Molecular Pathogenic Basis for GABRG2 Mutations Associated With a Spectrum of Epilepsy Syndromes, From Generalized Absence Epilepsy to Dravet Syndrome.
Molecular Pathogenic Basis for GABRG2 Mutations Associated With a Spectrum of Epilepsy Syndromes, From Generalized Absence Epilepsy to Dravet Syndrome.
复制标题
DOI：
10.1001/jamaneurol.2016.0449
复制
发表时间：
2016-08-01
期刊：
影响因子：
29
通讯作者：
Macdonald RL
中科院分区：
文献类型：
--
作者：
Kang JQ;Macdonald RL
GABAA受体γ2亚基基因GABRG2在哺乳动物大脑中大量表达，其编码的γ2亚基组装成αβγ2受体，这是大脑中主要的GABAA受体亚型。 γ2 亚基在 GABAA 受体运输和突触聚集中发挥着关键作用。合成后，它们驻留在内质网 (ER) 内，与其他结合配偶体（例如 α 和 β 亚基）寡聚，并进一步组装成五聚体受体。只有正确组装的受体才能穿过内质网到达细胞表面和突触，并在被 GABA 激活时传导氯离子电流。 GABRG2 突变与单纯性热性惊厥 (FS) 和遗传性癫痫综合征相关，包括儿童失神性癫痫 (CAE)、全身性癫痫伴热性惊厥附加 (GEFS+) 和 Dravet 综合征 (DS)/婴儿期严重肌阵挛性癫痫 (SMEI)。突变包括错义、无义和移码突变以及剪接位点和缺失突变。这些突变已在编码序列和非编码序列（如剪接位点）中得到鉴定。在编码序列中，这些突变存在于多个位置，包括胞外N末端、跨膜结构域和TM3-TM4胞内环。所有这些突变都降低了通道功能，但程度不同，机制也不同，包括无义介导的 mRNA 衰减 (NMD)、内质网相关蛋白降解 (ERAD)、配对亚基的显性失活抑制、导致细胞应激和细胞死亡的突变亚基聚集以及门控缺陷。我们的结论是，与GABRG2突变相关的癫痫表型异质性可能与GABAA受体通道功能的降低程度和差异性显性失活抑制有关，以及与每个突变γ2亚基产生的突变亚基蛋白代谢相关的毒性以及不同的遗传背景有关。
The GABAA receptor γ2 subunit gene GABRG2 is abundantly expressed in the mammalian brain and its encoded γ2 subunit is assembled into αβγ2 receptors, which are the major GABAA receptor isoforms in the brain. The γ2 subunits play a critical role in GABAA receptor trafficking and clustering at synapses. They reside inside the endoplasmic reticulum (ER) after synthesis where they oligomerize with other binding partners, such as α and β subunits, and further assemble into pentameric receptors. Only correctly assembled receptors can traffick beyond the ER and reach the cell surface and synapses where they conduct chloride ion current when activated by GABA. Mutations in GABRG2 have been associated simple febrile seizures (FS) and with genetic epilepsy syndromes including, childhood absence epilepsy (CAE), generalized epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome (DS)/severe myoclonic epilepsy in infancy (SMEI). The mutations include missense, nonsense and frameshift mutations as well as splice site and deletion mutations. The mutations have been identified in both coding and noncoding sequences like splice sites. In the coding sequence, these mutations are found in multiple locations including the extracellular N-terminus, transmembrane domains and TM3-TM4 intracellular loop. All of these mutations reduced channel function but to different extents and by diverse mechanisms including nonsense mediated mRNA decay (NMD), ER associated protein degradation (ERAD), dominant negative suppression of partnering subunits, mutant subunit aggregation causing cell stress and cell death and gating defects. We conclude that the epilepsy phenotypic heterogeneity associated with GABRG2 mutations may be related to the extent of the reduction of GABAA receptor channel function and the differential dominant negative suppression as well to toxicity related to the metabolism of mutant subunit proteins resulting from each mutant γ2 subunit in addition to different genetic backgrounds.