Johnston Ann J, Kang Jing-Qiong, Shen Wangzhen, Pickrell William O, Cushion Thomas D, Davies Jeffrey S, Baer Kristin, Mullins Jonathan G L, Hammond Carrie L, Chung Seo-Kyung, Thomas Rhys H, White Cathy, Smith Phil E M, Macdonald Robert L, Rees Mark I
Wales Epilepsy Research Network, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
Neurology and Molecular Neuroscience Research Group, Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
Neurobiol Dis. 2014 Apr;64:131-141. doi: 10.1016/j.nbd.2013.12.013. Epub 2014 Jan 7.
Genetic mutations in voltage-gated and ligand-gated ion channel genes have been identified in a small number of Mendelian families with genetic generalised epilepsies (GGEs). They are commonly associated with febrile seizures (FS), childhood absence epilepsy (CAE) and particularly with generalised or genetic epilepsy with febrile seizures plus (GEFS+). In clinical practice, despite efforts to categorise epilepsy and epilepsy families into syndromic diagnoses, many generalised epilepsies remain unclassified with a presumed genetic basis. During the systematic collection of epilepsy families, we assembled a cohort of families with evidence of GEFS+ and screened for variations in the γ2 subunit of the γ-aminobutyric acid (GABA) type A receptor gene (GABRG2). We detected a novel GABRG2(p.R136*) premature translation termination codon in one index-case from a two-generation nuclear family, presenting with an unclassified GGE, a borderline GEFS+ phenotype with learning difficulties and extended behavioural presentation. The GABRG2(p.R136*) mutation segregates with the febrile seizure component of this family's GGE and is absent in 190 healthy control samples. In vitro expression assays demonstrated that γ2(p.R136*) subunits were produced, but had reduced cell-surface and total expression. When γ2(p.R136*) subunits were co-expressed with α1 and β2 subunits in HEK 293T cells, GABA-evoked currents were reduced. Furthermore, γ2(p.R136*) subunits were highly-expressed in intracellular aggregations surrounding the nucleus and endoplasmic reticulum (ER), suggesting compromised receptor trafficking. A novel GABRG2(p.R136*) mutation extends the spectrum of GABRG2 mutations identified in GEFS+ and GGE phenotypes, causes GABAA receptor dysfunction, and represents a putative epilepsy mechanism.
在少数患有遗传性全身性癫痫（GGEs）的孟德尔家族中，已鉴定出电压门控和配体门控离子通道基因的基因突变。它们通常与热性惊厥（FS）、儿童失神癫痫（CAE）相关，特别是与伴有热性惊厥附加症的全身性或遗传性癫痫（GEFS+）有关。在临床实践中，尽管努力将癫痫和癫痫家族分类为综合征诊断，但许多全身性癫痫仍未分类，推测具有遗传基础。在系统性收集癫痫家族的过程中，我们组建了一组有GEFS+证据的家族队列，并筛查了γ-氨基丁酸（GABA）A型受体基因（GABRG2）γ2亚基的变异情况。我们在一个两代核心家庭的一名先证者中检测到一种新的GABRG2（p.R136*）过早翻译终止密码子，该先证者患有未分类的GGE，具有边缘性GEFS+表型，伴有学习困难和广泛的行为表现。GABRG2（p.R136*）突变与该家族GGE的热性惊厥成分共分离，在190份健康对照样本中未出现。体外表达试验表明，产生了γ2（p.R136*）亚基，但细胞表面和总表达量降低。当γ2（p.R136*）亚基与α1和β2亚基在HEK 293T细胞中共表达时，GABA诱发电流降低。此外，γ2（p.R136*）亚基在细胞核和内质网（ER）周围的细胞内聚集体中高度表达，提示受体转运受损。一种新的GABRG2（p.R136*）突变扩展了在GEFS+和GGE表型中鉴定出的GABRG2突变谱，导致GABAA受体功能障碍，并代表一种推定的癫痫机制。
