (alpha-MyHC) filament organization [13].
 

Other interactions of MYBPC3

  • These results suggested that MYH7 and MYBPC3 were the predominant genes responsible for HCM, and TNNT2 mutation less proportionally contributed to Chinese HCM [1].
  • 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 [2].
  • The organization of human MYBPC3 and screening for mutations in a panel of French families with FHC were established using polymerase chain reaction, single-strand conformation polymorphism, and sequencing [2].
  • Partial amino acid sequences proved that the 15- and 14-kDa fragments are located at the C termini of cardiac MyBP-C and skeletal MyBP-H, respectively [16].
 

Analytical, diagnostic and therapeutic context of MYBPC3

  • METHODS: Using deoxyribonucleic acid from 389 unrelated patients with HCM, each protein coding exon of MYBPC3 was analyzed for mutations by polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing [4].
  • Site-directed mutagenesis identifies a LAGGGRRIS loop in the N-terminal region of cardiac MyBP-C as the key substrate site for phosphorylation by both PKA and a calmodulin-dependent protein kinase associated with the native protein [8].

References

  1. Mutations profile in Chinese patients with hypertrophic cardiomyopathy. Song, L., Zou, Y., Wang, J., Wang, Z., Zhen, Y., Lou, K., Zhang, Q., Wang, X., Wang, H., Li, J., Hui, R. Clin. Chim. Acta (2005) [Pubmed]
  2. 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. Carrier, L., Bonne, G., Bährend, E., Yu, B., Richard, P., Niel, F., Hainque, B., Cruaud, C., Gary, F., Labeit, S., Bouhour, J.B., Dubourg, O., Desnos, M., Hagège, A.A., Trent, R.J., Komajda, M., Fiszman, M., Schwartz, K. Circ. Res. (1997) [Pubmed]
  3. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. Erdmann, J., Raible, J., Maki-Abadi, J., Hummel, M., Hammann, J., Wollnik, B., Frantz, E., Fleck, E., Hetzer, R., Regitz-Zagrosek, V. J. Am. Coll. Cardiol. (2001) [Pubmed]
  4. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. Van Driest, S.L., Vasile, V.C., Ommen, S.R., Will, M.L., Tajik, A.J., Gersh, B.J., Ackerman, M.J. J. Am. Coll. Cardiol. (2004) [Pubmed]
  5. Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties. Keller, D.I., Coirault, C., Rau, T., Cheav, T., Weyand, M., Amann, K., Lecarpentier, Y., Richard, P., Eschenhagen, T., Carrier, L. J. Mol. Cell. Cardiol. (2004) [Pubmed]
  6. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Watkins, H., Conner, D., Thierfelder, L., Jarcho, J.A., MacRae, C., McKenna, W.J., Maron, B.J., Seidman, J.G., Seidman, C.E. Nat. Genet. (1995) [Pubmed]
  7. Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. 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. Nat. Genet. (1995) [Pubmed]
  8. Phosphorylation switches specific for the cardiac isoform of myosin binding protein-C: a modulator of cardiac contraction? Gautel, M., Zuffardi, O., Freiburg, A., Labeit, S. EMBO J. (1995) [Pubmed]
  9. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Erdmann, J., Daehmlow, S., Wischke, S., Senyuva, M., Werner, U., Raible, J., Tanis, N., Dyachenko, S., Hummel, M., Hetzer, R., Regitz-Zagrosek, V. Clin. Genet. (2003) [Pubmed]
  10. Novel mutations in sarcomeric protein genes in dilated cardiomyopathy. Daehmlow, S., Erdmann, J., Knueppel, T., Gille, C., Froemmel, C., Hummel, M., Hetzer, R., Regitz-Zagrosek, V. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  11. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. 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. Circulation (1998) [Pubmed]
  12. Physiological consequences of tropomyosin mutations associated with cardiac and skeletal myopathies. Michele, D.E., Metzger, J.M. J. Mol. Med. (2000) [Pubmed]
  13. COOH-terminal truncated human cardiac MyBP-C alters myosin filament organization. Sébillon, P., Bonne, G., Flavigny, J., Venin, S., Rouche, A., Fiszman, M., Vikstrom, K., Leinwand, L., Carrier, L., Schwartz, K. C. R. Acad. Sci. III, Sci. Vie (2001) [Pubmed]
  14. Comparison of two murine models of familial hypertrophic cardiomyopathy. McConnell, B.K., Fatkin, D., Semsarian, C., Jones, K.A., Georgakopoulos, D., Maguire, C.T., Healey, M.J., Mudd, J.O., Moskowitz, I.P., Conner, D.A., Giewat, M., Wakimoto, H., Berul, C.I., Schoen, F.J., Kass, D.A., Seidman, C.E., Seidman, J.G. Circ. Res. (2001) [Pubmed]
  15. Myosin binding protein C, a phosphorylation-dependent force regulator in muscle that controls the attachment of myosin heads by its interaction with myosin S2. Kunst, G., Kress, K.R., Gruen, M., Uttenweiler, D., Gautel, M., Fink, R.H. Circ. Res. (2000) [Pubmed]
  16. Isoform-specific interaction of the myosin-binding proteins (MyBPs) with skeletal and cardiac myosin is a property of the C-terminal immunoglobulin domain. Alyonycheva, T.N., Mikawa, T., Reinach, F.C., Fischman, D.A. J. Biol. Chem. (1997) [Pubmed]
 
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