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

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 alter-ation 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. Fur-ther studies on network level are necessary to understand which circuits are affected and how this induces general-ized seizures. eBioMedicine ebiom.2022.104244. Copyright (C) 2022 The Authors. Published by Elsevier B.V.

Automated summary

Deleterious KCNQ5 variants identified in GGE lead to LOF and are partially associated with mild to moderate intellectual disability. When mutant channels are co-expressed with wild-type channels, a significant dominant-negative effect is observed.