PUBLICATION

Cardiac troponin T is essential in sarcomere assembly and cardiac contractility

Authors
Sehnert, A.J., Huq, A., Weinstein, B.M., Walker, C., Fishman, M., and Stainier, D.Y.
ID
ZDB-PUB-020514-12
Date
2002
Source
Nature Genetics   31(1): 106-110 (Journal)
Registered Authors
Fishman, Mark C., Huq, Anja, Sehnert, Amy, Stainier, Didier, Walker, Charline, Weinstein, Brant M.
Keywords
none
MeSH Terms
  • Animals
  • Base Sequence
  • Cardiomyopathy, Hypertrophic, Familial/genetics
  • Cloning, Molecular
  • DNA/genetics
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Myocardial Contraction/genetics
  • Myocardial Contraction/physiology*
  • Myocardium/metabolism
  • Myocardium/pathology
  • Phenotype
  • Sarcomeres/pathology
  • Troponin T/deficiency
  • Troponin T/genetics
  • Troponin T/physiology*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/physiology
(all 21)
PubMed
11967535 Full text @ Nat. Genet.
Abstract
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. Mutant proteins are thought to act through a dominant-negative mode that impairs function of heart muscle. TNNT2 mutations can also lead to dilated cardiomyopathy, a leading cause of heart failure. 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 alpha-tropomyosin (Tpma) and cardiac troponins C and I (Tnni3), forms a calcium-sensitive regulatory complex within sarcomeres. 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.
Genes / Markers
Figures
No images available
Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b109
    		Small Deletion
    tc300b
      		Point Mutation
      1 - 2 of 2
      Show
      Human Disease / Model
      Sequence Targeting Reagents
      Fish
      Antibodies
      Orthology
      Engineered Foreign Genes
      No data available
      Mapping
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      Citation
      Sehnert, A.J., Huq, A., Weinstein, B.M., Walker, C., Fishman, M., and Stainier, D.Y. (2002) Cardiac troponin T is essential in sarcomere assembly and cardiac contractility. Nature Genetics. 31(1):106-110.