Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies.
Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies.
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DOI：
10.1016/j.ebiom.2022.104244
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发表时间：
2022-10
期刊：
影响因子：
11.1
通讯作者：
Lerche, Holger
中科院分区：
文献类型：
--
作者：
Krueger, Johanna;Schubert, Julian;Kegele, Josua;Labalme, Audrey;Mao, Miaomiao;Heighway, Jacqueline;Seebohm, Guiscard;Yan, Pu;Koko, Mahmoud;Aslan-Kara, Kezban;Caglayan, Hande;Steinhoff, Bernhard J.;Weber, Yvonne G.;Keo-Kosal, Pascale;Berkovic, Samuel F.;Hildebrand, Michael S.;Petrou, Steven;Krause, Roland;May, Patrick;Lesca, Gaetan;Maljevic, Snezana;Lerche, Holger
编码电压门控K+通道KV7.5的KCNQ 5中的从头错义变体已被描述为引起发育性和癫痫性脑病（DEE）或智力残疾（ID）。我们着手确定遗传性全身性癫痫（GGE）中与疾病相关的KCNQ 5变体及其潜在机制。通过下一代测序研究了1292个GGE家系。在哺乳动物细胞中结合同源性建模进行全细胞膜片钳记录、生物素化和磷脂覆盖测定。我们确定了三个有害的杂合错义变体，一个截短和剪接位点的改变，在五个独立的家庭与GGE占主导地位的缺席癫痫发作，两个变体也与轻度至中度ID。所有的错义变体显示出强烈的电流密度下降，表明功能丧失（LOF）。当突变通道与野生型（WT）KV7.5或KV7.5和KV7.3通道共表达时，三种变体也显示出对WT通道的显著显性负效应。其他门控参数不变。生物素化测定表明变异体的正常表面表达。R359 C变体改变PI（4，5）P2-相互作用。我们的研究确定了GGE中有害的KCNQ 5变体，部分与轻度至中度ID相结合。疾病机制是LOF，部分通过功能缺陷产生显性负效应。KV7.5通道的LOF将降低M电流，可能导致表达KV7.5的神经元的兴奋性增加。网络水平的进一步研究是必要的，以了解哪些电路受到影响，以及这是如何引起全身性癫痫发作。DFG/FNR研究单位FOR-2715（德国/德国），BMBF罕见病网络Treat-ION（德国），“无癫痫”基金会（德国）。
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. 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. 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. 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. DFG/FNR Research Unit FOR-2715 (Germany/Luxemburg), BMBF rare disease network Treat-ION (Germany), foundation ‘no epilep’ (Germany).
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影响因子：
30.8
作者：
Charlier, C;Singh, NA;Leppert, M
通讯作者：
Leppert, M
DOI：
10.1152/ajpheart.00065.2006
发表时间：
2007-03-01
影响因子：
4.8
作者：
Brueggemann, Lioubov I.;Moran, Christopher J.;Byron, Kenneth L.
通讯作者：
Byron, Kenneth L.
影响因子：
5.6
作者：
Scheffer IE;Berkovic S;Capovilla G;Connolly MB;French J;Guilhoto L;Hirsch E;Jain S;Mathern GW;Moshé SL;Nordli DR;Perucca E;Tomson T;Wiebe S;Zhang YH;Zuberi SM
通讯作者：
Zuberi SM
影响因子：
56.9
作者：
Biervert, C;Schroeder, BC;Steinlein, OK
通讯作者：
Steinlein, OK
影响因子：
64.5
作者：
Kubisch, C;Schroeder, BC;Jentsch, TJ
通讯作者：
Jentsch, TJ