Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development
Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development
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DOI：
10.1016/j.neuron.2020.01.042
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发表时间：
2020-05-06
期刊：
影响因子：
16.2
通讯作者：
Sherr, Elliott H.
中科院分区：
文献类型：
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作者：
Lennox, Ashley L.;Hoye, Mariah L.;Sherr, Elliott H.
RNA解旋酶DDX 3X中的从头生殖系突变占女性不明原因智力残疾（ID）病例的1%-3%，并与自闭症，脑畸形和癫痫有关。然而，DDX 3X突变损害脑功能的发育和分子机制尚不清楚。在这里，我们使用人类和小鼠遗传学和细胞生物学和生物化学方法来阐明致病性DDX 3X变异破坏大脑发育的机制。我们报告了迄今为止DDX 3X突变的最大临床队列（n = 107），证明了复发性显性错义突变、多小脑回症和最严重的临床结局之间的显著相关性。我们发现，Ddx 3x通过调节神经元的产生来控制皮质发育。严重的DDX 3X错义突变严重破坏RNA解旋酶活性，诱导神经祖细胞和神经元中的异位RNA蛋白颗粒，并损害翻译。总之，这些结果揭示了DDX 3X综合征和神经发育疾病发病机制中的高光异常RNA代谢的关键机制。
De novo germline mutations in the RNA helicase DDX3X account for 1%-3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here, we use human and mouse genetics and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n = 107), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and high-light aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.