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Originally published In Press as doi:10.1074/jbc.M206369200 on October 10, 2002
J. Biol. Chem., Vol. 277, Issue 52, 50275-50285, December 27, 2002
Cardiac Troponin T Variants Produced by Aberrant Splicing of
Multiple Exons in Animals with High Instances of Dilated
Cardiomyopathy*
Brandon J.
Biesiadecki ,
Benjamin D.
Elder,
Zhi-Bin
Yu, and
Jian-Ping
Jin§
From the Department of Physiology and Biophysics, Case Western
Reserve University School of Medicine, Cleveland, Ohio
44106-4970
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.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported in part by Training Grant T32-HL07887 from the National
Institutes of Health.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AY005140, AY005141, AY005142, AY005143, AF519619, AF519620,
AF519741, AF519742, AF519743, AF519744, AF519745, AF519746, AY119684,
AY120356, and AY120357.
§
To whom correspondence should be addressed: Dept. of Physiology and
Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4970. Tel.: 216-368-5525; Fax:
216-368-3952; E-mail: jxj12@po.cwru.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
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