De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder
De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder
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DOI：
10.1016/j.ajhg.2017.09.014
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发表时间：
2017-11-02
影响因子：
9.8
通讯作者：
Kreienkamp, Hans-Juergen
中科院分区：
文献类型：
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作者：
Lessel, Davor;Schob, Claudia;Kreienkamp, Hans-Juergen
DHX30是DExH盒解旋酶家族的成员，其使用ATP水解来解链RNA二级结构。在这里，我们确定了6个不同的从头错义突变DHX30在12个无关的个体受到全面发展迟缓（GDD），智力残疾（ID），严重的语言障碍和步态异常。虽然四个突变是复发性的，但两个是独特的，其中一个影响一个复发突变的密码子。所有的氨基酸变化都位于高度保守的解旋酶基序内，并且在不同的体外测定中发现其损害ATP酶活性或RNA识别。此外，蛋白质变体表现出增加的触发应激颗粒（SG）形成的倾向，导致全局翻译抑制。因此，我们的研究结果强调了翻译控制在中枢神经系统发育和功能中的重要作用，并为DHX30功能障碍如何导致神经发育障碍提供了分子见解。
DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.