EEF1A2 mutations in epileptic encephalopathy/intellectual disability: Understanding the potential mechanism of phenotypic variation
EEF1A2 mutations in epileptic encephalopathy/intellectual disability: Understanding the potential mechanism of phenotypic variation
复制标题
癫痫性脑病/智力障碍中的 EEF1A2 突变：了解表型变异的潜在机制
DOI：
10.1016/j.yebeh.2020.106955
复制
发表时间：
2020-04-01
影响因子：
2.6
通讯作者：
Wang, Yaqin
中科院分区：
文献类型：
--
作者：
Long, Kexin;Wang, Hua;Wang, Yaqin
EEF 1A 2编码蛋白质延伸因子1-α 2，其参与蛋白质生物合成期间氨酰转移RNA（tRNA）与核糖体A位点的鸟苷三磷酸（GTP）依赖性结合，并在中枢神经系统中高度表达。EEF 1A 2的新生突变已在广泛神经功能缺损患者中发现，包括难治性癫痫、地球仪发育迟缓和严重智力残疾。然而，表型变异的机制尚不清楚。使用下一代测序，我们确定了一个新的和复发性的从头突变，c.294C> A; p.（Phe98Leu）和c.208G>A; p.（Gly 70 Ser），在Lennox-Gastaut综合征患者中。进一步的系统分析显示，所有EEF 1A 2突变与癫痫和智力残疾相关，表明其在神经发育中的关键作用。t-RNA结合位点或GTP水解结构域发生严重分子改变的错义突变与早发性严重癫痫相关，这表明临床表达可能由突变位置和分子效应的改变决定。这项研究突出了EEF 1A 2基因型与表型之间的潜在关系，有助于临床实践中评估EEF 1A 2突变的致病性。(C)2020爱思唯尔公司All rights reserved.
EEF1A2 encodes protein elongation factor 1-alpha 2, which is involved in Guanosine triphosphate (GTP)dependent binding of aminoacyl-transfer RNA (tRNA) to the A-site of ribosomes during protein biosynthesis and is highly expressed in the central nervous system. De novo mutations in EEF1A2 have been identified in patients with extensive neurological deficits, including intractable epilepsy, globe developmental delay, and severe intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using nextgeneration sequencing, we identified a novel and a recurrent de novo mutation, c.294C> A; p.(Phe98Leu) and c.208G>A; p.(Gly70Ser), in patients with Lennox-Gastaut syndrome. The further systematic analysis revealed that all EEF1A2 mutations were associated with epilepsy and intellectual disability, suggesting its critical role in neurodevelopment. Missense mutations with severe molecular alteration in the t-RNA binding sites or GTP hydrolysis domain were associated with early-onset severe epilepsy, indicating that the clinical expression was potentially determined by the location of mutations and alteration of molecular effects. This study highlights the potential genotype-phenotype relationship in EEF1A2 and facilitates the evaluation of the pathogenicity of EEF1A2 mutations in clinical practice. (C) 2020 Elsevier Inc. All rights reserved.