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A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3

Nature Genetics volume 3, pages 333–337 (1993)Cite this article

Abstract

Familial hypertrophic cardiomyopathy (FHC) is caused by missense mutations in the β cardiac myosin heavy chain (MHC) gene in less than half of affected individuals. To identify the location of another gene involved in this disorder, a large family with FHC not linked to the β MHC gene was studied. Linkage was detected between the disease in this family and a locus on chromosome 1q3 (maximum multipoint lod score = 8.47). Analyses in other families with FHC not linked to the β MHC gene, revealed linkage to the chromosome 1 locus in two and excluded linkage in six. Thus mutations in at least three genetic loci can cause FHC. Three sarcomeric contractile proteins — troponin I, tropomyosin and actin — are strong candidate FHC genes at the chromosome 1 locus.

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References

  1. Jarcho, J.A. et al. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. New Eng. J. Med. 321, 1372–1378 (1989).

    Article  CAS  PubMed  Google Scholar 

  2. Solomon, S.D. et al. Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease. J. clin. Invest. 86, 993–939 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Maron, B.J., Bonow, R.O., Cannon, R.O., Leon, M.B. & Epstein, S.E. Hypertrophic cardiomyopathy: interrelations of clinical manifestations, pathophysiology, and therapy. New Engl. J. Med. 316, 780–789 (1987).

    Article  CAS  PubMed  Google Scholar 

  4. McKenna, W.J. Hypertrophic cardiomyopathy. In Diseases of the Heart, (eds Julian, D.G., Camm, A.J., Fox, K.M., Hall, R.J.C., Poole-Wilson. P.A.) (Bailliere Tindall, London, 1989).

    Google Scholar 

  5. Watkins, H. et al. Characteristics and prognostic significance of myosin missense mutations in familial hypertrophic cardiomyopathy. New Engl. J. Med. 326, 1108–1114 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Geisterfer-Lowrance, A.A.T. et al. A molecular basis for familial hypertrophic cardiomyopathy: A β cardiac myosin heavy chain gene missense mutation. Cell 62, 999–1006 (1990).

    Article  CAS  PubMed  Google Scholar 

  7. Schwartz, K. et al. Exclusion of cardiac myosin heavy chain and actin gene involvement in hypertrophic cardiomyopathy of several French families. Circ. Res. 71, 3–8 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Kurabayashi, M., Komuro, I., Tsuchimochi, H., Takaku, F. & Yazaki, Y. Molecular cloning and characterization of human atrial and ventricular myosin alkali light chain cDNA clones. J. biol. Chem. 263, 13930–13936 (1988).

    CAS  PubMed  Google Scholar 

  9. Weber, J.L. & May, P.E. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am. J. hum. Genet. 44, 388–396 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Litt, M. & Luty, J.A. A hypervariable microsatellite revealed by in vitro amplification of a dinucleotide repeat within the cardiac muscle actin gene. Am. J. hum. Genet. 44, 397–401 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Macera, M.J., Szabo, P., Wadgaonkar, R., Siddiqui, M.A.Q. & Verma, R.S. Localization of the gene coding for ventricular myosin regulatory light chain (MYL2) to chromosome 12 q23-q24.3. Genomics 13, 829–831 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Webb, G.C., Coggan, M., Ichinose, A. & Board, P.G. Localization of the factor XIIIB subunit gene (F13B) to chromosomal bands 1q31-32. 1 and restriction fragment polymorphism at the locus. Hum. Genet. 81, 157–160 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Nishimura, D.Y. & Murray, J.C. A tetranucleotide repeat for the F13B locus. Nucl. Acids Res. 20, 1167 (1992).

    PubMed  PubMed Central  Google Scholar 

  14. Cox, D.W., Nakamura, Y. & Gedde-Dahl, T. Report of the committee on the genetic constitution of chromosome 14. Cytogenet. Cell Genet. 55, 183–188 (1990).

    Article  CAS  PubMed  Google Scholar 

  15. Dracopoli, N.C. et al. The CEPH consortium linkage map of human chromosome 1. Genomics 9, 686–700 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. Collins, A., Keats, B.J., Dracopoli, N., Shields, D.C. & Motion, N.E. Integration of gene maps: Chromosome 1. Proc. natn. Acad. Sci. U.S.A. 89, 4598–4602 (1992).

