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: 4.35). 03/2010; 18(7):776-82. DOI: 10.1038/ejhg.2010.19
Source: PubMed


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.

Download full-text


Available from: Marzia De Bortoli
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Arrhythmogenic Cardiomyopathy (ACM) is an inherited cardiac disease characterized by myocardial atrophy, fibro-fatty replacement, and a high risk of ventricular arrhythmias that lead to sudden death. In 2009, genetic data from 57 publications were collected in the ARVD/C Genetic Variants Database (freeware available at, which comprised 481 variants in eight ACM-associated genes. In recent years, deep genetic sequencing has increased our knowledge of the genetics of ACM, revealing a large spectrum of nucleotide variations for which pathogenicity needs to be assessed. As of April 20 2014, we have updated the ARVD/C Database into the ARVD/C database to contain more than 1400 variants in 12 ACM-related genes (PKP2, DSP, DSC2, DSG2, JUP, TGFB3, TMEM43, LMNA, DES, TTN, PLN, CTNNA3) as reported in more than 160 references. Of these, only 411 nucleotide variants have been reported as pathogenic, while the significance of the other approximately 1000 variants is still unknown. This comprehensive collection of ACM genetic data represents a valuable source of information on the spectrum of ACM-associated genes and aims to facilitate the interpretation of genetic data and genetic counseling. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2015 · Human Mutation
  • Source
    • "The DSC2a protein contains the full ICS domain, whereas this module is significantly truncated in the DSC2b isoform. The ratio of isoforms appears to be controlled in a tissue-specific manner,7 suggesting an important regulatory role for tissue integrity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cellular adhesion mediated by cardiac desmosomes is a prerequisite for proper electric propagation mediated by gap junctions in the myocardium. However, the molecular principles underlying this interdependence are not fully understood. The purpose of this study was to determine potential causes of right ventricular conduction abnormalities in a patient with borderline diagnosis of arrhythmogenic right ventricular cardiomyopathy. To assess molecular changes, the patient's myocardial tissue was analyzed for altered desmosomal and gap junction (connexin43) protein levels and localization. In vitro functional studies were performed to characterize the consequences of the desmosomal mutations. Loss of plakoglobin signal was evident at the cell junctions despite expression of the protein at control levels. Although the distribution of connexin43 was not altered, total protein levels were reduced and changes in phosphorylation were observed. The truncation mutant in desmocollin-2a is deficient in binding plakoglobin. Moreover, the ability of desmocollin-2a to directly interact with connexin43 was abolished by the mutation. No pathogenic potential of the desmoglein-2 missense change was identified. The observed abnormalities in gap junction protein expression and phosphorylation, which precede an overt cardiac phenotype, likely are responsible for slow myocardial conduction in this patient. At the molecular level, altered binding properties of the desmocollin-2a mutant may contribute to the changes in connexin43. In particular, the newly identified interaction between the desmocollin-2a isoform and connexin43 provides novel insights into the molecular link between desmosomes and gap junctions.
    Full-text · Article · May 2011 · Heart rhythm: the official journal of the Heart Rhythm Society
  • Source
    • "Our findings suggest that this mutant protein is normally processed into its mature form and can be incorporated into the desmosomes of HL-1 cells and cardiomyocytes (Figures 3 and 4). In contrast to only minor changes in localization observed in our experiments (Figure 3), a recent report by De Bortoli et al.18 suggested the mis-localization of this variant in HL-1 cells. The use of a GFP fusion protein construct in their experiments might artificially have obscured the real localization of the mutant protein. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent immunohistochemical studies observed the loss of plakoglobin (PG) from the intercalated disc (ID) as a hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), suggesting a final common pathway for this disease. However, the underlying molecular processes are poorly understood. We have identified novel mutations in the desmosomal cadherin desmocollin 2 (DSC2 R203C, L229X, T275M, and G371fsX378). The two missense mutations (DSC2 R203C and T275M) have been functionally characterized, together with a previously reported frameshift variant (DSC2 A897fsX900), to examine their pathogenic potential towards PG's functions at the ID. The three mutant proteins were transiently expressed in various cellular systems and assayed for expression, processing, localization, and binding to other desmosomal components in comparison to wild-type DSC2a protein. The two missense mutations showed defects in proteolytic cleavage, a process which is required for the functional activation of mature cadherins. In both cases, this is thought to cause a reduction of functional DSC2 at the desmosomes in cardiac cells. In contrast, the frameshift variant was incorporated into cardiac desmosomes; however, it showed reduced binding to PG. Despite different modes of action, for all three variants, the reduced ability to provide a ligand for PG at the desmosomes was observed. This is in agreement with the reduced intensity of PG at these structures observed in ARVC patients.
    Full-text · Article · Nov 2010 · Cardiovascular Research
Show more