Purpose. Dominant mutations in genes encoding desmosomal proteins are reported to cause arrhythmogenic cardiomyopathy (AC), a heart muscle disease associated with ventricular arrhythmias, heart failure and risk of sudden death. Recessive mutations in the same genes most frequently cause cardiocutaneous syndromes. We present here a clinical and genetic study of 4 apparently unrelated AC families in which the cardiac-restricted phenotype is determined by a homozygous Desmocollin-2 (DSC2) mutation.
Methods. We performed an exon-by-exon analysis of the DSC2 gene on 80 unrelated Italian index patients diagnosed affected with AC according to revised 2010 Task Force criteria. Segregation of the detected DSC2 mutation was studied and haplotypes were reconstructed to determine whether this mutation was recurrent or founder. To evaluate the pathogenic potentials of the DSC2 mutation, 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 HL-1 cells.
Results. We identified the p.D179G homozygous mutation in DSC2 gene in 4 (5%) out of 80 Italian index cases. One of them resulted to carry an additional PKP2 frameshift mutation. Haplotype analysis revealed a conserved haplotype among all DSC2 mutation carriers, strongly indicating a common founder. A severe form of biventricular cardiomyopathy with typical electrical features of AC was diagnosed in all homozygous mutation carriers, whereas heterozygous family members were clinically asymptomatic. In vitro functional studies on HL-1 cells showed that DSC2-GFP-D179G protein correctly localizes at the intercalated discs.
Conclusions. This is the first founder homozygous mutation in DSC2 gene invariably associated with a severe AC phenotype in the Italian population. These findings could be important for risk stratification and mutation screening strategy.