Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy

Jose Renato Pinto, Jill D. Siegfried, Michelle S. Parvatiyar, Duanxiang Li, Nadine Norton, Michelle A. Jones, Jingsheng Liang, James D. Potter, Ray E. Hershberger

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

TNNC1, which encodes cardiac troponin C (cTnC), remains elusive as a dilated cardiomyopathy (DCM) gene. Here, we report the clinical, genetic, and functional characterization of four TNNC1 rare variants (Y5H, M103I, D145E, and I148V), all previously reported by us in association with DCM (Hershberger, R. E., Norton, N., Morales, A., Li, D., Siegfried, J. D., and Gonzalez-Quintana, J. (2010) Circ. Cardiovasc. Genet. 3, 155-161); in the previous study, two variants (Y5H and D145E) were identified in subjects who also carried MYH7 and MYBPC3 rare variants, respectively. Functional studies using the recombinant human mutant cTnC proteins reconstituted into porcine papillary skinned fibers showed decreased Ca 2+ sensitivity of force development (Y5H and M103I). Furthermore, the cTnC mutants diminished (Y5H and I148V) or abolished (M103I) the effects of PKA phosphorylation on Ca 2+ sensitivity. Only M103I decreased the troponin activation properties of the actomyosin ATPase when Ca 2+ was present. CD spectroscopic studies of apo (absence of divalent cations)-, Mg 2+-,and Ca 2+/Mg 2+-bound states indicated that all of the cTnC mutants (except I148V in the Ca 2+/Mg 2+ condition) decreased the α-helical content. These results suggest that each mutation alters the function/ability of the myofilament to bind Ca 2+ as a result of modifications in cTnC structure. One variant (D145E) that was previously reported in association with hypertrophic cardiomyopathy and that produced results in vivo in this study consistent with prior hypertrophic cardiomyopathy functional studies was found associated with the MYBPC3 P910T rare variant, likely contributing to the observed DCM phenotype. We conclude that these rare variants alter the regulation of contraction in some way, and the combined clinical, molecular, genetic, and functional data reinforce the importance of TNNC1 rare variants in the pathogenesis of DCM.

Original languageEnglish
Pages (from-to)34404-34412
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number39
DOIs
StatePublished - Oct 30 2011
Externally publishedYes

Fingerprint

Troponin C
Dilated Cardiomyopathy
Hypertrophic Cardiomyopathy
Association reactions
Viverridae
Phosphorylation
Troponin
Myofibrils
Divalent Cations
Myosins
Molecular Biology
Swine
Genes
Chemical activation
Phenotype
Mutation
Fibers
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Pinto, J. R., Siegfried, J. D., Parvatiyar, M. S., Li, D., Norton, N., Jones, M. A., ... Hershberger, R. E. (2011). Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy. Journal of Biological Chemistry, 286(39), 34404-34412. https://doi.org/10.1074/jbc.M111.267211

Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy. / Pinto, Jose Renato; Siegfried, Jill D.; Parvatiyar, Michelle S.; Li, Duanxiang; Norton, Nadine; Jones, Michelle A.; Liang, Jingsheng; Potter, James D.; Hershberger, Ray E.

In: Journal of Biological Chemistry, Vol. 286, No. 39, 30.10.2011, p. 34404-34412.

Research output: Contribution to journalArticle

Pinto, JR, Siegfried, JD, Parvatiyar, MS, Li, D, Norton, N, Jones, MA, Liang, J, Potter, JD & Hershberger, RE 2011, 'Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy', Journal of Biological Chemistry, vol. 286, no. 39, pp. 34404-34412. https://doi.org/10.1074/jbc.M111.267211
Pinto JR, Siegfried JD, Parvatiyar MS, Li D, Norton N, Jones MA et al. Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy. Journal of Biological Chemistry. 2011 Oct 30;286(39):34404-34412. https://doi.org/10.1074/jbc.M111.267211
Pinto, Jose Renato ; Siegfried, Jill D. ; Parvatiyar, Michelle S. ; Li, Duanxiang ; Norton, Nadine ; Jones, Michelle A. ; Liang, Jingsheng ; Potter, James D. ; Hershberger, Ray E. / Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 39. pp. 34404-34412.
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