Deleterious Rare Variants Reveal Risk for Loss of GABAA Receptor Function in Patients with Genetic Epilepsy and in the General Population
Deleterious Rare Variants Reveal Risk for Loss of GABAA Receptor Function in Patients with Genetic Epilepsy and in the General Population
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DOI：
10.1371/journal.pone.0162883
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发表时间：
2016-09-13
期刊：
影响因子：
3.7
通讯作者：
Macdonald, Robert L.
中科院分区：
文献类型：
--
作者：
Hernandez, Ciria C.;Klassen, Tara L.;Macdonald, Robert L.
遗传性癫痫（GEs）约占所有癫痫疾病的50%，家族形式包括单一GABA(A)受体亚基基因（gabr）的突变。在144例散发性GE病例（gec）中，237个离子通道基因的外显子组测序鉴定出520个GABR变体。在这些变异中，11个GABR基因中的33个罕见变异存在于24个gec中。为了评估gec中变异的功能风险，我们选择了GABRA中发现的8个变异，GABRB中发现的3个变异，GABRG中发现的3个变异，并将它们与普通人群中发现的18个变异GABRA1 (n = 9), GABRB3 （n = 7）和GABRG2 （n = 2）进行比较。为了识别有害变体并深入了解结构-功能关系，我们研究了32个变体的门控特性、表面表达和结构扰动。GABAA受体功能的显著降低与被标记为有害的变异密切相关，这些变异位于n端和跨膜区域。此外，沿着β +/ α - GABA结合界面绘制的17个变体中有12个与通道门控的减少有关，并且通过硅模拟预测会导致受体的结构重排。GABRA1、GABRB3和GABRG2的错义或无义主要损害亚基生物发生。相反，GABR变异体通过损害门控来影响受体功能，这表明GABR癫痫易感性变异体和致病突变中有不同的机制在起作用。在散发性GEs患者中发现的单个GABR变异对功能的影响保证了分子诊断的使用，并将最终通过使用个性化方法改善遗传性癫痫的治疗。
Genetic epilepsies (GEs) account for approximately 50% of all seizure disorders, and familial forms includemutations in single GABA(A) receptor subunit genes (GABRs). In 144 sporadic GE cases (GECs), exome sequencing of 237 ion channel genes identified 520 GABR variants. Among these variants, 33 rare variants in 11 GABR genes were present in 24 GECs. To assess functional risk of variants in GECs, we selected 8 variants found in GABRA, 3 in GABRB, and 3 in GABRG and compared them to 18 variants found in the general population for GABRA1 (n = 9), GABRB3 (n = 7), and GABRG2 (n = 2). To identify deleterious variants and gain insight into structure-function relationships, we studied the gating properties, surface expression and structural perturbations of the 32 variants. Significant reduction of GABAA receptor function was strongly associated with variants scored as deleterious and mapped within the N-terminal and transmembrane domains. In addition, 12 out of 17 variants mapped along the beta+/alpha- GABA binding interface, were associated with reduction in channel gating and were predicted to cause structural rearrangements of the receptor by in silico simulations. Missense or nonsensemutations of GABRA1, GABRB3 and GABRG2 primarily impair subunit biogenesis. In contrast, GABR variants affected receptor function by impairing gating, suggesting that different mechanisms are operating in GABR epilepsy susceptibility variants and disease-causingmutations. The functional impact of single GABR variants found in individuals with sporadic GEs warrants the use of molecular diagnosis and will ultimately improve the treatment of genetic epilepsies by using a personalized approach.