The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutation in arrhythmogenic right ventricular cardiomyopathy

Abstract

Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), an autosomal-dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement. We screened 112 ARVC/D probands for mutations in desmocollin-2 (DSC2) gene and detected two different amino-acid substitutions (p.E102K, p.I345T) and a frameshift variation (p.A897KfsX4) in 7 (6.2%) patients. DSC2a variant p.A897KfsX4, previously reported as a p.E896fsX900 mutation, was identified in five unrelated probands. Four of them were found to carry one or two mutations in different ARVC/D genes. Unexpectedly, p.A897KfsX4 variation was also found in 6 (1.5%) out of 400 control chromosomes. In vitro functional studies showed that, unlike wild-type DSC2a, this C-terminal mutated protein was localised in the cytoplasm. p.A897KfsX4 variation affects the last five amino acids of the DSC2a isoform but not of DSC2b. In contrast with what we found in other human tissues, in the heart DSC2b is more expressed than DSC2a, suggesting that relative deficiency of DSC2a might be compensated by isoform b. In conclusion, DSC2 gene mutations are not frequently involved in ARVC/D. The p.A897KfsX4 variation, identified in several Italian healthy control subjects, which affects only one of the two DSC2 isoforms, may be considered a rare variant, though possibly affecting phenotypic expression of concomitant ARVC/D mutations

Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin-2 mutations

“…18 Although a low expression level of the DSC2a isoform in the myocardium 18 may contribute to the lack of an overt phenotype in these individuals, our functional studies demonstrate a pathogenic potential of this variant: its impaired binding to PG cannot directly be compensated by the DSC2b isoform, which does not bind PG ( Figure 5A ). However, the cytoplasmic domain of DSG2 appears to have redundant functions in binding PG in the desmosomes.…”

Familial Evaluation in Arrhythmogenic Right Ventricular Cardiomyopathy

“…The 58-year-old father, with no known cardiovascular disease, had frequent ventricular ectopics (Ͼ700 in 24 hours). Although the E896fsX900 frameshift variant has been reported in control subjects, 10,12 it was associated with the disease in this family, and preliminary and unpublished data from our laboratory showed functional abnormalities of this variant, and, therefore, we considered it as a possible cause of disease.…”

“…11 ‡This variant has been found in controls and its pathogenic role is controversial. 10,12 §This variant has been reported in control subjects and has a higher prevalence in patients with dilated cardiomyopathy. 8…”

“…The PKP2 gene variant I819N is a novel variant (not present in 300 control subjects) and was found in the proband's mother, who had T-wave inversion in V 1 to V 3 but no documented arrhythmias. The DSC2 gene variant E896fsX900 is a frameshift variant causing a premature stop coding and has been described as a polymorphism 10,12 because it has been found in control subjects. In this family, the sister and father of the proband carried the DSC2 gene variant.…”

Mechanistic Basis of Desmosome-Targeted Diseases

“…ARVC-linked mutations in the DSG2 IA region include short deletions due to frameshifts as well as a G638R substitution next to the transmembrane domain, which could conceivably promote binding to negatively charged lipids in the plasma membrane [61]. The ICS region is required for DSG1 binding to plakoglobin through a 1:1 complex, with key hydrophobic residues involved having been mapped by alanine scanning mutagenisis [62,63].…”