مورد إلكتروني
Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies
| العنوان: | Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies |
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| المؤلفون: | 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 |
| بيانات النشر: | ELSEVIER 2022-09-09 |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | 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). |
| مصطلحات الفهرس: | Journal Article |
| URL: | |
| الإتاحة: | Open access content. Open access content CC BY https://creativecommons.org/licenses/by/4.0 |
| أرقام أخرى: | UMV oai:jupiter.its.unimelb.edu.au:11343/322494 Krueger, J., Schubert, J., Kegele, J., Labalme, A., Mao, M., Heighway, J., Seebohm, G., Yan, P., Koko, M., Aslan-Kara, K., Caglayan, H., Steinhoff, B. J., Weber, Y. G., Keo-Kosal, P., Berkovic, S. F., Hildebrand, M. S., Petrou, S., Krause, R., May, P. ,... Lerche, H. (2022). Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies. EBIOMEDICINE, 84, https://doi.org/10.1016/j.ebiom.2022.104244. 10.1016/j.ebiom.2022.104244 2352-3964 2352-3964 1373006790 |
| المصدر المساهم: | UNIV OF MELBOURNE From OAIster®, provided by the OCLC Cooperative. |
| رقم الأكسشن: | edsoai.on1373006790 |
| قاعدة البيانات: | OAIster |
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