Two novel missense mutations in the N-terminal domain of DSC2 (p.E102K and p.I345T) associated with ARVC cause the protein to predominantly localize in the cytoplasm rather than the cell membrane in vitro.
Observational (n=54)
Do missense mutations in the N-terminus of DSC2 associated with ARVC affect its intracellular localization in vitro?
Missense mutations in the N-terminal domain of DSC2 associated with ARVC lead to abnormal cytoplasmic localization of the protein in vitro, suggesting a pathogenic mechanism.
BACKGROUND: 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. METHODS: Mutation 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. RESULTS: We 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. CONCLUSION: The 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.
Beffagna et al. (Fri,) conducted a observational in Arrhythmogenic right ventricular cardiomyopathy (n=54). DSC2 missense mutations (p.E102K and p.I345T) vs. Wild-type DSC2 was evaluated on Intracellular localization of DSC2 in vitro. Two novel missense mutations in the N-terminal domain of DSC2 (p.E102K and p.I345T) associated with ARVC cause the protein to predominantly localize in the cytoplasm rather than the cell membrane in vitro.
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