Genetic Study Of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

Background and Objective: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D is a primary disease of the myocardium charac-terized byfibroadiposis replacing cardiac myocytes, predominantly in the right ventricle. Theclinical phenotype is characterized by ventricular arrhythmias originating from theright ventricle, sudden cardiac death, right ventricular dilation, local aneurysms, andheart failure., At present, it was reported that the pathogenesis of ARVC/D arerelation to inflammation, immunity, degeneration, cell apoptosis, gene mutation andother factors.Desmosome protein gene mutation is one of the important pathogenesis.The SCN5A gene, encoding for the α subunit of cardiac voltage-gated sodiumchannel-Nav1.5, is one of the well known genes for dilated cardiomyopathy,However, to date, there is no report about SCN5A mutations in ARVC/D. Recentstudy show that the cardiac sodium channel Nav1.5and desmosomal proteinplakophilin-2are co-localized at the intercalated disks, and furthermore demonstratethat the plakophilin-2interacts with Nav1.5. Whether the Nav1.5involved in thepathogenesis of ARVC/D is unkown. In this study, we will firstly explore themolecular genetic correlation between ARVC/D and sodium channel SCN5A.Methods:12patients according to the diagnostic guideline of ARVC/D revised in2010were collected. Genomic DNA was extracted from peripheral blood. All theexons and exon-intron boundaries of the SCN5A gene and desmosomal genes knownto be associated with ARVC/D, including DSC2, DSG2, DSP, JUP and PKP2weresequenced through the direct DNA sequencing. Gene variation comparing with200normal control subjects ensure gene mutation or SNP.Results: A total of12unrelated index patients were collected. A new missenseheterozygote mutation I137M in SCN5A gene. The mutation sited at the exon4of theSCN5A and the S1segment in Domain I of Nav1.5, consisted of an C-to-Gsubstitution at nucleotide site411(c.411C＞G), which predicted a substitution ofisoleucine for methionine at codon site137(p. Ile137Met, I137M). I137M was aconservative site in SCN5A gene and the encoding protein–Nav1.5may have a functional defect. Four SNPs in SCN5A（H558R, R1192Q, D1819D, A29A）havebeen found. All of SNPs have been reported in NCBI-SNP-Geneview. The SNPsdistribution from H558R, R1192Q, D1819D and A29A are similar with those reportedin the NCBI-SNP-Geneview.8patients have been found the SNP of12ARVC/Dpatients (66.6%). Fisher probabilities test shows that there is no difference in theincidence of the SNP between the two groups (P>0.05).Conclusion: Our study for the first time find a new SCN5A mutation–I137M inpatients with ARVC/D. The mutational sodium channel may result in the function ofNav1.5defected and destroy the “desmosomal-related complex” and cause thegenesis of ARVC/D. No novel SNP of SCN5A has been found in our study, However,four SNPs in SCN5A（H558R, R1192Q, D1819D, A29A）have been found.