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PLoS One. 2012;7(10):e47097. doi: 10.1371/journal.pone.0047097. Epub 2012 Oct 10.

In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations.

Author information

1
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development, Clinic of Thoracic and Cardiovascular Surgery, Heart and Diabetes Centre NRW, Ruhr-University Bochum, Bad Oeynhausen, Germany.

Abstract

BACKGROUND:

Although numerous sequence variants in desmoglein-2 (DSG2) have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), the functional impact of new sequence variations is difficult to estimate.

METHODOLOGY/PRINCIPAL FINDINGS:

To test the functional consequences of DSG2-variants, we established an expression system for the extracellular domain and the full-length DSG2 using the human cell line HT1080. We established new tools to investigate ARVC-associated DSG2 variations and compared wild-type proteins and proteins with one of the five selected variations (DSG2-p.R46Q, -p.D154E, -p.D187G, -p.K294E, -p.V392I) with respect to prodomain cleavage, adhesion properties and cellular localisation.

CONCLUSIONS/SIGNIFICANCE:

The ARVC-associated DSG2-p.R46Q variation was predicted to be probably damaging by bioinformatics tools and to concern a conserved proprotein convertase cleavage site. In this study an impaired prodomain cleavage and an influence on the DSG2-properties could be demonstrated for the R46Q-variant leading to the classification of the variant as a potential gain-of-function mutant. In contrast, the variants DSG2-p.K294E and -p.V392I, which have an arguable impact on ARVC pathogenesis and are predicted to be benign, did not show functional differences to the wild-type protein in our study. Notably, the variants DSG2-p.D154E and -p.D187G, which were predicted to be damaging by bioinformatics tools, had no detectable effects on the DSG2 protein properties in our study.

PMID:
23071725
PMCID:
PMC3468437
DOI:
10.1371/journal.pone.0047097
[Indexed for MEDLINE]
Free PMC Article

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