Abstract
BackgroundTroponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study.MethodsWe have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM), along with 160 healthy controls, inhabited in the same geographical region of southern India.ResultsOur study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q) mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM). The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++). The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E) mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85%) with a rare codon (GAA: 14%). Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E) of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T) exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing.ConclusionOur study has provided valuable information regarding the prevalence of TNNI3 mutations in Indian HCM patients and its risk assessment, these will help in genetic counseling and to adopt appropriate treatment strategies.
Highlights
Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity
As there is no comprehensive study on Indian population, we have analysed all the exons and the exon-intron boundries of TNNI3 gene of Indian cardiomyopathy patients to assign its role in the etiology of cardiomyopathy among Indian populations
Screening of all the exons including the exon-intron boundaries of the TNNI3 gene in 101 individuals with hypertrophic cardiomyopathy patients (HCM) (Table 1) along with 160 healthy controls from India revealed a total of 16 mutations, including 15 SNPs, and a 4 bp deletion/insertion polymorphism (Table 2)
Summary
Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). Inherited cardiomyopathy is a disorder of ‘cardiac muscle’ associated with abnormalities of cardiac wall thickness, chamber size, contraction, relaxation, conduction and rhythm, were found to be the major cause of heart failure. It is different from other heart disease, as it frequently affects all the age groups, including young children, adults and competitive athletes [1]. Analysis of cardiac beta myosin heavy chain (MYH7) and myosin binding protein C (MyBPC3) in Indian HCM and DCM patients revealed few genetic variants associated with the disease [7,8]. As there is no comprehensive study on Indian population, we have analysed all the exons and the exon-intron boundries of TNNI3 gene of Indian cardiomyopathy patients to assign its role in the etiology of cardiomyopathy among Indian populations
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