Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: insights into disease pathogenesis and troponin function.

Mutations in a number of cardiac sarcomeric protein genes cause hypertrophic cardiomyopathy (HCM). Previous findings indicate that HCM-causing mutations associated with a truncated cardiac troponin T (TnT) and missense mutations in the beta-myosin heavy chain share abnormalities in common, acting as dominant negative alleles that impair contractile performance. In contrast, Lin et al. [Lin, D., Bobkova, A., Homsher, E. & Tobacman, L. S. (1996) J. Clin. Invest. 97, 2842-2848] characterized a TnT point mutation (Ile79Asn) and concluded that it might lead to hypercontractility and, thus, potentially a different mechanism for HCM pathogenesis. In this study, three HCM-causing cardiac TnT mutations (Ile79Asn, Arg92Gln, and DeltaGlu160) were studied in a myotube expression system. Functional studies of wild-type and mutant transfected myotubes revealed that all three mutants decreased the calcium sensitivity of force production and that the two missense mutations (Ile79Asn and Arg92Gln) increased the unloaded shortening velocity nearly 2-fold. The data demonstrate that TnT can alter the rate of myosin cross-bridge detachment, and thus the troponin complex plays a greater role in modulating muscle contractile performance than was recognized previously. Furthermore, these data suggest that these TnT mutations may cause disease via an increased energetic load on the heart. This would represent a second paradigm for HCM pathogenesis.

[1]  D. Manstein,et al.  Modulation of actin affinity and actomyosin adenosine triphosphatase by charge changes in the myosin motor domain. , 1998, Biochemistry.

[2]  M. Geeves,et al.  The muscle thin filament as a classical cooperative/allosteric regulatory system. , 1998, Journal of molecular biology.

[3]  S. Rosenfeld,et al.  Kinetic Tuning of Myosin via a Flexible Loop Adjacent to the Nucleotide Binding Pocket* , 1998, The Journal of Biological Chemistry.

[4]  B. Maron,et al.  A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity. , 1998, Circulation research.

[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]  H. Watkins,et al.  Sudden death due to troponin T mutations. , 1997, Journal of the American College of Cardiology.

[8]  H. Sugi,et al.  Characterization of mutant myosins of Dictyostelium discoideum equivalent to human familial hypertrophic cardiomyopathy mutants. Molecular force level of mutant myosins may have a prognostic implication. , 1997, The Journal of clinical investigation.

[9]  Y. Fujio,et al.  Novel missense mutation in cardiac troponin T gene found in Japanese patient with hypertrophic cardiomyopathy. , 1997, Journal of molecular and cellular cardiology.

[10]  M. Yacoub,et al.  Codon 102 of the cardiac troponin T gene is a putative hot spot for mutations in familial hypertrophic cardiomyopathy. , 1996, Circulation.

[11]  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.

[12]  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.

[13]  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.

[14]  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.

[15]  L. Leinwand,et al.  Contractile protein mutations and heart disease. , 1996, Current opinion in cell biology.

[16]  J. Beckmann,et al.  Cardiac myosin binding protein–C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy , 1995, 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. Seidman,et al.  Familial hypertrophic cardiomyopathy: a genetic model of cardiac hypertrophy. , 1995, Human molecular genetics.

[19]  I. Rayment,et al.  Structural interpretation of the mutations in the beta-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[20]  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.

[21]  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.

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

[23]  L. Leinwand,et al.  Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction. , 1994, The Journal of biological chemistry.

[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.  Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. , 1992, The New England journal of medicine.

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

[27]  B. Brenner,et al.  Effect of Ca2+ on cross-bridge turnover kinetics in skinned single rabbit psoas fibers: implications for regulation of muscle contraction. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Hanh T. Nguyen,et al.  Intricate combinatorial patterns of exon splicing generate multiple regulated troponin T isoforms from a single gene , 1985, Cell.

[29]  R. F. Siemankowski,et al.  Kinetics of the interaction between actin, ADP, and cardiac myosin-S1. , 1984, The Journal of biological chemistry.

[30]  K. Edman.  The velocity of unloaded shortening and its relation to sarcomere length and isometric force in vertebrate muscle fibres. , 1979, The Journal of physiology.

[31]  H. Sweeney,et al.  Structure-function analysis of cytoskeletal/contractile proteins in avian myotubes. , 1997, Methods in cell biology.

[32]  H. Sweeney,et al.  Mutational analysis of motor proteins. , 1996, Annual review of physiology.