Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy

POPDC2 encodes the Popeye domain-containing protein 2, which has an important role in cardiac pacemaking and conduction, due in part to its cyclic AMP (cAMP)-dependent binding and regulation of TREK-1 potassium channels. Loss of Popdc2 in mice results in sinus pauses and bradycardia, and morpholino-mediated knockdown of popdc2 in zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in POPDC2 in four families with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects, and hypertrophic cardiomyopathy. Using homology modeling, we show that the identified variants are predicted to diminish the ability of POPDC2 to bind cAMP. In in vitro electrophysiological studies, we demonstrated that, in contrast with wild-type POPDC2, variants found in affected individuals failed to increase TREK-1 current density. While muscle biopsy of an affected individual did not show clear myopathic disease, it showed significantly reduced abundance of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1-POPDC2 complex is impaired by pathogenic variants in either protein. Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and POPDC2 was most prevalent in AV node, AV node pacemaker, and AV bundle cells. Using population-level genetic data of more than 1 million individuals, we show that none of the familial variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up. Our findings provide evidence for bi-allelic variants in POPDC2 causing a Mendelian autosomal recessive cardiac syndrome.

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Journal
The American Journal of Human Genetics
Published
2025-05-22
DOI
https://doi.org/10.1016/j.ajhg.2025.04.016
Citations
1
Primary Topic
Cardiomyopathy and Myosin Studies
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article
Field-Weighted Citation Impact
1.39

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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy

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Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy

Mie Topholm Bruun, Michela Ripolone, Arthur A.M. Wilde, Eleonora Aronica, Antonio M. A. Miranda, Hreinn Stefánsson, Lorenzo Monserrat, Forrest Z. Bowling, Yasmine Aguib, Søren A Rand, Kristen Fishler, Francesco Fortunato, Connie R. Bezzina, Karel van Duijvenboden, Henrik Ullum, Erik Sørensen, Kazumasa Kanemaru, Klaus Brusgaard, James J. Cranley, Michele Nicastro, Leander Beekman, Dario Ronchi, Pieter G. Postema, Elisabeth M. Lodder, Giacomo P. Comi, Alexa M.C. Vermeer, Pernille Mathiesen Tørring, Deanna Alexis Carere, Christopher T. Cummings, Ingeborg E. van Zeggeren, Lincoln Nadauld, Hilma Hólm, Daníel F. Guðbjartsson, Mona Allouba, Ronald Wilders, Jens Mogensen, Imke Christiaans, Lukáš Mach, Mariëlle Alders, Michela Noseda, Henning Bundgaard, Paul A. van der Zwaag, Hildur M. Aegisdottir, Erna V. Ivarsdottir, Ole Birger Pedersen, David de Uña, Trine Juul, Jonas Ghouse, Henrik Kjærulf Jensen, Sisse Rye Ostrowski, Sally‐Ann B. Clur, Arie O. Verkerk, Bo Gregers Winkel, Alex V. Postma, Najim Lahrouchi, Bitten Aagaard, Simona Zanotti, Christian Erikstrup, José L. Santomé, Vinicius Tragante, Ástrós Skúladóttir, Sean J. Jurgens, Lotte Saaby, J. Peter van Tintelen, Kirk U. Knowlton, Michael V. Airola, Garðar Sveinbjörnsson, Lingshuang Wu, Rob Zwart, Mette Christiansen, Rafik Tadros
article en
1 citations

Abstract

POPDC2 encodes the Popeye domain-containing protein 2, which has an important role in cardiac pacemaking and conduction, due in part to its cyclic AMP (cAMP)-dependent binding and regulation of TREK-1 potassium channels. Loss of Popdc2 in mice results in sinus pauses and bradycardia, and morpholino-mediated knockdown of popdc2 in zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in POPDC2 in four families with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects, and hypertrophic cardiomyopathy. Using homology modeling, we show that the identified variants are predicted to diminish the ability of POPDC2 to bind cAMP. In in vitro electrophysiological studies, we demonstrated that, in contrast with wild-type POPDC2, variants found in affected individuals failed to increase TREK-1 current density. While muscle biopsy of an affected individual did not show clear myopathic disease, it showed significantly reduced abundance of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1-POPDC2 complex is impaired by pathogenic variants in either protein. Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and POPDC2 was most prevalent in AV node, AV node pacemaker, and AV bundle cells. Using population-level genetic data of more than 1 million individuals, we show that none of the familial variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up. Our findings provide evidence for bi-allelic variants in POPDC2 causing a Mendelian autosomal recessive cardiac syndrome.

The American Journal of Human GeneticsVol. 112(7)
Statens Serum Institut (DK), Intermountain Healthcare (US), Universidade da Coruña (ES), University of Copenhagen (DK), Nebraska Medical Center (US), deCODE Genetics (Iceland) (IS), University Medical Center Groningen (NL), University of Groningen (NL), University of Milan (IT), Aalborg University Hospital (DK), Montreal Heart Institute (CA), Odense University Hospital (DK), Aarhus University Hospital (DK), Wellcome Sanger Institute (GB), Copenhagen University Hospital (DK), Rigshospitalet (DK), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), British Heart Foundation (GB), Zealand University Hospital (DK), Emma Kinderziekenhuis (NL), Lung Institute (US), Amsterdam Neuroscience (NL), Magdi Yacoub Heart Foundation (EG), Lillebaelt Hospital (DK), ERN GUARD-Heart (NL), Amsterdam University Medical Centers (NL), Ferrari (Italy) (IT), Imperial College London (GB), University of Nebraska Medical Center (US), Stony Brook University (US), University of Amsterdam (NL)
American Heart Association, Wellcome Trust, Deutsches Zentrum für Herz-Kreislaufforschung, British Society for Heart Failure, Università degli Studi di Milano, Dipartimenti di Eccellenza, National Institute for Health and Care Research, British Heart Foundation, Rosetrees Trust, Canada Research Chairs, ZonMw, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health
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Openalex Percentile: Top 19%
Cardiomyopathy and Myosin Studies
1.39
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