Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene.

Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy accompanied by myofibrillar disarrays. Molecular genetic analyses have revealed that mutations in 8 different genes cause HCM. Mutations in these disease genes, however, could be found in about half of HCM patients, suggesting that there are other unknown disease gene(s). Because the known disease genes encode sarcomeric proteins expressed in the cardiac muscle, we searched for a disease-associated mutation in the titin gene in 82 HCM patients who had no mutation in the known disease genes. A G to T transversion in codon 740, from CGC to CTC, replacing Arginine with Leucine was found in a patient. This mutation was not found in more than 500 normal chromosomes and increased the binding affinity of titin to alpha-actitin in the yeast two-hybrid assay. These observations suggest that the titin mutation may cause HCM in this patient via altered affinity to alpha-actinin.

[1]  J A Osborne,et al.  Familial dilated cardiomyopathy locus maps to chromosome 2q31. , 1999, Circulation.

[2]  B. Hainque,et al.  Familial hypertrophic cardiomyopathy: from mutations to functional defects. , 1998, Circulation research.

[3]  M. Gautel,et al.  Molecular structure of the sarcomeric Z‐disk: two types of titin interactions lead to an asymmetrical sorting of α‐actinin , 1998, The EMBO journal.

[4]  K. Suzuki,et al.  Tissue-specific expression and alpha-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs. , 1997, Journal of molecular biology.

[5]  M. Matsuzaki,et al.  Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy , 1997, Nature Genetics.

[6]  H. Watkins,et al.  Effects of two hypertrophic cardiomyopathy mutations in alpha-tropomyosin, Asp175Asn and Glu180Gly, on Ca2+ regulation of thin filament motility. , 1997, Biochemical and biophysical research communications.

[7]  A. Marian,et al.  Expression of a mutant (Arg92Gln) human cardiac troponin T, known to cause hypertrophic cardiomyopathy, impairs adult cardiac myocyte contractility. , 1997, Circulation research.

[8]  H. Yajima,et al.  The N-Terminal Z Repeat 5 of Connectin/Titin Binds to the C-Terminal Region of α-Actinin , 1997 .

[9]  K. Maruyama,et al.  Connectin/titin, giant elastic protein of muscle , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  R. Chisholm,et al.  Substitution Mutations in the Myosin Essential Light Chain Lead to Reduced Actin-activated ATPase Activity Despite Stoichiometric Binding to the Heavy Chain* , 1997, The Journal of Biological Chemistry.

[11]  A. Kimura.  Symposium on gene abnormalities in medical diseases. 3. Molecular genetics of hypertrophic cardiomyopathy in Japan. , 1997, Internal medicine.

[12]  M. Ikebe,et al.  Functional analysis of the mutations in the human cardiac beta-myosin that are responsible for familial hypertrophic cardiomyopathy. Implication for the clinical outcome. , 1996, The Journal of clinical investigation.

[13]  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.

[14]  M. Gautel,et al.  The central Z-disk region of titin is assembled from a novel repeat in variable copy numbers. , 1996, Journal of cell science.

[15]  E. Homsher,et al.  Altered cardiac troponin T in vitro function in the presence of a mutation implicated in familial hypertrophic cardiomyopathy. , 1996, The Journal of clinical investigation.

[16]  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.

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

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

[19]  Siegfried Labeit,et al.  Titins: Giant Proteins in Charge of Muscle Ultrastructure and Elasticity , 1995, Science.

[20]  L. Fananapazir,et al.  Abnormal contractile properties of muscle fibers expressing beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy. , 1995, The Journal of clinical investigation.

[21]  Christine E. Seidman,et al.  α-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: A disease of the sarcomere , 1994, Cell.

[22]  S. L'Hernault,et al.  Additional sequence complexity in the muscle gene, unc-22, and its encoded protein, twitchin, of Caenorhabditis elegans. , 1993, Genetics.

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

[24]  W. Zhu,et al.  Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy. , 1993, The Journal of clinical investigation.

[25]  J. Seidman,et al.  A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3 , 1993, Nature Genetics.

[26]  T. Sasazuki,et al.  Novel missense mutation in cardiac ? myosin heavy chain gene found in a japanese patient with hypertrophic cardiomyopathy , 1992 .

[27]  J. Seidman,et al.  A molecular basis for familial hypertrophic cardiomyopathy: A β cardiac myosin heavy chain gene missense mutation , 1990, Cell.

[28]  P. Anderson,et al.  Functions of the myosin ATP and actin binding sites are required for C. elegans thick filament assembly , 1990, Cell.

[29]  S. Solomon,et al.  Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. , 1989, The New England journal of medicine.

[30]  R. Waterston,et al.  Sequence of an unusually large protein implicated in regulation of myosin activity in C. elegans , 1989, Nature.

[31]  M. Davies.  The current status of myocardial disarray in hypertrophic cardiomyopathy. , 1984, British heart journal.

[32]  R. Bonow,et al.  Hypertrophic cardiomyopathy. , 1987, Disease-a-month : DM.