Functional analysis of a troponin I (R145G) mutation associated with familial hypertrophic cardiomyopathy

Rosalyn Lang, Aldrin V Gomes, Jiaju Zhao, Philippe R. Housmans, Todd Miller, James D. Potter

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Abstract

Familial hypertrophic cardiomyopathy has been associated with several mutations in the gene encoding human cardiac troponin I (HCTnI). A missense mutation in the inhibitory region of TnI replaces an arginine residue at position 145 with a glycine and cosegregates with the disease. Results from several assays indicate that the inhibitory function of HCTnIR145G is significantly reduced. When HCTnIR145G was incorporated into whole troponin, TnR145G (HCTnT·HCTnIR145G·HCTnC), only partial inhibition of the actin-tropomyosin-myosin ATPase activity was observed in the absence of Ca2+ compared with wild type Tn (HCTnT·HCTnI·HCTnC). Maximal activation of actin-tropomyosin-myosin ATPase in the presence of Ca2+ was also decreased in TnR145G when compared with Tn. Using skinned cardiac muscle fibers, we determined that in comparison with the wild type complex 1) the complex containing HCTnIR145G only inhibited 84% of Ca2+-unregulated force, 2) the recovery of Ca2+-activated force was decreased, and 3) there was a significant increase in the Ca2+ sensitivity of force development. Computer modeling of troponin C and I variables predicts that the primary defect in TnI caused by these mutations would lead to diastolic dysfunction. These results suggest that severe diastolic dysfunction and somewhat decreased contractility would be prominent clinical features and that hypertrophy could arise as a compensatory mechanism.

Original languageEnglish (US)
Pages (from-to)11670-11678
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number14
DOIs
StatePublished - Apr 5 2002
Externally publishedYes

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Familial Hypertrophic Cardiomyopathy
Functional analysis
Tropomyosin
Troponin I
Myosins
Actins
Troponin C
Mutation
Gene encoding
Troponin
Missense Mutation
Glycine
Hypertrophy
Arginine
Muscle
Assays
Myocardium
Chemical activation
Recovery
Defects

ASJC Scopus subject areas

  • Biochemistry

Cite this

Functional analysis of a troponin I (R145G) mutation associated with familial hypertrophic cardiomyopathy. / Lang, Rosalyn; Gomes, Aldrin V; Zhao, Jiaju; Housmans, Philippe R.; Miller, Todd; Potter, James D.

In: Journal of Biological Chemistry, Vol. 277, No. 14, 05.04.2002, p. 11670-11678.

Research output: Contribution to journalArticle

Lang, Rosalyn ; Gomes, Aldrin V ; Zhao, Jiaju ; Housmans, Philippe R. ; Miller, Todd ; Potter, James D. / Functional analysis of a troponin I (R145G) mutation associated with familial hypertrophic cardiomyopathy. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 14. pp. 11670-11678.
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