title: 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.
authors.affiliation: Department of Biology, University of Padua, Padua, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: De Bortoli
authors.forename: Giorgia
authors.initials: G
authors.lastname: Beffagna
authors.forename: Barbara
authors.initials: B
authors.lastname: Bauce
authors.forename: Alessandra
authors.initials: A
authors.lastname: Lorenzon
authors.forename: Gessica
authors.initials: G
authors.lastname: Smaniotto
authors.forename: Ilaria
authors.initials: I
authors.lastname: Rigato
authors.forename: Martina
authors.initials: M
authors.lastname: Calore
authors.forename: Ilena E A
authors.initials: IE
authors.lastname: Li Mura
authors.forename: Cristina
authors.initials: C
authors.lastname: Basso
authors.forename: Gaetano
authors.initials: G
authors.lastname: Thiene
authors.forename: Gerolamo
authors.initials: G
authors.lastname: Lanfranchi
authors.forename: Gian Antonio
authors.initials: GA
authors.lastname: Danieli
authors.forename: Andrea
authors.initials: A
authors.lastname: Nava
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rampazzo
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D004252:DNA Mutational Analysis; D051187:Desmocollins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C081561:DSC2 protein, human; D051187:Desmocollins; D050505:Mutant Proteins; D020033:Protein Isoforms