DDX17 is an RNA helicase shown to be involved in critical processes during the early phases of neuronal differentiation. Globally, we compiled a case-series of 11 patients with neurodevelopmental phenotypes harbouring de novo monoallelic variants in DDX17. All 11 patients in our case series had a neurodevelopmental phenotype, whereby intellectual disability, delayed speech and language, and motor delay predominated. We performed in utero cortical electroporation in the brain of developing mice, assessing axon complexity and outgrowth of electroporated neurons, comparing wild-type and Ddx17 knockdown. We then undertook ex vivo cortical electroporation on neuronal progenitors to quantitatively assess axonal development at a single cell resolution. Mosaic ddx17 crispants and heterozygous knockouts in Xenopus tropicalis were generated for assessment of morphology, behavioural assays, and neuronal outgrowth measurements. We further undertook transcriptomic analysis of neuroblastoma SH-SY5Y cells, to identify differentially expressed genes in DDX17-KD cells compared to controls. Knockdown of Ddx17 in electroporated mouse neurons in vivo showed delayed neuronal migration as well as decreased cortical axon complexity. Mouse primary cortical neurons revealed reduced axon outgrowth upon knockdown of Ddx17 in vitro. The axon outgrowth phenotype was replicated in crispant ddx17 tadpoles and in heterozygotes. Heterozygous tadpoles had clear neurodevelopmental defects and showed an impaired neurobehavioral phenotype. Transcriptomic analysis identified a statistically significant number of differentially expressed genes involved in neurodevelopmental processes in DDX17-KD cells compared to control cells. We have identified potential neurodevelopment disease-causing variants in a gene not previously associated with genetic disease, DDX17. We provide evidence for the role of the gene in neurodevelopment in both mammalian and non-mammalian species and in controlling the expression of key neurodevelopment genes.

中文翻译：

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DDX17 中的单等位基因从头变异可引起神经发育障碍


DDX17 是一种 RNA 解旋酶，被证明参与神经元分化早期的关键过程。在全球范围内，我们汇编了 11 例神经发育表型在 DDX17 中携带新发单等位基因变异的病例系列。我们病例系列中的所有 11 名患者都有神经发育表型，其中智力障碍、言语和语言延迟以及运动发育迟缓占主导地位。我们在发育中的小鼠大脑中进行了子宫内皮质电穿孔，评估轴突复杂性和电穿孔神经元的生长，比较野生型和 Ddx17 敲低。然后，我们对神经元祖细胞进行了离体皮层电穿孔，以在单细胞分辨率下定量评估轴突发育。产生非洲爪蟾中的花叶 ddx17 脆片和杂合敲除物，用于评估形态学、行为测定和神经元生长测量。我们进一步对神经母细胞瘤 SH-SY5Y 细胞进行了转录组学分析，以鉴定与对照组相比 DDX17-KD 细胞中的差异表达基因。在体内电穿孔小鼠神经元中敲低 Ddx17 显示神经元迁移延迟以及皮质轴突复杂性降低。小鼠原代皮质神经元显示，在体外敲低 Ddx17 后，轴突生长减少。轴突生长表型在脆皮 ddx17 蝌蚪和杂合子中复制。杂合蝌蚪具有明显的神经发育缺陷，并表现出受损的神经行为表型。转录组学分析发现，与对照细胞相比，DDX17-KD 细胞中参与神经发育过程的差异表达基因数量具有统计学意义。 我们已经在以前与遗传病无关的基因 DDX17 中发现了潜在的神经发育致病变异。我们为该基因在哺乳动物和非哺乳动物物种的神经发育中的作用以及控制关键神经发育基因的表达提供了证据。