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

Greta Marie Pohl; Manuel Göz; Anna Gaertner; Andreas Brodehl; Tolga Cimen; Ardan M Saguner; Eric Schulze-Bahr; Volker Walhorn; Dario Anselmetti; Hendrik Milting

doi:10.3389/fcvm.2023.1127261

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

Front Cardiovasc Med. 2023 May 19:10:1127261. doi: 10.3389/fcvm.2023.1127261. eCollection 2023.

Affiliations

¹ Erich & Hanna Klessmann-Institute for Cardiovascular Research and Development & Clinic for Thoracic and Cardiovascular Surgery, Heart- and Diabetes Center NRW, D-32545 Bad Oeynhausen, University Hospital of the Ruhr-University Bochum, Bad Oeynhausen, Germany.
² Experimental Biophysics and Applied Nanoscience, Faculty of Physics, University of Bielefeld, NRW, Bielefeld, Germany.
³ Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Zürich, Switzerland.
⁴ Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.

Abstract

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.

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 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.

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.

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.

Keywords: DSC2; arrhythmogenic cardiomyopathy; desmocollin-2; desmosome; genetic variants; intracellular transport; prodomain; signal peptide.

Grants and funding

HM and DA received funding by the Deutsche Forschungsgemeinschaft (DFG, AN 370/6-2 & MI 1146/2-2) and the Erich and Hanna Klessmann Foundation (Gütersloh, Germany). AB and HM are thankful for funding by the Ruhr-University Bochum (FoRUM, F937R2). The Zurich ARVC Program is supported by the Georg und Bertha Schwyzer-Winiker Foundation; Baugarten Foundation; USZ Foundation (Wild Grant); and Swiss Heart Foundation grant no. FF17019 and FF21073.