Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.

BACKGROUND Mutations in the gene for cardiac myosin-binding protein C account for approximately 15 percent of cases of familial hypertrophic cardiomyopathy. The spectrum of disease-causing mutations and the associated clinical features of these gene defects are unknown. METHODS DNA sequences encoding cardiac myosin-binding protein C were determined in unrelated patients with familial hypertrophic cardiomyopathy. Mutations were found in 16 probands, who had 574 family members at risk of inheriting these defects. The genotypes of these family members were determined, and the clinical status of 212 family members with mutations in the gene for cardiac myosin-binding protein C was assessed. RESULTS Twelve novel mutations were identified in probands from 16 families. Four were missense mutations; eight defects (insertions, deletions, and splice mutations) were 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 percent of adults under the age of 50 years who had a mutation in the cardiac myosin-binding protein C 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 other mutations in the genes for sarcomere proteins. Most deaths due to cardiac causes in these families occurred suddenly. CONCLUSIONS The clinical expression of mutations in the gene for cardiac myosin-binding protein C is often delayed until middle age or old age. Delayed expression of cardiac hypertrophy and a favorable clinical course may hinder recognition of the heritable nature of mutations in the cardiac myosin-binding protein C gene. Clinical screening in adult life may be warranted for members of families characterized by hypertrophic cardiomyopathy.

[1]  W. Rottbauer,et al.  Novel splice donor site mutation in the cardiac myosin-binding protein-C gene in familial hypertrophic cardiomyopathy. Characterization Of cardiac transcript and protein. , 1997, The Journal of clinical investigation.

[2]  K. Chien,et al.  Point Mutations in Human β Cardiac Myosin Heavy Chain Have Differential Effects on Sarcomeric Structure and Assembly: An ATP Binding Site Change Disrupts Both Thick and Thin Filaments, Whereas Hypertrophic Cardiomyopathy Mutations Display Normal Assembly , 1997, The Journal of cell biology.

[3]  M. Komajda,et al.  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. , 1997, Circulation research.

[4]  J. Seidman,et al.  Clinical features of hypertrophic cardiomyopathy caused by mutation of a "hot spot" in the alpha-tropomyosin gene. , 1997, Journal of the American College of Cardiology.

[5]  R. Kucherlapati,et al.  Mutations in human cause limb and cardiac malformation in Holt-Oram syndrome , 1997, Nature Genetics.

[6]  J. Seidman,et al.  Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy. Evidence for a dominant negative action. , 1996, The Journal of clinical investigation.

[7]  S. Winegrad,et al.  Alteration of myosin cross bridges by phosphorylation of myosin-binding protein C in cardiac muscle. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Seidman,et al.  Missense mutation in the pore region of HERG causes familial long QT syndrome. , 1996, Circulation.

[9]  Frederick J. Schoen,et al.  A Mouse Model of Familial Hypertrophic Cardiomyopathy , 1996, Science.

[10]  I. Rayment,et al.  Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle , 1996, Nature Genetics.

[11]  T. Mikawa,et al.  The carboxyl terminus of myosin binding protein C (MyBP-C, C-protein) specifies incorporation into the A-band of striated muscle. , 1996, Journal of cell science.

[12]  J. Seidman,et al.  Mutations in the cardiac myosin binding protein–C gene on chromosome 11 cause familial hypertrophic cardiomyopathy , 1995, Nature Genetics.

[13]  J. Beckmann,et al.  Cardiac myosin binding protein–C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy , 1995, Nature Genetics.

[14]  J. Gardin,et al.  Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. , 1995, Circulation.

[15]  Wigle Ed.  Novel insights into the clinical manifestations and treatment of hypertrophic cardiomyopathy. , 1995 .

[16]  M. Gautel,et al.  Phosphorylation switches specific for the cardiac isoform of myosin binding protein‐C: a modulator of cardiac contraction? , 1995, The EMBO journal.

[17]  J. Seidman,et al.  Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. , 1995, The New England journal of medicine.

[18]  J. Sanger,et al.  The premyofibril: evidence for its role in myofibrillogenesis. , 1994, Cell motility and the cytoskeleton.

[19]  S. Solomon,et al.  Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. , 1994, The Journal of clinical investigation.

[20]  S. Solomon,et al.  Left ventricular hypertrophy and morphology in familial hypertrophic cardiomyopathy associated with mutations of the beta-myosin heavy chain gene. , 1993, Journal of the American College of Cardiology.

[21]  J. Beckmann,et al.  Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11 , 1993, Nature Genetics.

[22]  F. E. Weber,et al.  Molecular cloning of chicken myosin-binding protein (MyBP) H (86-kDa protein) reveals extensive homology with MyBP-C (C-protein) with conserved immunoglobulin C2 and fibronectin type III motifs. , 1993, The Journal of biological chemistry.

[23]  P. Nihoyannopoulos,et al.  Identification of a mutation in the beta cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy. , 1993, British heart journal.

[24]  S. Little,et al.  Development, multiplexing, and application of ARMS tests for common mutations in the CFTR gene. , 1992, American journal of human genetics.

[25]  L. Fananapazir,et al.  Differences in Clinical Expression of Hypertrophic Cardiomyopathy Associated With Two Distinct Mutations in the β‐Myosin Heavy Chain Gene: A 908Leu→Val Mutation and a 403Arg→gGln Mutation , 1992, Circulation.

[26]  W. Mckenna,et al.  The management of hypertrophic cardiomyopathy. , 1997, The New England journal of medicine.

[27]  J. Seidman,et al.  Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. , 1992, The New England journal of medicine.

[28]  J. Seidman,et al.  Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes. , 1991, The New England journal of medicine.

[29]  H. C. Hartzell,et al.  Alterations in Ca2+ sensitive tension due to partial extraction of C- protein from rat skinned cardiac myocytes and rabbit skeletal muscle fibers , 1991, The Journal of general physiology.

[30]  B. Gersh,et al.  Natural history of hypertrophic cardiomyopathy in the elderly. , 1990, Journal of the American College of Cardiology.

[31]  S. Solomon,et al.  Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease. , 1990, The Journal of clinical investigation.

[32]  C Summers,et al.  Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). , 1989, Nucleic acids research.

[33]  B. Healy,et al.  Hypertrophic cardiomyopathy in the elderly. Distinctions from the young based on cardiac shape. , 1989, Circulation.

[34]  B. Maron,et al.  Elderly patients with hypertrophic cardiomyopathy: a subset with distinctive left ventricular morphology and progressive clinical course late in life. , 1989, Journal of the American College of Cardiology.

[35]  S. Friedman,et al.  Hypertrophic cardiomyopathy in the elderly. A frequently misdiagnosed disease. , 1986, Archives of internal medicine.

[36]  Hart Hc.  Effects of phosphorylated and unphosphorylated C-protein on cardiac actomyosin ATPase. , 1985 .

[37]  K. Yamamoto,et al.  The C-proteins of rabbit red, white, and cardiac muscles. , 1983, The Journal of biological chemistry.