Journal article
Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies
J Krüger, J Schubert, J Kegele, A Labalme, M Mao, J Heighway, G Seebohm, P Yan, M Koko, K Aslan-Kara, H Caglayan, BJ Steinhoff, YG Weber, P Keo-Kosal, SF Berkovic, MS Hildebrand, S Petrou, R Krause, P May, G Lesca Show all
Ebiomedicine | ELSEVIER | Published : 2022
Abstract
Background: De novo missense variants in KCNQ5, encoding the voltage-gated K+ channel KV7.5, have been described to cause developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. Methods: 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with homology modelling. Findings: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent famili..
View full abstractGrants
Awarded by Broad Institute
Funding Acknowledgements
We thank all the patients and their families for participating in this study. We also thank the following consortia for providing the variants and phenotypic data of the investigated individuals: EuroEPINOMICS-CoGIE Consortium (six individuals from two families) , Epi25 Collaborative (one individual) , and Epi4K (three individuals from three families) . This work was supported by the Research Unit FOR-2715, funded by the German Research Foundation (DFG) and the Fond Nationale de la Recherche (FNR) in Luxembourg (grants Le1030/16-1/2 to HL, INTER/DFG/17/11583046 to RK/PM, and We4896/4-1/2 to YGW) , by the German Federal Ministry for Education and Research (BMBF, Treat-ION, 01GM1907A/B/C/H and 01GM2210A/B/H to HL, YGW, RK, PM) and by the European Science Foundation (EuroEPINOMICS-CoGIE project, grants from national funding agencies: DFG Le1030/11-1/2 to HL, FNR INTER/ESF/10/02/CoGIE to Rudi Balling/RK/PM) . The foundation ?no epilep? funded patient recruitment (to HL) . Epi25 was supported by the National Human Genome Research Institute (NHGRI) grants UM1 HG008895 and 5U01HG009088-02, and the Stanley Center for Psychiatric Research at the Broad Institute. The Epi4K study was supported by a National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH) grant (ID: U01NS077367) . We acknowledge the contribution of the HPC facilities of the University of Luxembourg (http://hpc.uni.lu) for computational support. We acknowledge support by the Open Access Publishing Fund of the University of Tubingen.