Skip to main content
SpringerLink
Log in

Malignant familial hypertrophic cardiomyopathy in a family with a 453Arg→Cys mutation in the β-myosin heavy chain gene: Coexistence of sudden death and end-stage heart failure

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Recent genotype-phenotype correlation studies in familial hypertrophic cardiomyopathy (FHC) have revealed that some mutations in the β-myosin heavy chain (BMHC) gene may be associated with a high incidence of sudden death and a poor prognosis. Coexistence of sudden death and end-stage heart failure in several families with FHC has recently being reported; however, the genetic basis of such families has not been clearly demonstrated. A three-generation Chinese familial hypertrophic cardiomyopathy (FHC) family (family HL I) with two cases of end-stage heart failure and three cases of sudden death was analyzed. The average age of death in the affected members in this family was 34 years old. Genetic linkage analysis using polymorphisms in the α- and β-myosin heavy chain genes revealed that FHC in this family is significantly linked to the BMHC gene without recombinations. Single-strand conformation polymorphism analysis of exons 8, 9 and 13 to 23 in the BMHC gene showed a polymorphic band on exon 14 that is in complete linkage with the disease status in this family. DNA sequencing analysis in the affected members revealed an 453Arg→Cys mutation in the BMHC gene. To our knowledge this is the first reported mutation of FHC in Chinese. Our data suggest that the 453Arg→Cys mutation is associated with a malignant clinical course in FHC due not only to sudden death but also to end-stage heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anan R, Greve G, Thierfelder L, Watkins HC, McKenna WJ, Solomon S, Vecchio C, Shono H, Nakao S, Tanaka H, Mares A Jr, Towbin JA, Spirito P, Roberts R, Seidman JG, Seidman CE (1994) Prognostic implications of novel β-cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. J Clin Invest 93:280–285

    Google Scholar 

  • Ando H, Imaizumi T, Urabe Y, Takeshita A, Nakamura M (1990) Apical segmental dysfunction in hypertrophic cardiomyopathy: subgroup with unique clinical features. J Am Coll Cardiol 16:1579–1588

    Google Scholar 

  • Carrier L, Hengstenberg C, Beckmann JS, Guicheney P, Dufour C, Bercovici J, Dausse E, Berebbi-Bertrand I, Wisnewski C, Pulvenis D, Feder L, Vignal A, Weissenbach J, Hillaire D, Feingold J, Bouhour JB, Hagege A, Desnos M, Isnard R, Dubourg O, Komajda M, Schwartz K (1993) Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11. Nat Genet 4:311–313

    Google Scholar 

  • Cecchi F, Maron BJ, Epstein SE (1989) Long-term outcome of patients with hypertrophic cardiomyopathy successfully resuscitated after cardiac arrest. J Am Coll Cardiol 13:1283–1288

    Google Scholar 

  • Cuda G, Fananapazir L, Zhu WS, Sellers JR, Epstein ND (1993) Skeletal muscle expression and abnormal function of β-myosin in hypertrophic cardiomyopathy. J Clin Invest 91:2861–2865

    Google Scholar 

  • Epstein ND, Fananapazir L, Lin HJ, Mulvihill J, White R, Lalouel JM, Lifton RP, Nienhuis AW, Leppert M (1992 a) Evidence of genetic heterogeneity in five kindreds with familial hypertrophic cardiomyopathy. Circulation 85:635–637

    Google Scholar 

  • Epstein ND, Cohn GM, Cyran F, Fananapazir L (1992b) Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the β-myosin heavy chain gene. Circulation 86:345–352

    Google Scholar 

  • Fananapazir L, Epstein ND (1994) Genotype-phenotype correlations in hypertrophic cardiomyopathy: insights provided by comparisons of kindreds with distinct and identical (3-myosin heavy chain gene mutations. Circulation 89:22–32

    Google Scholar 

  • Fananapazir L, Tracy CM, Leon MB, (1989) Electrophysiologic abnormalities in patients with hypertrophic cardiomyopathy: a consecutive analysis in 155 patients. Circulation 80: 1259–1268

    Google Scholar 

  • Fighali S, Krajczer Z, Edelman S, Leachman RD (1987) Progression of hypertrophic cardiomyopathy into a hypokinetic left ventricle: high incidence in patients with midventricular obstruction. J Am Coll Cardiol 9:288–294

    Google Scholar 

  • Geisterfer-Lowrance AAT, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG (1990) A molecular basis for familial hypertrophic cardiomyopathy: a β-cardiac myosin heavy chain gene missense mutation. Cell 62:999–1006

    Google Scholar 

  • Hecht GM, Klues HG, Roberts WC, Maron BJ (1993) Coexistence of sudden death and end-stage heart failure in familial hypertrophic cardiomyopathy. J Am Coll Cardiol 22:489–497

    Google Scholar 

  • Jarcho JA, McKenna W, Pare JAP, Solomon SD, Holcombe RF, Dickie S, Levi T, Donis-Keller H, Seidman JG, Seidman CE (1989) Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med 321:1372–1378

    Google Scholar 

  • Ko YL, Lien WP, Chen JJ, Wu CW, Tang TK, Liew CC (1992 a) No evidence for linkage of familial hypertrophic cardiomyopathy and chromosome 14q1 locus D14S26 in a Chinese family: evidence for genetic heterogeneity. Hum Genet 89:597–601

    Google Scholar 

  • Ko YL, Lei MH, Chen JJ, Lin JL, Chen JJ, Kuan P, Lien WP (1992b) Inheritance of hypertrophic cardiomyopathy in Chinese: M-mode and two-dimensional echocardiographic analysis of 28 families. J Formos Med Assoc 1992; 91:669–673

