Popeye Domain Containing Protein 2 (POPDC2) and inherited forms of AV block: Mechanistic investigations on the modulation of cardiac ion channels by POPDC2

• Applicant: Professor Dr. Niels Decher, Ph.D.
• Subject Area: Anatomy and Physiology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448645077

Mutations in genes encoding ion channels or their accessory subunits are the primary cause of inherited forms of cardiac arrhythmias. Despite great progress in the understanding of the genetic origins of ventricular arrhythmias, the genetic origins of diseases with impaired impulse generation or conduction mostly remain elusive. In this context, the identification of Popeye Domain Containing Proteins (POPDC) as ion channel modulators was highly relevant, in particular as POPDC2 knock-out mice showed a stress-induced sino-atrial bradycardia. In the progress of this study on the phenotype of the POPDC2 knock-out mice, we were able to show in my laboratory that POPDCs modulate the two-pore-domain potassium channel TREK-1 in a cAMP-dependent manner. Currently it remains unclear whether POPDC proteins also modulate other cardiac ion channels, which is one of the major questions we would like to address within this project proposed here. After we contributed functional investigations on the disease-causing mechanism of the first reported POPDC1 mutations in patients which suffer from muscular dystrophy und AV blockades, we have utilized a whole exome sequencing approach in twins with a third degree AV block and identified a heterozygous mutation in POPDC2 as the most likely disease-causing genetic defect. The aim of the proposed project is to functionally characterize this POPDC2W188* mutation and to identify the disease-causing mechanism. Moreover, we aim to identify within this project the molecular mechanisms of the TREK-1 modulation by POPDC proteins. An essential task of the proposed project is however the identification of the disease-causing mechanism of the POPDC2W188* mutation which we plan to achieve by the functional analyses of transgenic POPDC2W188* mice for instance. Our investigations should provide an essential contribution towards the understanding of the molecular modulation of TREK-1 and other cardiac ion channels and thus provide the functional evidence how the POPDC2W188* gene defect is leading to inherited conduction disorders.

• DFG Programme: Research Grants