PDF(Pubmed)
Abstract：
Dravet syndrome is a rare, catastrophic epileptic encephalopathy that begins in the first year of life, usually with febrile or afebrile hemiclonic or generalized tonic-clonic seizures followed by status epilepticus. De novo variants in genes that mediate synaptic transmission such as SCN1A and PCDH19 are often associated with Dravet syndrome. Recently, GABAA receptor subunit genes (GABRs) encoding α1 (GABRA1), β3 (GABRB3) and γ2 (GABRG2), but not β2 (GABRB2) or β1 (GABRB1), subunits are frequently associated with Dravet syndrome or Dravet syndrome-like phenotype. We performed next generation sequencing on 870 patients with Dravet syndrome and identified nine variants in three different GABRs. Interestingly, the variants were all in genes encoding the most common GABAA receptor, the α1β2γ2 receptor. Mutations in GABRA1 (c.644T>C, p. L215P; c.640C>T, p. R214C; c.859G>A; V287I; c.641G>A, p. R214H) and GABRG2 (c.269C>G, p. T90R; c.1025C>T, p. P342L) presented as de novo cases, while in GABRB2 two variants were de novo (c.992T>C, p. F331S; c.542A>T, p. Y181F) and one was autosomal dominant and inherited from the maternal side (c.990_992del, p.330_331del). We characterized the effects of these GABR variants on GABAA receptor biogenesis and channel function. We found that defects in receptor gating were the common deficiency of GABRA1 and GABRB2 Dravet syndrome variants, while mainly trafficking defects were found with the GABRG2 (c.269C>G, p. T90R) variant. It seems that variants in α1 and β2 subunits are less tolerated than in γ2 subunits, since variant α1 and β2 subunits express well but were functionally deficient. This suggests that all of these GABR variants are all targeting GABR genes that encode the assembled α1β2γ2 receptor, and regardless of which of the three subunits are mutated, variants in genes coding for α1, β2 and γ2 receptor subunits make them candidate causative genes in the pathogenesis of Dravet syndrome.
摘要：
德拉韦综合征是一种罕见的，灾难性的癫痫性脑病始于生命的第一年，通常伴有高热或无热半张力或全身性强直阵挛性癫痫发作，随后伴有癫痫持续状态。介导突触传递的基因如SCN1A和PCDH19中的从头变体通常与Dravet综合征相关。最近,GABAA受体亚基基因（GABRs）编码α1（GABRA1），β3（GABRB3）和γ2（GABRG2），但不是β2（GABRB2）或β1（GABRB1），亚基通常与Dravet综合征或Dravet综合征样表型相关。我们对870例Dravet综合征患者进行了下一代测序，并在三种不同的GABR中鉴定了9种变异。有趣的是,这些变异都是编码最常见的GABAA受体的基因，α1β2γ2受体。GABRA1中的突变（c.644T>C，p.L215P；c.640C>T，p.R214C；c.859G>A；V287I；c.641G>A，p。R214H）和GABRG2（c.269C>G，p.T90R；c.1025C>T，p.P342L)表示为从头病例，而在GABRB2中，两个变体是从头的(c.992T>C，p.F331S;c.542A>T,p。Y181F）和一个是常染色体显性遗传，遗传自母体（c.990_992del，第330页331del)。我们表征了这些GABR变体对GABAA受体生物发生和通道功能的影响。我们发现受体门控缺陷是GABRA1和GABRB2Dravet综合征变体的常见缺陷，虽然主要是在GABRG2上发现了贩运缺陷(c.269>G，p.T90R）变体。似乎α1和β2亚基的变体的耐受性低于γ2亚基，因为变体α1和β2亚基表达良好，但功能缺陷。这表明所有这些GABR变体都靶向编码组装的α1β2γ2受体的GABR基因，不管这三个亚基中的哪一个是突变的，编码α1，β2和γ2受体亚基的基因中的变体使它们成为Dravet综合征发病机理中的候选致病基因。
