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 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 of trans-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.
Biesiadecki
Brandon J
BJ
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970, USA.
Elder
Benjamin D
BD
Yu
Zhi-Bin
ZB
Jin
Jian-Ping
JP
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002415:Cats; D003001:Cloning, Molecular; D017931:DNA Primers; D004195:Disease Models, Animal; D004285:Dogs; D005091:Exons; D014644:Genetic Variation; D006168:Guinea Pigs; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008322:Mammals; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D020107:Troponin T / Q000235:genetics*; D014422:Turkeys
D017931:DNA Primers; D011994:Recombinant Proteins; D020107:Troponin T; D007545:Isoproterenol