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Mutations in the beta-myosin heavy chain gene are believed to cause hypertrophic cardiomyopathy (HCM) by acting as dominant negative alleles. In contrast, a truncated cardiac troponin T (TnT) that causes HCM implies that altered stoichiometry of contractile proteins may also cause cardiac hypertrophy. Wild-type and HCM-mutant (truncated) TnT were studied in a novel quail myotube expression system. Unexpectedly, antibody staining demonstrated incorporation of both forms of human cardiac TnT into the sarcomeres of quail myotubes. Functional studies of wild type and mutant transfected myotubes of normal appearance revealed that calcium-activated force of contraction was normal upon incorporation of wild type TnT, but greatly diminished for the mutant TnT. These findings indicate that HCM-causing mutations in TnT and beta-myosin heavy chain share abnormalities in common, acting as dominant negative alleles that impair contractile performance. This diminished force output is the likely stimulus for hypertrophy in the human heart.

Original publication

DOI

10.1172/JCI119063

Type

Journal article

Journal

J Clin Invest

Publication Date

01/12/1996

Volume

98

Pages

2456 - 2461

Keywords

Amino Acid Sequence, Animals, Cardiomyopathy, Hypertrophic, Cells, Cultured, DNA, Complementary, Embryo, Nonmammalian, Exons, Genes, Dominant, Humans, Molecular Sequence Data, Myocardial Contraction, Myocardium, Myosin Heavy Chains, Point Mutation, Polymerase Chain Reaction, Quail, Sarcomeres, Sequence Deletion, Troponin, Troponin T