Am J Physiol Cell Physiol AJP: Endocrinology and Metabolism
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Am J Physiol Cell Physiol 277: C225-C232, 1999;
0363-6143/99 $5.00
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Vol. 277, Issue 2, C225-C232, August 1999

Functional changes in troponin T by a splice donor site mutation that causes hypertrophic cardiomyopathy

Hiroyuki Nakaura1,2, Sachio Morimoto1, Fumi Yanaga1, Masashi Nakata3, Hirofumi Nishi2, Tsutomu Imaizumi2, and Iwao Ohtsuki1

1 Department of Clinical Pharmacology, Faculty of Medicine, Kyushu University, Higashi-ku, Fukuoka 812-8582; and 2 Third Department of Medicine and 3 Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan

A splice donor site mutation in intron 15 of the cardiac troponin T (TnT) gene has been shown to cause familial hypertrophic cardiomyopathy (HCM). In this study, two truncated human cardiac TnTs expected to be produced by this mutation were expressed in Escherichia coli and partially (50-55%) exchanged into rabbit permeabilized cardiac muscle fibers. The fibers into which a short truncated TnT, which lacked the COOH-terminal 21 amino acids because of the replacement of 28 amino acids with 7 novel residues, had been exchanged generated a Ca2+-activated maximum force that was slightly, but statistically significantly, lower than that generated by fibers into which wild-type TnT had been exchanged when troponin I (TnI) was phosphorylated by cAMP-dependent protein kinase. A long truncated TnT simply lacking the COOH-terminal 14 amino acids had no significant effect on the maximum force-generating capability in the fibers with either phosphorylated or dephosphorylated TnI. Both these two truncated TnTs conferred a lower cooperativity and a higher Ca2+ sensitivity on the Ca2+-activated force generation than did wild-type TnT, independent of the phosphorylation of TnI by cAMP-dependent protein kinase. The results demonstrate that the splice donor site mutation in the cardiac TnT gene impairs the regulatory function of the TnT molecule, leading to an increase in the Ca2+ sensitivity, and a decrease in the cooperativity, of cardiac muscle contraction, which might be involved in the pathogenesis of HCM.

calcium sensitivity; cooperativity; truncated mutant; skinned fiber


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