Cardiomyopathy related desmocollin-2 prodomain variants affect the intracellular cadherin transport and processing

  • \(\bf Background:\) Arrhythmogenic cardiomyopathy can be caused by genetic variants in desmosomal cadherins. Since cardiac desmosomal cadherins are crucial for cell-cell-adhesion, their correct localization at the plasma membrane is essential. \(\bf Methods:\) Nine desmocollin-2 variants at five positions from various public genetic databases (p.D30N, p.V52A/I, p.G77V/D/S, p.V79G, p.I96V/T) and three additional conserved positions (p.C32, p.C57, p.F71) within the prodomain were investigated \(\textit {in vitro}\) using confocal microscopy. Model variants (p.C32A/S, p.V52G/L, p.C57A/S, p.F71Y/A/S, p.V79A/I/L, p.I96l/A) were generated to investigate the impact of specific amino acids. \(\bf Results:\) We revealed that all analyzed positions in the prodomain are critical for the intracellular transport. However, the variants p.D30N, p.V52A/I and p.I96V listed in genetic databases do not disturb the intracellular transport revealing that the loss of these canonical sequences may be compensated. \(\bf Conclusion:\) As disease-related homozygous truncating desmocollin-2 variants lacking the transmembrane domain are not localized at the plasma membrane, we predict that some of the investigated prodomain variants may be relevant in the context of arrhythmogenic cardiomyopathy due to disturbed intracellular transport.

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Author:Greta Marie PohlGND, Manuel GözGND, Anna Gärtner-RommelORCiDGND, Andreas BrodehlORCiDGND, Tolga CimenGND, Ardan Muammer SagunerORCiDGND, Eric Schulze-BahrGND, Volker WalhornGND, Dario AnselmettiORCiDGND, Hendrik MiltingORCiDGND
Parent Title (English):Frontiers in cardiovascular medicine
Publisher:Frontiers Media
Place of publication:Lausanne
Document Type:Article
Date of Publication (online):2023/01/11
Date of first Publication:2023/05/19
Publishing Institution:Ruhr-Universität Bochum, Universitätsbibliothek
Tag:Open Access Fonds
DSC2; arrhythmogenic cardiomyopathy; desmocollin-2; desmosome; genetic variants; intracellular transport; prodomain; signal peptide
Issue:Article 1127261
First Page:1127261-01
Last Page:1127261-20
Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum.
Institutes/Facilities:Herz- und Diabeteszentrum NRW
Erich und Hanna Klessmann-Institut für kardiovaskuläre Forschung und Entwicklung
Dewey Decimal Classification:Technik, Medizin, angewandte Wissenschaften / Medizin, Gesundheit
open_access (DINI-Set):open_access
Licence (English):License LogoCreative Commons - CC BY 4.0 - Attribution 4.0 International