👤 Calambur Narasimhan

Mutations in sarcomeric genes are the leading cause for cardiomyopathies. However, not many genetic studies have been carried out on Indian cardiomyopathy patients. We performed sequence analyses of a thin filament sarcomeric gene, α-tropomyosin (TPM1), in 101 hypertrophic cardiomyopathy (HCM) patients and 147 dilated cardiomyopathy (DCM) patients against 207 ethnically matched healthy controls, revealing 13 single nucleotide polymorphisms (SNPs). Of these, one mutant, S215L, was identified in two unrelated HCM cases-patient #1, aged 44, and patient #2, aged 65-and was cosegregating with disease in these families as an autosomal dominant trait. In contrast, S215L was completely absent in 147 DCM and 207 controls. Patient #1 showed a more severe disease phenotype, with poor prognosis and a family history of sudden cardiac death, than patient #2. Therefore, these two patients and the family members positive for S215L were further screened for variations in MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, and ACTC. Interestingly, two novel thick filaments, D896N (homozygous) and I524K (heterozygous) mutations, in the MYH7 gene were identified exclusively in patient #1 and his family members. Thus, we strongly suggest that the coexistence of these digenic mutations is rare, but leads to severe hypertrophy in a South Indian familial hypertrophic cardiomyopathy (FHCM). Show less

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. Show less

Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disorder affecting the cardiac muscle and exhibits varied clinical symptoms because of genetic heterogeneity. Several disease causing genes have been identified and most code for sarcomere proteins. In the current study, we have carried out clinical and molecular analysis of FHC patients from India. FHC was detected using echocardiography and by analysis of clinical symptoms and family history. Disease causing mutations in the β-cardiac myosin heavy chain (MYH7) and Myosin binding protein C3 (MYBPC3) genes were identified using Polymerase Chain Reaction-Deoxyribose Nucleic Acid (PCR-DNA) sequencing. Of the 55 patient samples screened, mutations were detected in only nineteen in the two genes; MYBPC3 mutations were identified in 12 patients while MYH7 mutations were identified in five, two patients exhibited double heterozygosity. All four MYH7 mutations were missense mutations, whereas only 3/9 MYPBC3 mutations were missense mutations. Four novel mutations in MYBPC3 viz. c.456delC, c.2128G>A (p.E710K), c.3641G>A (p.W1214X), and c.3656T>C (p.L1219P) and one in MYH7 viz. c.965C>T (p.S322F) were identified. A majority of missense mutations affected conserved amino acid residues and were predicted to alter the structure of the corresponding mutant proteins. The study has revealed a greater frequency of occurrence of MYBPC3 mutations when compared to MYH7 mutations. Show less

Heart failure is a leading cause of mortality in South Asians. However, its genetic etiology remains largely unknown. Cardiomyopathies due to sarcomeric mutations are a major monogenic cause for heart failure (MIM600958). Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin binding protein C (MYBPC3) that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations (initial study OR = 5.3 (95% CI = 2.3-13), P = 2 x 10(-6); replication study OR = 8.59 (3.19-25.05), P = 3 x 10(-8); combined OR = 6.99 (3.68-13.57), P = 4 x 10(-11)) and that disrupts cardiomyocyte structure in vitro. Its prevalence was found to be high (approximately 4%) in populations of Indian subcontinental ancestry. The finding of a common risk factor implicated in South Asian subjects with cardiomyopathy will help in identifying and counseling individuals predisposed to cardiac diseases in this region. Show less