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

• Published in: Journal of molecular and cellular cardiology 2008-08, Vol.45 (2), p.281-288
• Main Authors: 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 J
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Amino Acid Sequence; Amino Acid Substitution - genetics; Animals; Calcium; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Hypertrophic - metabolism; Cardiomyopathy, Hypertrophic - pathology; Cardiovascular; Cells, Cultured; Cohort Studies; Female; Genetic Predisposition to Disease; Genetics; HCM; Humans; Hypertrophic cardiomyopathy; Male; Mice; Middle Aged; Molecular Sequence Data; Mutation; Mutation, Missense - genetics; Rats; Swine; TnC; Troponin C; Troponin C - classification; Troponin C - genetics; Troponin C - physiology
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2008.05.003

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.