The highly conserved Elongator complex is a translational regulator that plays a critical role in neurodevelopment, neurological diseases, and brain tumors. Numerous clinically relevant variants have been reported in the catalytic Elp123 subcomplex, while no missense mutations in the accessory subcomplex Elp456 have been described. Here, we identify ELP4 and ELP6 variants in patients with developmental delay, epilepsy, intellectual disability, and motor dysfunction. We determine the structures of human and murine Elp456 subcomplexes and locate the mutated residues. We show that patient-derived mutations in Elp456 affect the tRNA modification activity of Elongator in vitro as well as in human and murine cells. Modeling the pathogenic variants in mice recapitulates the clinical features of the patients and reveals neuropathology that differs from the one caused by previously characterized Elp123 mutations. Our study demonstrates a direct correlation between Elp4 and Elp6 mutations, reduced Elongator activity, and neurological defects. Foremost, our data indicate previously unrecognized differences of the Elp123 and Elp456 subcomplexes for individual tRNA species, in different cell types and in different key steps during the neurodevelopment of higher organisms.

中文翻译：

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神经发育过程中两个伸长肌亚群的功能分歧

高度保守的 Elongator 复合物是一种翻译调节因子，在神经发育、神经系统疾病和脑肿瘤中起关键作用。在催化 Elp123 亚群中报道了许多临床相关的变体，而在辅助亚群 Elp456 中没有错义突变被描述。在这里，我们确定了发育迟缓、癫痫、智力障碍和运动功能障碍患者的ELP4和ELP6变体。我们确定人和鼠 Elp456 亚复合体的结构并定位突变残基。我们表明，患者衍生的 Elp456 突变影响 Elongator在体外的 tRNA 修饰活性以及在人和鼠细胞中。对小鼠的致病变异进行建模可以概括患者的临床特征，并揭示与先前表征的Elp123突变引起的神经病理学不同。我们的研究表明Elp4和Elp6突变、延长器活性降低和神经系统缺陷之间存在直接相关性。最重要的是，我们的数据表明 Elp123 和 Elp456 亚复合体在高等生物神经发育过程中的不同细胞类型和不同关键步骤中之前未被识别的差异。