Functional consequences of the mutations in human cardiac troponin I gene found in familial hypertrophic cardiomyopathy

Fumi Takahashi-Yanaga, Sachio Morimoto, Keita Harada, Reiko Minakami, Fumie Shiraishi, Mika Ohta, Qun Wei Lu, Toshiyuki Sasaguri, Iwao Ohtsuki

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79 Citations (Scopus)


Functional consequences of the six mutations (R145G, R145Q, R162W, ΔK183, G203S, K206Q) in cardiac troponin I (cTnI) that cause familial hypertrophic cardiomyopathy (HCM) were studied using purified recombinant human cTnI. The missense mutations R145G and R145Q in the inhibitory region of cTnI reduced the intrinsic inhibitory activity of cTnI without changing the apparent affinity for actin. On the other hand, the missense mutation R162W in the second troponin C binding region and the deletion mutation ΔK183 near the second actin-tropomyosin region reduced the apparent affinity of cTnI for actin without changing the intrinsic inhibitory activity. Ca2- titration of a fluorescent probe-labeled human cardiac troponin C (cTnC) showed that only R162W mutation impaired the cTnC-cTnI interaction determining the Ca2+ affinity of the N-terminal regulatory domain of cTnC. Exchanging the human cardiac troponin into isolated cardiac myofibrils or skinned cardiac muscle fibers showed that the mutations R145G, R145Q, R162W, ΔK183 and K206Q induced a definite increase in the Ca2+-sensitivitiy of myofibrillar ATPase activity and force generation in skinned muscle fibers. Although the mutation G203S also showed a tendency to increase the Ca2+ sensitivity in both myofibrils and skinned muscle fibers, no statistically significant difference compared with wild-type cTnI could be detected. These results demonstrated that most of the HCM-linked cTnI mutations did affect the regulatory processes involving the cTnI molecule, and that at least five mutations (R145G, R145Q, R162W, ΔK183, K206Q) increased the Ca2- sensitivity of cardiac muscle contraction.

Original languageEnglish
Pages (from-to)2095-2107
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Issue number12
Publication statusPublished - 2001

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


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