Novel troponin T mutation in familial dilated cardiomyopathy with gender-dependant severity

• Published in: Molecular genetics and metabolism Vol. 83; no. 1; pp. 188 - 196
• Main Authors: Stefanelli, Christopher B., Rosenthal, Amnon, Borisov, Andrei B., Ensing, Gregory J., Russell, Mark W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2004
• Subjects: Adult; Aged; Alanine - genetics; Amino Acid Sequence; Amino Acid Substitution; Binding Sites; Cardiomyopathy, Hypertrophic, Familial - etiology; Cardiomyopathy, Hypertrophic, Familial - genetics; Child; Child, Preschool; Conserved Sequence; Dilated cardiomyopathy; Female; Gender; Genetic Linkage; Humans; Male; Molecular Sequence Data; Mutation; Phenotype; Serine - genetics; Severity of Illness Index; Sex Factors; Tei index; Troponin T; Troponin T - genetics; Troponin T - metabolism; Gender; Mutation; Dilated cardiomyopathy; Tei index; Troponin T
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2004.04.013

Mutations in sarcomeric proteins can lead to either hypertrophic or dilated cardiomyopathy depending on their effects on the structural and functional properties of the contractile unit of the heart. Mutations in cardiac troponin T, which binds the calcium-responsive troponin complex to α-tropomyosin, have been shown to result in cardiac hypertrophy or cardiac dilatation and heart failure, depending on the nature of the specific mutation. In this study, we report the identification of a novel cardiac troponin T mutation (A171S) leading to dilated cardiomyopathy and sudden cardiac death. In contrast to prior described mutations, the A171S mutation results in a significant gender difference in the severity of the observed phenotype with adult males (over 20 years of age) demonstrating more severe ventricular dilatation [left ventricular end diastolic dimension (LVEDD) 7.1 vs. 5.1 cm; P=0.01, t test] and left ventricular dysfunction [left ventricular shortening fraction (LVSF) 21 vs. 34%; P=0.04, t test] than adult females. The described mutation substitutes a hydrophilic amino acid for a hydrophobic one in a highly conserved domain involved in the interaction between troponin T and α-tropomyosin. Interestingly, four previously described mutations within 12 amino acids of A171 lead to a hypertrophic phenotype, suggesting that further characterization of the functional consequences of the A171S mutation may lead to a better understanding of the pathophysiology of DCM and of the functional differences between HCM- and DCM-causing mutations in cardiac troponin T.