Cardiac Troponin T Variants Produced by Aberrant Splicing of Multiple Exons in Animals with High Instances of Dilated Cardiomyopathy

Adult cardiac muscle normally expresses a single cardiac troponin T (cTnT). As a potential pathogenic mechanism for turkey dilated cardiomyopathy, the splice-out of a normally constitutive exon generates an additional low molecular weight cTnT with altered conformation and function. We further found...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-12, Vol.277 (52), p.50275-50285
Main Authors: Biesiadecki, Brandon J., Elder, Benjamin D., Yu, Zhi-Bin, Jin, Jian-Ping
Format: Article
Language:English
Subjects:
Alternative Splicing
Amino Acid Sequence
Animals
Base Sequence
Cardiomyopathy, Dilated - genetics
Cats
Cloning, Molecular
Disease Models, Animal
DNA Primers
Dogs
Exons
Genetic Variation
Guinea Pigs
Humans
Isoproterenol - pharmacology
Mammals
Mice
Mice, Transgenic
Molecular Sequence Data
Myocardial Contraction - drug effects
Myocardium - metabolism
Rats
Recombinant Proteins - metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Troponin T - genetics
Turkeys
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Summary:Adult cardiac muscle normally expresses a single cardiac troponin T (cTnT). As a potential pathogenic mechanism for turkey dilated cardiomyopathy, the splice-out of a normally constitutive exon generates an additional low molecular weight cTnT with altered conformation and function. We further found that aberrant splicing of cTnT also occurs in several mammals correlating to dilated cardiomyopathy. Skipping of the same exon as that in the turkey was found in the canine cTnT. Splice-out of the adjacent exon 6 occurred in the guinea pig cTnT. Retention of the embryonic exon 5 was found in the cTnT of cat, dog, and guinea pig. These aberrant splicing variants significantly altered the structure of cTnT to sustain functional effects as that in the myopathic turkey cTnT. The genomic sequence of canine cTnT gene shows no specific alterations. However, the alternative splicing patterns of canine cTnT are different in developing cardiac and skeletal muscles, suggesting abnormality oftrans-regulatory factors. Transgenic expression of the aberrant cTnT variants resulted in contractile changes in mouse cardiomyocytes. The findings support the hypothesis that thin filament heterogeneity due to the co-expression of alternatively spliced cTnT variants may desynchronize myocardial contraction and contribute to the pathogenesis and pathophysiology of cardiomyopathy and heart failure.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M206369200