A novel arginine to tryptophan (R144W) mutation in troponin T (cTnT) gene in an indian multigenerational family with dilated cardiomyopathy (FDCM)

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 cardiomyop...

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Published inPloS one Vol. 9; no. 7; p. e101451
Main Authors Rani, Deepa Selvi, Dhandapany, Perundurai S, Nallari, Pratibha, Narasimhan, Calambur, Thangaraj, Kumarasamy
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 03.07.2014
Public Library of Science (PLoS)
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Summary: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.
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Competing Interests: The authors have declared that no competing interests exist.
Conceived and designed the experiments: DSR PN KT. Performed the experiments: DSR PSD. Analyzed the data: DSR KT. Contributed reagents/materials/analysis tools: DSR PSD PN CN KT. Wrote the paper: DSR. Provided input on manuscript writing: KT.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0101451