Novel mutations in arrhythmogenic right ventricular cardiomyopathy from Indian population.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive condition with right ventricular myocardium being replaced by fibro-fatty tissue. The spectrum of the expression may range from benign palpitations to the most malignant sudden death. Most of the mutations identified for the condition are localized in desmosomal proteins although three other nondesmosomal genes (cardiac ryanodine receptor-2, TGF-β3, and TMEM43) have also been implicated in ARVC. Both desmosomal and nondesmosomal genes were screened in a set of patients from local population. MATERIALS AND METHODS: A set of 34 patients from local population were included in this study. Diagnosis was based on the criteria proposed by task force of European Society of Cardiology/International Society and Federation of Cardiology. Polymerase chain reaction-based single-strand conformation polymorphism analysis was carried out, and samples with abnormal band pattern were commercially sequenced. RESULTS: Screening of cardiac ryanodine receptor revealed an insertion of a base in the intronic region of exon-28 in a patient, leading to a creation of a cryptic splice site. Screening of plakohilin-2 for mutations revealed an abnormal band pattern in three patients. Two of them had similar abnormal band pattern for exon-3.1. Sequencing revealed a novel 2 base pair deletion (433_434 delCT), which would lead to premature truncation of the protein (L145EfsX8). Another patient showed abnormal band pattern for exon-3.2 and sequencing revealed a missense mutation C792T leading to amino acid change P244L, in N-terminal, and this substitution may cause disturbances in the various protein–protein interactions. CONCLUSION: This study reports novel cardiac ryanodine receptor (RyR-2) mutations and Pkp-2 for the first time from Indian population.

Comparison of Uhl’s anomaly, right ventricular outflow tract ventricular tachycardia (RVOT VT) & arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) with an insight into genetics of ARVD/C.

Among the right ventricular conditions, Uhl’s anomaly, arrhythmogenic right ventricular dysplasia / cardiomyopathy (ARVD/C) and right ventricular outflow tract ventricular tachycardia (RVOT VT) are disorders that exhibit pathogenic changes involving the right ventricular (RV) myocardium, and are expected to be severe or milder forms of the same condition. The review focuses on the aspect whether the three RV disorders are a spectrum of the same disease. ARVD/C is the only condition among these to be genetically well characterized. Also, variations in the clinical expression of ARVD/C due to the genetic heterogeneity are examined. Based on clinical manifestations, age at onset, gender ratio and the possible molecular mechanisms implicated, Uhl’s anomaly, ARVD/C and RVOT VT may be considered as separate entities. Further, to differentiate between the three RV disorders, the molecular studies on ARVD/C might be helpful. An attempt was made to differentiate between the eleven different types of ARVD/Cs based on clinical symptoms presented including the progression of the disease to the left ventricle, ventricular arrhythmias and clinical characteristics like ECG, SAECG, ECHO and histopathological studies.

Genetic variation in exon 5 of troponin - I gene in hypertrophic cardiomyopathy cases.

BACKGROUND: Cardiomyopathies are a heterogeneous group of heart muscle disorders and are classified as 1) Hypertrophic Cardiomyopathy (HCM) 2) Dilated cardiomyopathy (DCM) 3) Restrictive cardiomyopathy (RCM) and 4) Arrhythmogenic right ventricular dysplasia (ARVD) as per WHO classification, of which HCM and DCM are common. HCM is a complex but relatively common form of inherited heart muscle disease with prevalence of 1 in 500 individuals and is commonly associated with sarcomeric gene mutations. Cardiac muscle troponin I (TNNI-3) is one such sarcomeric protein and is a subunit of the thin filament-associated troponin-tropomyosin complex involved in calcium regulation of skeletal and cardiac muscle contraction. Mutations in this gene were found to be associated with a history of sudden cardiac death in HCM patients. AIM: Therefore the present study aims to identify for mutations associated with troponin I gene in a set of HCM patients from Indian population. MATERIALS AND METHODS: Mutational analyses of 92 HCM cases were carried out following PCR based SSCP analysis. RESULTS: The study revealed band pattern variation in 3 cases from a group of 92 HCM patients. This band pattern variation, on sequencing revealed base changes, one at nt 2560 with G>T transversion in exon-5 region with a wobble and others at nt 2479 and nt 2478 with G>C and C>G transversions in the intronic region upstream of the exon 5 on sequencing. Further analysis showed that one of the probands showed apical form of hypertrophy, two others showing asymmetric septal hypertrophy. Two of these probands showed family history of the condition. CONCLUSIONS: Hence, the study supports earlier reports of involvement of TNNI-3 in the causation of apical and asymmetrical forms of hypertrophy.