    Google Scholar 

  • Ko YL, Lin JL, Lei MH, Chen JJ, Tsou JS, Kuan P, Lien WP (1995) Apical segmental dysfunction in hypertrophic cardiomyopathy: progression into end-stage heart failure with sudden cardiac death. Cardiology 86:436–440

    Google Scholar 

  • Liew CC, Sole MJ, Yamaguchi-Takihara K, Kellam B, Anderson D, Lin L, Liew JC (1990) Complete sequence and organization of the human cardiac β-myosin heavy chain gene. Nucleic Acids Res 18:3647–3651

    Google Scholar 

  • Louie L, Edwards W (1994) Hypertrophic cardiomyopathy. Prog Cardiol Vase Dis 8:298–309

    Google Scholar 

  • Maron BJ, Fananapazir L (1992) Sudden cardiac death in hypertrophic cardiomyopathy. Circulation [Suppl 1] 85:1–63

    Google Scholar 

  • Maron BJ, Epstein SE, Roberts WC (1979) Hypertrophic cardiomyopathy and transmural myocardial infarction without significant atherosclerosis of the extramural coronary arteries. Am J Cardiol 43:1086–1102

    Google Scholar 

  • Maron BJ, Savage DD, Wolfson JK, (1981) Prognostic significance of 24 hour ambulatory electrocardiographic monitoring in patients with hypertrophic cardiomyopathy: a prospective study. Am J Cardiol 48:252–257

    Google Scholar 

  • Maron BJ, Nichols PF III, Pickle LW, Wesley YE, Mulvihill JJ (1984) Patterns of inheritance in hypertrophic cardiomyopathy: assessment by M-mode and two-dimensional echocardiography. Am J Cardiol 53:1087–1094

    Google Scholar 

  • Maron BJ, Bonow RO, Canon RO, Leon MB, Epstein SE (1987) Hypertrophic cardiomyopathy: interrelations of clinical manifestations, pathophysiology and therapy. N Engl J Med 316: 780–789

    Google Scholar 

  • Orita M, Suzuki Y, Sekiya T, Hayashi K (1989) Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5: 874–879

    Google Scholar 

  • Perryman MB, Yu QT, Marian AJ, Mares A, Czemuszewicz G Jr, Ifegwu J, Hill R, Roberts R (1992) Expression of a missense mutation in the messenger RNA for (3-myosin heavy chain in myocardial tissue in hypertrophic cardiomyopathy. J Clin Invest 90:271–277

    Google Scholar 

  • Rosenzweig A, Watkins A, Hwang DS, Miri M, McKenna W, Traill TA, Seidman JG, Seidman CE (1991) Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes. N Engl J Med 325:1753–1760

    Google Scholar 

  • Schwartz K, Beckmann JS, Dufour C, Fougerousse F, Faure L, Carrier L, Hengstenberg C, Cambien F, Cohen D, Ferriere M, (1992) Exclusion of myosin heavy chain and cardiac actin gene involvement in hypertrophic cardiomyopathy of several French families. Circ Res 71: 3–8

    Google Scholar 

  • Spirito P, Maron BJ, Bonow RO, Epstein SE (1987) Occurrence and significance of progressive left ventricular wall thinning and relative cavity dilatation in hypertrophic cardiomyopathy. Am J Cardiol 59:123–129

    Google Scholar 

  • Thierfelder L, MacRae C, Watkins H, McKenna W, Vosberg H-P, Seidman JG, Seidman CE (1993 a) Two new loci for hypertrophic cardiomyopathy map to chromosome 1582 (CMH3) and llq (CMH4). Circulation 88:1–573

    Google Scholar 

  • Thierfelder L, MacRae C, Watkins H, Tomfohrde J, Williams M, McKenna W, Bohm K, Noeske G, Schlepper M, Bowcock A, Vosberg HP, Seidman JG, Seidman CE (1993 b) A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2. Proc Natl Acad Sci USA 90:6270–6274

    Google Scholar 

  • Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg H-P, Seidman JG, Seidman CE (1994) α-Tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 77:713–725

    Google Scholar 

  • Watkins H, Rosenzweig A, Hwang DS, Levi T, Mckenna W, Seidman CE, Seidman JG (1992) Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med 326:1108–1114

    Google Scholar 

  • Watkins H, MacRae C, Thierfelder L, Chou YH, Frenneaux M, McKenna W, Seidman JG, Seidman CE (1993) A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3. Nat Genet 3:333–337

    Google Scholar 

Download references

Author information

Author notes

  1. Y. L. Ko

    Present address: Chang Gung Memorial Hospital, 199, Tung Hwa North Road, Taipei, Taiwan, Republic of China

Authors and Affiliations

  1. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China

    Y. L. Ko, J. J. Chen, J. J. Cheng, P. Kuan & W. P. Lien

  2. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China

    T. K. Tang, S. Y. Lin, Y. C. Liou & C. W. Wu

  3. Department of Clinical Chemistry, University of Toronto, Toronto Hospital, Toronto, Canada

    C. C. Liew

Authors
  1. Y. L. Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. J. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. J. Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Kuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W. P. Lien
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. K. Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Y. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y. C. Liou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. W. Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C. C. Liew
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ko, Y.L., Chen, J.J., Cheng, J.J. et al. Malignant familial hypertrophic cardiomyopathy in a family with a 453Arg→Cys mutation in the β-myosin heavy chain gene: Coexistence of sudden death and end-stage heart failure. Hum Genet 97, 585–590 (1996). https://doi.org/10.1007/BF02281865

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02281865

Keywords

Search

Navigation