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POPDC2 a novel susceptibility gene for conduction disorders

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Rinné et al. POPDC2 manuscript 2020-02-05-Niels 2020-05-22.docxAccepted version1.12 MBMicrosoft WordView/Open
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Title: POPDC2 a novel susceptibility gene for conduction disorders
Authors: Rinné, S
Ortiz-Bonnin, B
Stallmeyer, B
Kiper, AK
Lisa Fortmüller, L
Schindler, RFR
Herbort-Brand, U
Kabir, NS
Dittmann, S
Friedrich, C
Zumhagen, S
Gualandi, F
Selvatici, R
Rapezzi, C
Arbustini, E
Ferlini, A
Larissa, F
Schulze-Bahr, E
Brand, T
Decher, N
Item Type: Journal Article
Abstract: Despite recent progress in the understanding of cardiac ion channel function and its role in inherited forms of ventricular arrhythmias, the molecular basis of cardiac conduction disorders often remains unresolved. We aimed to elucidate the genetic background of familial atrioventricular block (AVB) using a whole exome sequencing (WES) approach. In monozygotic twins with a third-degree AVB and in another, unrelated family with first-degree AVB, we identified a heterozygous nonsense mutation in the POPDC2 gene causing a premature stop at position 188 (POPDC2W188*), deleting parts of its cAMP binding-domain. Popeye-domain containing (POPDC) proteins are predominantly expressed in the skeletal muscle and the heart, with particularly high expression of POPDC2 in the sinoatrial node of the mouse. We now show by quantitative PCR experiments that in the human heart the POPDC-modulated two-pore domain potassium (K2P) channel TREK 1 is preferentially expressed in the atrioventricular node. Co-expression studies in Xenopus oocytes revealed that POPDC2W188* causes a loss-of-function with impaired TREK-1 modulation. Consistent with the high expression level of POPDC2 in the murine sinoatrial node, POPDC2W188* knock-in mice displayed stress-induced sinus bradycardia and pauses, a phenotype that was previously also reported for POPDC2 and TREK-1 knock-out mice. We propose that the POPDC2W188* loss-of-function mutation contributes to AVB pathogenesis by an aberrant modulation of TREK 1, highlighting that POPDC2 represents a novel arrhythmia gene for cardiac conduction disorders.
Issue Date: Aug-2020
Date of Acceptance: 9-Jun-2020
URI: http://hdl.handle.net/10044/1/80907
DOI: 10.1016/j.yjmcc.2020.06.005
ISSN: 0022-2828
Publisher: Elsevier
Start Page: 74
End Page: 83
Journal / Book Title: Journal of Molecular and Cellular Cardiology
Volume: 145
Copyright Statement: © 2020 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor/Funder: Medical Research Council (MRC)
British Heart Foundation
British Heart Foundation
Funder's Grant Number: MR/J010383/1
PG/14/46/30911
PG/19/13/34247
Keywords: Arrhythmia
Atrioventricular block
Ion channels
Whole exome sequencing
Cardiovascular System & Hematology
1102 Cardiorespiratory Medicine and Haematology
1116 Medical Physiology
Publication Status: Published
Online Publication Date: 2020-06-11
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



This item is licensed under a Creative Commons License Creative Commons