De novo GABRA1 variants in childhood epilepsies and the molecular subregional effects

作者：Wenhui Liu, Sheng Luo, Dongming Zhang, Zi-sheng Lin, Song Lan, Xin Li, Yi‐Wu Shi, Tao Su, Yong‐Hong Yi, Peng Zhou, Bing-Mei Li · 发表于：Frontiers in Molecular Neuroscience · 年份：2024 · DOI：10.3389/fnmol.2023.1321090 · 被引用次数：22 · 研究领域：Genomics and Rare Diseases、Epilepsy research and treatment、Metabolism and Genetic Disorders

Background The GABRA1 gene, encoding the GABRAR subunit α1, plays vital roles in inhibitory neurons. Previously, the GABRA1 gene has been identified to be associated with developmental and epileptic encephalopathy (DEE) and idiopathic generalized epilepsy (IGE). This study aims to explore the phenotypic spectrum of GABRA1 and molecular subregional effect analysis. Methods Trios-based whole-exome sequencing was performed in patients with epilepsy. Previously reported GABRA1 mutations were systematically reviewed to analyze the molecular subregional effects. Results De novo GABRA1 mutations were identified in six unrelated patients with heterogeneous epilepsy, including three missense mutations (p.His83Asn, p.Val207Phe, and p.Arg214Cys) and one frameshift mutation (p.Thr453Hisfs*47). The two missense mutations, p.His83Asn and p.Val207Phe, were predicted to decrease the protein stability but no hydrogen bond alteration, with which the two patients also presented with mild genetic epilepsy with febrile seizures plus and achieved seizure-free status by monotherapy. The missense variant p.Arg214Cys was predicted to decrease protein stability and destroy hydrogen bonds with surrounding residues, which was recurrently identified in three cases with severe DEE. The frameshift variant p.Thr453Hisfs*47 was located in the last fifth residue of the C-terminus and caused an extension of 47 amino acids, with which the patients presented with moderated epilepsy with generalized tonic-clonic ...