Department of Pediatrics, Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Division of Neonatology and Newborn Medicine, Massachusetts General Hospital for Children, Boston, MA, USA.
Am J Hum Genet. 2023 Jan 5;110(1):120-145. doi: 10.1016/j.ajhg.2022.11.011. Epub 2022 Dec 16.
Eukaryotic initiation factor-4A2 (EIF4A2) is an ATP-dependent RNA helicase and a member of the DEAD-box protein family that recognizes the 5' cap structure of mRNAs, allows mRNA to bind to the ribosome, and plays an important role in microRNA-regulated gene repression. Here, we report on 15 individuals from 14 families presenting with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies, all of whom have extremely rare de novo mono-allelic or inherited bi-allelic variants in EIF4A2. Neurodegeneration was predominantly reported in individuals with bi-allelic variants. Molecular modeling predicts these variants would perturb structural interactions in key protein domains. To determine the pathogenicity of the EIF4A2 variants in vivo, we examined the mono-allelic variants in Drosophila melanogaster (fruit fly) and identified variant-specific behavioral and developmental defects. The fruit fly homolog of EIF4A2 is eIF4A, a negative regulator of decapentaplegic (dpp) signaling that regulates embryo patterning, eye and wing morphogenesis, and stem cell identity determination. Our loss-of-function (LOF) rescue assay demonstrated a pupal lethality phenotype induced by loss of eIF4A, which was fully rescued with human EIF4A2 wild-type (WT) cDNA expression. In comparison, the EIF4A2 variant cDNAs failed or incompletely rescued the lethality. Overall, our findings reveal that EIF4A2 variants cause a genetic neurodevelopmental syndrome with both LOF and gain of function as underlying mechanisms.
真核起始因子 4A2（EIF4A2）是一种依赖于 ATP 的 RNA 解旋酶，也是 DEAD 盒蛋白家族的成员，它可以识别 mRNA 的 5' 帽结构，使 mRNA 与核糖体结合，并在 microRNA 调控的基因抑制中发挥重要作用。在这里，我们报告了 14 个家系中的 15 位个体，他们表现为全面发育迟缓、智力障碍、低张力、癫痫和结构性脑异常，所有这些个体均存在 EIF4A2 中极其罕见的新生单等位基因或遗传双等位基因变异。神经退行性变主要发生在双等位基因变异的个体中。分子建模预测这些变异会破坏关键蛋白结构域中的相互作用。为了确定 EIF4A2 变异在体内的致病性，我们在果蝇（黑腹果蝇）中检查了单等位基因变异，并发现了特定于变体的行为和发育缺陷。EIF4A2 的果蝇同源物是 eIF4A，它是 decapentaplegic (dpp) 信号的负调节剂，调节胚胎模式形成、眼睛和翅膀形态发生以及干细胞身份确定。我们的功能丧失（LOF）挽救实验证明，eIF4A 的缺失会导致果蝇幼虫死亡，而人 EIF4A2 野生型（WT）cDNA 的表达可以完全挽救这一表型。相比之下，EIF4A2 变体 cDNA 未能或不完全挽救致死表型。总的来说，我们的研究结果表明，EIF4A2 变体引起的遗传神经发育综合征的潜在机制包括 LOF 和功能获得。
