A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patient

IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY
Li Yang, Xingyu Wan, Ran Hua, Junhong Jiang, Baotian Wang, Rui Tao, De Wu
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Abstract

Background

Variants in the GABRA2 gene, which encodes the α2 subunit of the γ-aminobutyric acid A receptor, have been linked to a rare form of developmental and epileptic encephalopathy (DEE) referred to as DEE78. Only eight patients have been reported globally. This study presents the clinical presentation and genetic analysis of a Chinese family with a child diagnosed with DEE78, due to a novel GABRA2 variant.

Methods

Genetic diagnosis was performed using trio-whole exome sequencing, followed by bioinformatics predictions of pathogenicity. Structural modeling assessed the potential impact of the variant. A mutant plasmid was constructed and transfected into 293 T cells. Western blotting (WB) was used to evaluate mutant protein expression, while co-immunoprecipitation (Co-IP) analyzed interactions with GABRB3 and GABRG2 proteins. Immunofluorescence (IF) assessed the subcellular localization of the mutant protein.

Results

The 6-year-old male proband presented with seizures starting at age two, along with global developmental delay and hypotonia. Genetic testing revealed a heterozygous de novo variant in GABRA2 gene (NM_000807: c.923C>T, p.Ala308Val). Structural modeling suggested that this variant is located within the extracellular domain, which may disrupt hydrogen bonding interactions with GABRB3 and GABRG2. WB and Co-IP showed reduced protein expression and impaired interactions, potentially destabilizing the pentamer receptor complex. If analysis revealed that the variant did not affect subcellular localization.

Conclusion

This study identified a novel likely pathogenic GABRA2 extracellular domain variant in a Chinese family causing the DEE phenotype. The results expand the genotypic and phenotypic spectrum of GABRA2-related DEE.

Abstract Image

一种新的新生GABRA2基因错义变异导致中国患者的发展性癫痫性脑病。
背景:编码γ-氨基丁酸A受体α2亚基的GABRA2基因变异与一种罕见的发育性和癫痫性脑病(DEE) (DEE78)有关。全球仅报告了8例患者。本研究介绍了一个中国家庭的临床表现和遗传分析,该家庭的孩子被诊断为DEE78,原因是一种新的GABRA2变异。方法:采用三全外显子组测序进行遗传诊断,然后进行生物信息学预测致病性。结构建模评估了该变体的潜在影响。构建突变质粒并转染293 T细胞。Western blotting (WB)用于评估突变蛋白的表达,而co-immunoprecipitation (Co-IP)分析与GABRB3和GABRG2蛋白的相互作用。免疫荧光(IF)评估突变蛋白的亚细胞定位。结果:6岁男性先证者在2岁时开始出现癫痫发作,同时伴有整体发育迟缓和张力低下。基因检测显示GABRA2基因的杂合新生变异(NM_000807: c.923C>T, p.Ala308Val)。结构建模表明,该变体位于细胞外结构域,可能会破坏与GABRB3和GABRG2的氢键相互作用。WB和Co-IP显示蛋白质表达减少和相互作用受损,潜在地破坏了五聚体受体复合物的稳定。如果分析显示变异不影响亚细胞定位。结论:本研究在一个中国家庭中发现了一种新的可能致病的GABRA2细胞外结构域变异,导致DEE表型。结果扩大了gabra2相关DEE的基因型和表型谱。
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来源期刊
Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)
CiteScore
9.10
自引率
1.90%
发文量
218
审稿时长
8 weeks
期刊介绍: Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.
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