High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity.
High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity.
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DOI：
10.1172/jci.insight.156314
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发表时间：
2022-03-08
期刊：
影响因子：
8
通讯作者：
George AL Jr
中科院分区：
文献类型：
--
作者：
Vanoye CG;Desai RR;Ji Z;Adusumilli S;Jairam N;Ghabra N;Joshi N;Fitch E;Helbig KL;McKnight D;Lindy AS;Zou F;Helbig I;Cooper EC;George AL Jr
KCNQ2编码电压门控钾通道KV7.2的数百个基因变异与早发性癫痫和/或发育障碍有关，但大多数变异的功能后果尚不清楚。缺乏对KCNQ2变体的功能注释阻碍了对可能受益于新兴精确疗法的个体的识别。据我们所知，我们使用自动膜片钳记录，以前所未有的规模评估79个错义KCNQ2变体和2个基础缺失KCNQ2变体的功能和药理学特性。在我们研究的变异体中，有18个已知的致病变异体，24个大多是罕见的群体变异体，以及39个功能效应不清楚的疾病相关变异体。我们分析了从9,480个细胞记录的电生理数据。已知的18个致病变异体的功能特性与以前发表的结果基本一致，并验证了自动膜片钳的这一目的。与罕见的群体变异体不同，大多数与疾病相关的KCNQ2变异体表现出显著的功能丧失和显性负效应，为致病性提供了强有力的证据。尽管在最大反应方面有很大的差异，但所有的变种对雷替加宾都有反应。我们的研究表明，显性-负性功能丧失是KCNQ2错义变体的常见机制。重要的是，我们观察到KCNQ2变异体对雷替加宾的反应因基因型而异，雷替加宾是一种建议用于KCNQ2发育性和癫痫脑病的精确治疗方法。
Hundreds of genetic variants in KCNQ2 encoding the voltage-gated potassium channel KV7.2 are associated with early onset epilepsy and/or developmental disability, but the functional consequences of most variants are unknown. Absent functional annotation for KCNQ2 variants hinders identification of individuals who may benefit from emerging precision therapies. We employed automated patch clamp recordings to assess at, to our knowledge, an unprecedented scale the functional and pharmacological properties of 79 missense and 2 inframe deletion KCNQ2 variants. Among the variants we studied were 18 known pathogenic variants, 24 mostly rare population variants, and 39 disease-associated variants with unclear functional effects. We analyzed electrophysiological data recorded from 9,480 cells. The functional properties of 18 known pathogenic variants largely matched previously published results and validated automated patch clamp for this purpose. Unlike rare population variants, most disease-associated KCNQ2 variants exhibited prominent loss-of-function with dominant-negative effects, providing strong evidence in support of pathogenicity. All variants responded to retigabine, although there were substantial differences in maximal responses. Our study demonstrated that dominant-negative loss-of-function is a common mechanism associated with missense KCNQ2 variants. Importantly, we observed genotype-dependent differences in the response of KCNQ2 variants to retigabine, a proposed precision therapy for KCNQ2 developmental and epileptic encephalopathy.
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DOI：
10.1016/s1474-4422(15)00199-4
发表时间：
2015-12
期刊：
The Lancet. Neurology
影响因子：
--
作者：
EpiPM Consortium
通讯作者：
EpiPM Consortium
影响因子：
5.6
作者：
Millichap JJ;Miceli F;De Maria M;Keator C;Joshi N;Tran B;Soldovieri MV;Ambrosino P;Shashi V;Mikati MA;Cooper EC;Taglialatela M
通讯作者：
Taglialatela M
影响因子：
44.1
作者：
Li, Xiaoxiao;Zhang, Qiansen;Guo, Jiangtao
通讯作者：
Guo, Jiangtao
DOI：
10.1073/pnas.211431298
发表时间：
2001-10-09
影响因子：
11.1
作者：
Dedek, K;Kunath, B;Steinlein, OK
通讯作者：
Steinlein, OK
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G