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

Department of Biology, University of Padua, Padua, Italy.
European journal of human genetics: EJHG (Impact Factor: 4.23). 03/2010; 18(7):776-82. DOI: 10.1038/ejhg.2010.19
Source: PubMed

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.

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Available from: Marzia De Bortoli, Aug 07, 2015
    • "It has been suggested, for instance, that the missense variant p.R490W in PKP2 may not be a causative mutation as it is located in exon 6, which is skipped in the cardiac isoform PKP2a [Gandjbakhch et al., 2011]. In another example, the p.A897KfsX4 frameshift variation in DSC2 was reclassified from pathogenic to a single-nucleotide polymorphism after it was identified in 1.5% of control subjects [De Bortoli et al., 2010]. "
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