| Autor: |
Johanna Krüger, Julian Schubert, Josua Kegele, Audrey Labalme, Miaomiao Mao, Jacqueline Heighway, Guiscard Seebohm, Pu Yan, Mahmoud Koko, Kezban Aslan-Kara, Hande Caglayan, Bernhard J. Steinhoff, Yvonne G. Weber, Pascale Keo-Kosal, Samuel F. Berkovic, Michael S. Hildebrand, Steven Petrou, Roland Krause, Patrick May, Gaetan Lesca, Snezana Maljevic, Holger Lerche |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
EBioMedicine, Vol 84, Iss , Pp 104244- (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2352-3964 |
| DOI: |
10.1016/j.ebiom.2022.104244 |
| Popis: |
Summary: 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). |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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