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Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies

Authors :
Krueger, J
Schubert, J
Kegele, J
Labalme, A
Mao, M
Heighway, J
Seebohm, G
Yan, P
Koko, M
Aslan-Kara, K
Caglayan, H
Steinhoff, BJ
Weber, YG
Keo-Kosal, P
Berkovic, SF
Hildebrand, MS
Petrou, S
Krause, R
May, P
Lesca, G
Maljevic, S
Lerche, H
Krueger, J
Schubert, J
Kegele, J
Labalme, A
Mao, M
Heighway, J
Seebohm, G
Yan, P
Koko, M
Aslan-Kara, K
Caglayan, H
Steinhoff, BJ
Weber, YG
Keo-Kosal, P
Berkovic, SF
Hildebrand, MS
Petrou, S
Krause, R
May, P
Lesca, G
Maljevic, S
Lerche, H
Publication Year :
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 families with GGE with predominant absence seizures; two variants were also associated with mild to moderate ID. All missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The R359C variant altered PI(4,5)P2-interaction. INTERPRETATION: Our study identified deleterious KCNQ5 variants in GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional deficits. LOF of KV7.5 channels will reduce the M-current, likely resulting in increased excitability of KV7.5-expressing neurons. Further studies on network level are necessary to understand which circuits are affected and how this induces generalized seizures. FUNDING: DFG/FNR Research Unit FOR-2715 (Germany/Luxemburg), BMBF rare disease network Treat-ION (Germany), foundation 'no epilep' (Germany).

Details

Database :
OAIster
Publication Type :
Electronic Resource
Accession number :
edsoai.on1373006790
Document Type :
Electronic Resource