Abstract
BackgroundMutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC), an autosomal dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement.We screened 54 ARVC probands for mutations in desmocollin-2 (DSC2), the only desmocollin isoform expressed in cardiac tissue.MethodsMutation screening was performed by denaturing high-performance liquid chromatography and direct sequencing.To evaluate the pathogenic potentials of the DSC2 mutations detected in patients affected with ARVC, full-length wild-type and mutated cDNAs were cloned in eukaryotic expression vectors to obtain a fusion protein with green fluorescence protein (GFP); constructs were transfected in neonatal rat cardiomyocytes and in HL-1 cells.ResultsWe identified two heterozygous mutations (c.304G>A (p.E102K) and c.1034T>C (p.I345T)) in two probands and in four family members. The two mutations p.E102K and p.I345T map to the N-terminal region, relevant to adhesive interactions.In vitro functional studies demonstrated that, unlike wild-type DSC2, the two N-terminal mutants are predominantly localised in the cytoplasm.ConclusionThe two missense mutations in the N-terminal domain affect the normal localisation of DSC2, thus suggesting the potential pathogenic effect of the reported mutations. Identification of additional DSC2 mutations associated with ARVC may result in increased diagnostic accuracy with implications for genetic counseling.
Highlights
Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC), an autosomal dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement.We screened 54 ARVC probands for mutations in desmocollin-2 (DSC2), the only desmocollin isoform expressed in cardiac tissue
The two missense mutations in the N-terminal domain affect the normal localisation of DSC2, suggesting the potential pathogenic effect of the reported mutations
Identification of additional DSC2 mutations associated with ARVC may result in increased diagnostic accuracy with implications for genetic counseling
Summary
Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC), an autosomal dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement.We screened 54 ARVC probands for mutations in desmocollin-2 (DSC2), the only desmocollin isoform expressed in cardiac tissue. Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC), an autosomal dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement. Pathogenic mutations underlying ARVC were detected in RyR2 (cardiac ryanodine receptor) [3] and in TGFβ3 (transforming growth factor-β3) [4] genes, finding mutations in genes encoding desmosomal proteins, namely Desmoplakin (DSP), Plakophilin-2 (PKP2) and Desmoglein-2 (DSG2) [5,6,7] led to current idea that ARVC is due to desmosomal dysfunction [8] This was further strengthened by two recent studies that reported mutations in the desmosomal desmocollin (DSC2) gene as the cause of ARVC [9,10]. Intercalated discs ultrastructural abnormalities consisting of decreased desmosome number and intercellular gap widening were observed in ARVC biopsy samples [12]
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