Abstract
Cardiomyopathy is a major cause of heart failure and sudden cardiac death; several mutations in sarcomeric protein genes have been associated with this disease. Our aim in the present study is to investigate the genetic variations in Troponin T (cTnT) gene and its association with dilated cardiomyopathy (DCM) in south-Indian patients. Analyses of all the exons and exon-intron boundaries of cTnT in 147 DCM and in 207 healthy controls had revealed a total of 15 SNPs and a 5 bp INDEL; of which, polymorphic SNPs were compared with the HapMap population data. Interestingly, a novel R144W mutation, that substitutes polar-neutral tryptophan for a highly conserved basic arginine in cTnT, altering the charge drastically, was identified in a DCM, with a family history of sudden-cardiac death (SCD). This mutation was found within the tropomyosin (TPM1) binding domain, and was evolutionarily conserved across species, therefore it is expected to have a significant impact on the structure and function of the protein. Family studies had revealed that the R144W is co-segregating with disease in the family as an autosomal dominant trait, but it was completely absent in 207 healthy controls and in 162 previously studied HCM patients. Further screening of the proband and three of his family members (positive for R144W mutant) with eight other genes β-MYH7, MYBPC3, TPM1, TNNI3, TTN, ACTC, MYL2 and MYL3, did not reveal any disease causing mutation, proposing the absence of compound heterozygosity. Therefore, we strongly suggest that the novel R144W unique/private mutant identified in this study is associated with FDCM. This is furthermore signifying the unique genetic architecture of Indian population.
Highlights
Dilated cardiomyopathy (DCM: OMIM 115200), is characterized by cardiac left ventricular dilation and systolic dysfunction, affects at least 1 in 2500 individuals [1], and a major cause for morbidity and mortality [2], including heart failure (HF) and sudden cardiac death (SCD) [3,4,5]
Sequencing of all the exons and the exon-intron boundaries (5373 bp) of Troponin T2 gene in 147 dilated cardiomyopathy (DCM) patients along with 207 healthy controls had revealed a total of 15 SNPs and a 5 bp INDEL (Fig. 1A to 1M and Table 1)
It has been shown initially that the mutations in the cTnT gene are responsible for approximately 15% cases of familial hypertrophic cardiomyopathy (FHCM) [27]
Summary
Dilated cardiomyopathy (DCM: OMIM 115200), is characterized by cardiac left ventricular dilation and systolic dysfunction, affects at least 1 in 2500 individuals [1], and a major cause for morbidity and mortality [2], including heart failure (HF) and sudden cardiac death (SCD) [3,4,5]. More than 30 nuclear genes, encoding for sarcomere (contractile apparatus), cytoskeletal and calcium homeostasis proteins of diverse functions, have been reported to cause FDCM [6]. Mutations in LMNA, MYH7, MYBPC3, TNNT2, SCN5A, and MYH6 genes have been accounted for approximately 75% of FDCM [12]. Most of the genes implicated in genetics of DCM/FDCM follow autosomal dominant mode of inheritance [6], though a few follow autosomal recessive, X-linked [10,13,14,15,16] and mitochondrial [16,17]. Recent studies had suggested that the double and triple mutations identified in sarcomere protein genes were found to be associated with early onset of HCM [18,19]
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