Cardiac myosin binding protein−C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by a ventricular hypertrophy predominantly affecting the inter-ventricular septum and associated with a large extent of myocardial and myofibrillar disarray¹. It is the most common cause of sudden death in the young. In the four disease loci found, three genes have been identified which code for -myosin heavy chain, cardiac tro-ponin T and -tropomyosin²⁻⁷. 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 sarcomere⁹⁻¹³. In two unrelated French families linked to CMH4, we found a mutation in a splice acceptor site of the MyBP-C gene, which causes the skipping of the associated exon and could produce truncated cardiac MyBP-Cs. 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.

1. Maron, B.J. et al. Hypertrophic cardiomyopathy: interrelations of clinical manifestations, pathophysiology, and therapy (first of two parts). New Engl. J. Med. 316, 780−789 (1987). | PubMed  | ISI | ChemPort |
2. Jarcho, J.A. et al. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14ql. New Engl. J. Med. 321, 1372−1378 (1989). | PubMed  | ISI | ChemPort |
3. Watkins, H. et al. A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3. Nature Genet. 3, 333−337 (1993). | PubMed  | ISI | ChemPort |
4. Thierfelder, L. et al. A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2. Proc. natn. Acad. Sci. U.S.A. 90, 6270−6274 (1993). | ChemPort |
5. Carrier, L. et al. Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11. Nature Genet. 4, 311−313 (1993). | PubMed  | ISI | ChemPort |
6. Geisterfer-Lowrance, A.A.T. et al. A molecular basis for familial hypertrophic cardiomyopathy: a cardiac myosin heavy chain gene missense mutation. Cell 62, 999−1006 (1990). | Article | PubMed  | ChemPort |
7. Thierfelder, L. et al. -troppmyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 77, 701−712 (1994). | Article | PubMed  | ISI |
8. Gautel, M., Zuffardi, O., Freiburg, A. & Labeit, S. Phospnorylation switches specific for the cardiac isoform of myosin binding protein C: a modulator of cardiac contraction? EMBO J. 14, 1952−1960 (1995). | PubMed  | ISI | ChemPort |
9. Offer, G., Moos, C. & Starr, R. A new protein of the thick filaments of vertebrate skeletal myofibrils. J. molec. Biol. 74, 653−676 (1973). | PubMed  | ISI | ChemPort |
10. Starr, R. & Offer, G. The interaction of C-protein with heavy meromyosin and subfragment-2. Biochem. J. 171, 813−616 (1978). | PubMed  | ISI | ChemPort |
11. Moos, C., Mason, C.M., Besterman, J.M., Feng, I.N.M. & Dubin, J.H. The binding of skeletal muscle C-protein to F-actin, and its relation to the interaction of actin with myosin subfragment-1. J. molec. Biol. 124, 571−586 (1978). | PubMed  | ISI | ChemPort |
12. Yamamoto, K. & Moos, C., The C-proteins of rabbit red, white, and cardiac muscles. J. biol. Chem. 258, 8395−8401 (1983). | PubMed  | ISI | ChemPort |
13. Fürst, D.O., Vinkemeyer, U. & Weber, K. Mammalian skeletal muscle C-protein: purification from bovine muscle, binding to titin and the characterization of a full-length cDNA. J. Cell Sci. 102, 769−778 (1992). | PubMed  | ISI |
14. James, M.R. et al. A radiation hybrid map of 506 STS markers spanning human chromosome 11. Nature Genet. 8, 70−76 (1994). | Article | PubMed  | ISI | ChemPort |
15. Einheber, S. & Fischman, D. Isolation and characterization of a cDNA clone encoding avian skeletal muscle C-protein: an intracellular member of the immunoglobulin superfamily. Proc. natn. Acad. Sci. U.S.A. 87, 2157−2161 (1990). | ChemPort |
16. Okagaki, T. et al. The major myosin-binding domain of skeletal muscle MyBP-C (C protein) resides in the COOH-terminal, immunoglobulin C2 motif. J. Cell Biol. 123, 619−626 (1993). | Article | PubMed  | ISI | ChemPort |
17. Koretz, J.F., Coluccio, L.M. & Bertasso, A.M. The aggregation characteristics of column-purified rabbit skeletal myosin in the presence and absence of C-protein at pH 7.0. Biophys. J. 37, 433−440 (1982). | PubMed  | ISI | ChemPort |
18. Moos, C. & Feng, I.N.M. Effect of C-Protein on actomyosin ATPase. Biochem. biophys. Acta 632, 141−149 (1980). | Article | PubMed  | ChemPort |
19. Hofmann, P.A., Hartzell, H.C. & Moss, R.L. Alterations in Ca²⁺ sensitive tension due to partial extraction of C-protein from rat skinned cardiac myocytes and rabbit skeletal muscle fibers. J. gen. Physiol. 97, 1141−1163 (1991). | Article | PubMed  | ISI | ChemPort |
20. Granzier, H.L. & Irving, T.C. Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments. Biophys. J. 68, 1027−1044 (1995). | PubMed  | ISI | ChemPort |
21. de Tombe, P. & ter Keurs, H. An internal viscous element limits unloaded velocity of sarcomere shortening in rat myocardium. J. Physiol. 454, 619−642 (1992). | PubMed  | ChemPort |
22. Sweitzer, N. & Moss, R. Determinants of loaded shortening velocity in single cardiac myocytes permeabilized with -hemolysin. Circulation Res. 73, 1150−1162 (1993). | PubMed  | ISI | ChemPort |
23. Hartzell, H.C. & Titus, L. Effects of cholinergic and adrenergic agonists on phosphorylation of a 165,000-dalton myofibrillar protein in intact cardiac muscle. J. biol. Chem. 257, 2111−2120 (1982). | PubMed  | ISI | ChemPort |
24. Schwartz, K. et al. Exclusion of myosin heavy chain and cardiac actin gene involvement in hypertrophic cardiomyopathies of several French families. Circulation Res. 71, 3−8 (1992). | PubMed  | ISI | ChemPort |
25. Weissenbach, J. et al. A second generation linkage map of the human genome. Nature 359, 794−801 (1992). | Article | PubMed  | ISI | ChemPort |
26. Vignal, A. Nonradioactive multiplex procedure for genotyping of microsatellite markers in Methods in Molecular Genetics: Chromosome and Gene Analysis 1 (ed. K.W. Adolph), 211−221 (Academic Press, Oriando, Florida, 1993). | ChemPort |
27. Don, R.H., Cox, P.T., Wainwright, B.J., Baker, K. & Mattick, J.S. Touchdown PCR to circumvent spurious priming during gene amplification. Nucl. Acids Res. 19, 4008 (1991). | PubMed  | ISI | ChemPort |
28. Ott, J. Linkage analysis and family classification under heterogeneity. Ann. hum. Genet. 47, 311−320 (1983). | PubMed  | ISI |
29. Bonne, G., Carrier, L., Komajda, M. & Schwartz, K. The COX8 gene is not the disease gene of the CMH4 locus in Familial Hypertrophic Cardiomyopathy. J. med. Genet. 32, 670−671 (1995). | PubMed  | ISI | ChemPort |

	Top

	Top