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J. Biol. Chem., Vol. 277, Issue 21, 18459-18468, May 24, 2002
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From the Department of Physiology and Biophysics, Case Western
Reserve University School of Medicine, Cleveland, Ohio 44106-4970
Troponin T is a central component of the thin
filament-associated troponin-tropomyosin system and plays an essential
role in the Ca2+ regulation of striated muscle
contraction. The importance of the structure and function of troponin T
is evident in the regulated isoform expression during development and
the point mutations resulting in familial hypertrophic and dilated
cardiomyopathies. We report here that turkeys with inherited dilated
cardiomyopathy and heart failure express an unusual low
molecular weight cardiac troponin T missing 11 amino acids due
to the splice out of the normally conserved exon 8-encoded segment. The
deletion of a 9-bp segment from intron 7 of the turkey cardiac troponin
T gene may be responsible for the weakened splicing of the downstream
exon 8 during mRNA processing. The exclusion of the exon 8-encoded segment results in conformational changes in cardiac troponin T, an
altered binding affinity for troponin I and tropomyosin, and an
increased calcium sensitivity of the actomyosin ATPase. Expression of
the exon 8-deleted cardiac troponin T prior to the development of
cardiomyopathy in turkeys indicates a novel RNA splicing disease
and provides evidence for the role of troponin T structure-function
variation in myocardial pathogenesis and heart failure.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF274301, AY005139, and AF374417.
Exon Skipping in Cardiac Troponin T of Turkeys with Inherited
Dilated Cardiomyopathy*
and
*
This work was supported by a grant from the March of Dimes
Foundation (to J.-P. J.).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 by National Institutes of Health Training Grant
T32-HL07887.
§
To whom correspondence should be addressed: Dept. of Physiology and
Biophysics, Case Western Reserve University School of Medicine, 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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