GW24-e0318 Analysis of SCN5A mutation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia

Objectives Arrhythmogenic right ventricular cardiomyopathy/Dysplasia (ARVC/D) is a genetically determined disorder, characterised by the two component: cardiomyopathy and arrhythmia. To date, the molecular pathogenesis underly this phenomenon is poorly understood. Whether the ion channel defect involved in the ARVC/D is unknown. The aim of this study was systematically evaluate the sodium channel variants in ARVC/D. Methods The patients according to the diagnostic guideline of ARVC/D revised in 2010 were collected. Genomic DNA was extracted from peripheral blood lymphocytes. All the exons and exon-intron boundaries of the SCN5A gene and desmosomal genes known to be associated with ARVC/D, including DSC2, DSG2, DSP, JUP and PKP2 were sequenced through the direct DNA sequencing. Results A total of 13 unrelated index patients were collected. A new missense heterozygote mutation I137M in SCN5A gene was found in one proband 5. The mutation sited at the exon 4 of the SCN5A and the S1 segment in Domain I of Nav1.5, consisted of an C-to-G substitution at nucleotide site 411 (c.411C>G), which predicted a substitution of isoleucine for methionine at codon site 137 (p. Ile137Met, I137M). I137M was not detected in the 400 healthy control chromosomes from individuals of the same ethnic background, which indicated that this mutation was a conservative site in SCN5A gene and the encoding protein- Nav1.5 may have a functional defect. Conclusions Our study for the first time systematically evaluates the sodium channel variants in patients with ARVC/D and find a new SCN5A mutation- I137M. The result increases the insight of genetic pathogenesis in ARVC/D. The mutational sodium channel may destroy the “desmosomal-related complex” and cause the genesis of ARVC/D.