A novel GABRG2 mutation, p.R136*, in a family with GEFS+ and extended phenotypes.
A novel GABRG2 mutation, p.R136*, in a family with GEFS+ and extended phenotypes.
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DOI：
10.1016/j.nbd.2013.12.013
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发表时间：
2014-04
影响因子：
6.1
通讯作者：
Rees MI
中科院分区：
文献类型：
--
作者：
Johnston AJ;Kang JQ;Shen W;Pickrell WO;Cushion TD;Davies JS;Baer K;Mullins JGL;Hammond CL;Chung SK;Thomas RH;White C;Smith PEM;Macdonald RL;Rees MI
电压门控和配体门控离子通道基因的基因突变已被确定在少数孟德尔家族遗传性全身性癫痫（GGEs）。它们通常与热性惊厥（FS），儿童失神癫痫（CAE），特别是全身性或遗传性癫痫伴热性惊厥+（GEFS+）有关。在临床实践中，尽管努力将癫痫和癫痫家族归类为综合征诊断，但许多全身性癫痫仍然无法根据假定的遗传基础进行分类。在系统收集癫痫家系的过程中，我们收集了一组有GEFS+证据的家系，并筛选了γ-氨基丁酸（GABA）A型受体基因（GABRG 2）γ2亚基的变异。我们在一个来自两代核心家族的索引病例中检测到一个新的GABRG 2（p.R136*）过早翻译终止密码子，该病例表现为未分类的GGE，边缘GEFS+表型，伴有学习困难和自闭症谱系障碍（ASD）。GABRG 2（p.R136*）突变与该家族GGE的热性惊厥组分分离，并且在190个健康对照样品中不存在。体外表达试验表明，γ2（p.R136*）亚基的产生，但减少了细胞表面和总的表达。当γ2（p.R136*）亚基与α1和β2亚基在HEK 293 T细胞中共表达时，GABA诱发的电流降低。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，表明受体运输受损。一种新的GABRG 2（p.R136*）突变扩展了GEFS+和GGE表型中鉴定的GABRG 2突变谱，导致GABAA受体功能障碍，并代表了一种推定的癫痫机制。
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 autism spectrum disorder (ASD). 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.
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影响因子：
14.9
作者：
Eswar, N;John, B;Sali, A
通讯作者：
Sali, A
影响因子：
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Engel, Jerome, Jr.
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Engel, Jerome, Jr.
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Combet, C;Blanchet, C;Deléage, G
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Deléage, G
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Essrich, C;Lorez, M;Lüscher, B
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Lüscher, B
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Berg, Anne T.;Berkovic, Samuel F.;Scheffer, Ingrid E.
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