Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C

Andrew P. Landstrom, Michelle S. Parvatiyar, Jose R. Pinto, Michelle L. Marquardt, J. Martijn Bos, David J. Tester, Steve R. Ommen, James D. Potter, Michael John Ackerman

Research output: Contribution to journalArticle

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Abstract

Hypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined by a hypertrophied left ventricle, is one of the main causes of sudden death in young athletes, and has been associated with mutations in most sarcomeric proteins (tropomyosin, troponin T and I, and actin, etc.). Many of these mutations appear to affect the functional properties of cardiac troponin C (cTnC), i.e., by increasing the Ca2+-sensitivity of contraction, a hallmark of HCM, yet surprisingly, prior to this report, cTnC had not been classified as a HCM-susceptibility gene. In this study, we show that mutations occurring in the human cTnC (HcTnC) gene (TNNC1) have the same prevalence (~ 0.4%) as well established HCM-susceptibility genes that encode other sarcomeric proteins. Comprehensive open reading frame/splice site mutation analysis of TNNC1 performed on 1025 unrelated HCM patients enrolled over the last 10 years revealed novel missense mutations in TNNC1: A8V, C84Y, E134D, and D145E. Functional studies with these recombinant HcTnC HCM mutations showed increased Ca2+ sensitivity of force development (A8V, C84Y and D145E) and force recovery (A8V and D145E). These results are consistent with the HCM functional phenotypes seen with other sarcomeric-HCM mutations (E134D showed no changes in these parameters). This is the largest cohort analysis of TNNC1 in HCM that details the discovery of at least three novel HCM-associated mutations and more strongly links TNNC1 to HCM along with functional evidence that supports a central role for its involvement in the disease. This study may help to further define TNNC1 as an HCM-susceptibility gene, a classification that has already been established for the other members of the troponin complex.

Original languageEnglish (US)
Pages (from-to)281-288
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume45
Issue number2
DOIs
StatePublished - Aug 2008

Fingerprint

Troponin C
Hypertrophic Cardiomyopathy
Mutation
Genes
Tropomyosin
Troponin T
Troponin
Troponin I
Missense Mutation
Sudden Death
Athletes
Open Reading Frames
Heart Ventricles
Actins
Cause of Death

Keywords

  • Calcium
  • Genetics
  • HCM
  • Hypertrophic cardiomyopathy
  • Mutation
  • TnC
  • Troponin C

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. / Landstrom, Andrew P.; Parvatiyar, Michelle S.; Pinto, Jose R.; Marquardt, Michelle L.; Bos, J. Martijn; Tester, David J.; Ommen, Steve R.; Potter, James D.; Ackerman, Michael John.

In: Journal of Molecular and Cellular Cardiology, Vol. 45, No. 2, 08.2008, p. 281-288.

Research output: Contribution to journalArticle

Landstrom, Andrew P. ; Parvatiyar, Michelle S. ; Pinto, Jose R. ; Marquardt, Michelle L. ; Bos, J. Martijn ; Tester, David J. ; Ommen, Steve R. ; Potter, James D. ; Ackerman, Michael John. / Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. In: Journal of Molecular and Cellular Cardiology. 2008 ; Vol. 45, No. 2. pp. 281-288.
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AU - Bos, J. Martijn

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