Cardiac troponin T is essential in sarcomere assembly and cardiac contractility

• Published in: Nature genetics Vol. 31; no. 1; pp. 106 - 110
• Main Authors: Sehnert, Amy J., Huq, Anja, Weinstein, Brant M., Walker, Charline, Fishman, Mark, Stainier, Didier Y. R.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2002; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Animals; Athletes; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Calcium; Cancer Research; Cardiomyocytes; Cardiomyopathy; Cardiomyopathy, Hypertrophic, Familial - genetics; Classical genetics, quantitative genetics, hybrids; Cloning, Molecular; Danio rerio; DNA - genetics; Edema; Embryos; Fundamental and applied biological sciences. Psychology; Gene Function; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Human Genetics; Humans; letter; Mice; Microscopy; Molecular Sequence Data; Mutants; Mutation; Myocardial Contraction - genetics; Myocardial Contraction - physiology; Myocardium - metabolism; Myocardium - pathology; Phenotype; Protein expression; Proteins; Sarcomeres - pathology; Troponin T - deficiency; Troponin T - genetics; Troponin T - physiology; Vertebrata; Zebrafish - embryology; Zebrafish - genetics; Zebrafish - physiology; San Francisco California; California; United States > US; Massachusetts; Heart; Tropomyosin; Contractility; Cardiovascular disease; Gene expression; Myocardial disease; Troponin T; Vertebrata; Brachydanio rerio; Troponin I; Molecular assembly; Heart disease; Pisces; Hypertrophic cardiomyopathy; Mutation; Sarcomere
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng875

Mutations of the gene ( TNNT2 ) encoding the thin-filament contractile protein cardiac troponin T are responsible for 15% of all cases of familial hypertrophic cardiomyopathy, the leading cause of sudden death in young athletes 1 , 2 . Mutant proteins are thought to act through a dominant-negative mode that impairs function of heart muscle 3 . TNNT2 mutations can also lead to dilated cardiomyopathy, a leading cause of heart failure 4 . Despite the importance of cardiac troponin T in human disease, its loss-of-function phenotype has not been described. We show that the zebrafish silent heart ( sih ) mutation affects the gene tnnt2 . We characterize two mutated alleles of sih that severely reduce tnnt2 expression: one affects mRNA splicing, and the other affects gene transcription. Tnnt2, together with α-tropomyosin (Tpma) and cardiac troponins C and I (Tnni3), forms a calcium-sensitive regulatory complex within sarcomeres 5 . Unexpectedly, in addition to loss of Tnnt2 expression in sih mutant hearts, we observed a significant reduction in Tpma and Tnni3, and consequently, severe sarcomere defects. This interdependence of thin-filament protein expression led us to postulate that some mutations in tnnt2 may trigger misregulation of thin-filament protein expression, resulting in sarcomere loss and myocyte disarray, the life-threatening hallmarks of TNNT2 mutations in mice and humans 6 , 7 .