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

Abstract

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.

Introduction

Dilated cardiomyopathy (DCM) is a common disorder of cardiac muscle that is characterized by ventricular dilatation and systolic dysfunction. It is commonly associated with cardiac arrhythmias, heart failure, and sudden death and is the most common reason for cardiac transplantation. Greater than 30% of DCM is caused by a genetic abnormality [1] that is most commonly inherited as an autosomal dominant trait. Autosomal recessive, X-linked, and mitochondrial patterns of inheritance have also been reported but are far less common.

Characterization of families and individuals with DCM has led to the identification of a number of genes that, when mutated, are capable of causing cardiac dilatation and sudden cardiac death. The DCM genes can be grouped into the following four main categories: (1) myocyte cytoskeletal proteins including desmin, titin, δ-sarcoglycan, plakoglobin, dystrophin, muscle LIM protein, α-actinin-2, and metavinculin; (2) sarcomeric proteins such as cardiac actin, cardiac troponin T, myosin binding protein C, α-tropomyosin, and β-myosin heavy chain; (3) nuclear envelope constituents such as lamin A/C and emerin; and (4) regulators of calcium homeostasis such as phospholamban [2], [3].

There is marked clinical heterogeneity of the disorder depending on the gene affected and the specific genetic mutation involved. Different mutations of the same gene can lead to varied manifestations with defects of some sarcomeric proteins leading to a hypertrophic, dilated, or hypertrophic then dilated phenotype depending on the mutation. Even within a family, where individuals harbor the same genetic abnormality, there can be marked variability in the disease severity depending on the presence of modifying genetic and non-genetic factors [4]. As additional genetic mutations are characterized, there is an increased understanding of the physiologic mechanisms that lead to cardiac dilatation and heart failure.

In this study, we sought to determine the genetic cause of an autosomal dominant form of dilated cardiomyopathy that afflicted a large, multigenerational family. The cardiomyopathy phenotype of the family was rather unique in that, although the inheritance was autosomal dominant, there was a disparity in the disease severity between males and females. Affected males tended to manifest greater left ventricular dilatation and systolic dysfunction.

Using linkage analysis, the most likely affected gene in this family was determined to be cardiac troponin T (TNNT2). Sequencing of the TNNT2 gene from an affected individual revealed a novel mutation that would be predicted to substitute a serine for a conserved alanine within a domain demonstrated to be critical for the binding of troponin T to α-tropomyosin. The proximity of this mutation to other mutations previously described to cause hypertrophic cardiomyopathy, and its differential manifestation based on gender suggest that further characterization of this specific mutation may identify functional differences between the hypertrophic and dilated cardiomyopathy associated troponin T mutations and may lend insight into an important modifying factor determining the severity of the disease.