Department of Human Genetics, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behavior, 6525 GA Nijmegen, The Netherlands.
Unit for Multidisciplinary Research in Biomedicine, Instituto de Ciências Biomédicas Abel Salazar/Universidade do Porto, 4050-313 Porto, Portugal.
Hum Mol Genet. 2021 Feb 25;29(24):3892-3899. doi: 10.1093/hmg/ddaa270.
Eukaryotic translation elongation factor 2 (eEF2) is a key regulatory factor in gene expression that catalyzes the elongation stage of translation. A functionally impaired eEF2, due to a heterozygous missense variant in the EEF2 gene, was previously reported in one family with spinocerebellar ataxia-26 (SCA26), an autosomal dominant adult-onset pure cerebellar ataxia. Clinical exome sequencing identified de novo EEF2 variants in three unrelated children presenting with a neurodevelopmental disorder (NDD). Individuals shared a mild phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly. Populational data and bioinformatic analysis underscored the pathogenicity of all de novo missense variants. The eEF2 yeast model strains demonstrated that patient-derived variants affect cellular growth, sensitivity to translation inhibitors and translational fidelity. Consequently, we propose that pathogenic variants in the EEF2 gene, so far exclusively associated with late-onset SCA26, can cause a broader spectrum of neurologic disorders, including childhood-onset NDDs and benign external hydrocephalus.
真核翻译延伸因子 2（eEF2）是基因表达的关键调节因子，催化翻译的延伸阶段。先前在一个具有脊髓小脑共济失调 26 型（SCA26）的家族中报道了一种由于 EEF2 基因的杂合错义变异导致功能受损的 eEF2，SCA26 是一种常染色体显性遗传的成人发病的纯小脑共济失调。临床外显子组测序在 3 名表现为神经发育障碍（NDD）的无亲缘关系的儿童中发现了 EEF2 变异的新生突变。个体表现出轻微的表型，包括运动延迟和相对大头与脑室扩大相关。群体数据和生物信息学分析强调了所有新生错义变异的致病性。酵母模型菌株中的 eEF2 表明，源自患者的变异会影响细胞生长、对翻译抑制剂的敏感性和翻译保真度。因此，我们提出，迄今为止与迟发性 SCA26 唯一相关的 EEF2 基因中的致病性变异可导致更广泛的神经疾病谱，包括儿童发病的 NDD 和良性外部脑积水。