    Article  CAS  Google Scholar 

  17. Edwards, A., Hammond, H.A., Jin, L., Caskey, C.T. & Chakraborty, R. Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics 12, 241–253 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. Nishimura, D.Y., Leysens, N.J. & Murray, J.C. A dinucleotide repeat for the D1S53 locus. Nucl. Acids Res. 20, 1167 (1992).

    PubMed  PubMed Central  Google Scholar 

  19. Epstein, N.E., Cohn, G.M., Cyran, F. & Fananapazir, L. Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the β-myosin heavy chain gene. Circulation 86, 345–352 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Gunning, P., Ponte, P., Kedes, L., Eddy, R. & Shows, T. Chromosomal location of the co-expressed human skeletal and cardiac actin genes. Proc. natn. Acad. Sci. U.S.A. 81, 1813–1817 (1984).

    Article  CAS  Google Scholar 

  21. Boheler, K.R. et al. Skeletal actin mRNA increases in the human heart during ontogenic development and is the major isoform of control and failing adult hearts. J. clin. Invest. 88, 323–30 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bakerman, P.R., Stenmark, K.R. & Fisher, J.H. α-skeletal actin messenger RNA increases in acute right ventricular hypertrophy. Am. J. Physiol. 258, L173–L178 (1990).

    CAS  PubMed  Google Scholar 

  23. Radice, P. The human tropomyosin gene involved in the generation of the TRK oncogene maps to chromosome 1q31. Oncogene 6, 2145–2148 (1991).

    CAS  PubMed  Google Scholar 

  24. Reinach, F.C. & MacLeod, A.R. Tissue-specific expression of the human tropomyosin gene involved in the generation of the trk oncogene. Nature 322, 648–650 (1986).

    Article  CAS  PubMed  Google Scholar 

  25. Wade, R., Eddy, R., Shows, T.B. & Kedes, L. cDNA sequence, tissue-specific expression, and chromosomal mapping of the human slow-twitch skeletal muscle isoform of troponin I. Genomics 7, 346–367 (1990).

    Article  CAS  PubMed  Google Scholar 

  26. Bhavsar, P.K. et al. Developmental expression of troponin I isoforms in fetal human heart. FEBS Letters 292, 5–8 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Hunkeler, N.M., Kullman, J. & Murphy, A.M. Troponin I isoform expression in human heart. Circ. Res. 69, 1409–1414 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Rosenzweig, A. et al. Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes. New Engl. J. Med. 326, 1753–1760 (1991).

    Article  Google Scholar 

  29. Watkins, H. et al. Sporadic hypertrophic cardiomyopathy due to De Novo myosin mutations. J. clin. Invest. 90, 1666–1671 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chou, Y-H., et al. The gene responsible for familial hypocalciuric hypercalcaemia maps to chromosome 3q in four unrelated families. Nature Genet. 1, 295–300 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. Polymeropoulos, M.H., Xiao, H., Rath, D.S. & Merrill, C.R. Dinucleotide repeat polymorphism at the human cardiac beta-myosin gene. Nucl. Acids Res. 19, 4019 (1991).

    PubMed  PubMed Central  Google Scholar 

  32. Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. natn. Acad. Sci. U.S.A. 81, 3443–3446 (1984).

    Article  CAS  Google Scholar 

  33. Ott, J. Analysis of human linkage 2nd edn (The Johns Hopkins University Press, Baltimore, 1992).

    Google Scholar 

  34. Kaplan, E.L. & Meier, P. Nonparametric estimation from incomplete observations. J. Am. Statist. Assoc. 53, 457–481 (1958).

    Article  Google Scholar 

  35. Lee, E.T. Statistical methods for survival data analysis. (Lifetime Learning Publications, Belmont: 1980).

    Google Scholar 

  36. Cox, D.R., Oakes, D. Analysis of survival data. (Chapman and Hall, New York, 1984).

    Google Scholar 

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Authors and Affiliations

  1. Cardiology Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115, USA

    Hugh Watkins, Ludwig Thierfelder & Christine E. Seidman

  2. Department of Cardiological Sciences, St. George's Hospital Medical School, London, SW17 ORE, UK

    Hugh Watkins, Calum MacRae & William McKenna

  3. Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Calum MacRae, Yah-Huei Chou & J.G. Seidman

  4. Department of Medicine, Royal Brisbane Hospital, Queensland, 4029, Australia

    Michael Frenneaux

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  1. Hugh Watkins
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Watkins, H., MacRae, C., Thierfelder, L. et al. A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3. Nat Genet 3, 333–337 (1993). https://doi.org/10.1038/ng0493-333

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  • DOI: https://doi.org/10.1038/ng0493-333

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