Hereditary spastic parapareses (HSPs) are clinically heterogeneous motor neuron diseases with variable age of onset and severity. Although variants in dozens of genes are implicated in HSPs, much of the genetic basis for pediatric-onset HSP remains unexplained. Here, we re-analyzed clinical exome-sequencing data from siblings with HSP of unknown genetic etiology and identified an inherited nonsense mutation (c.523C>T [p.Arg175Ter]) in the highly conserved RAB1A. The mutation is predicted to produce a truncated protein with an intact RAB GTPase domain but without two C-terminal cysteine residues required for proper subcellular protein localization. Additional RAB1A mutations, including two frameshift mutations and a mosaic missense mutation (c.83T>C [p.Leu28Pro]), were identified in three individuals with similar neurodevelopmental presentations. In rescue experiments, production of the full-length, but not the truncated, RAB1a rescued Golgi structure and cell proliferation in Rab1-depleted cells. In contrast, the missense-variant RAB1a disrupted Golgi structure despite intact Rab1 expression, suggesting a dominant-negative function of the mosaic missense mutation. Knock-down of RAB1A in cultured human embryonic stem cell-derived neurons resulted in impaired neuronal arborization. Finally, RAB1A is located within the 2p14–p15 microdeletion syndrome locus. The similar clinical presentations of individuals with RAB1A loss-of-function mutations and the 2p14–p15 microdeletion syndrome implicate loss of RAB1A in the pathogenesis of neurodevelopmental manifestations of this microdeletion syndrome. Our study identifies a RAB1A-related neurocognitive disorder with speech and motor delay, demonstrates an essential role for RAB1a in neuronal differentiation, and implicates RAB1A in the etiology of the neurodevelopmental sequelae associated with the 2p14–p15 microdeletion syndrome.

遗传性痉挛性截瘫 (HSP) 是一种临床异质性运动神经元疾病，发病年龄和严重程度各不相同。尽管热休克蛋白涉及数十个基因的变异，但儿科发病的热休克蛋白的大部分遗传基础仍然无法解释。在这里，我们重新分析了遗传病因未知的 HSP 兄弟姐妹的临床外显子组测序数据，并在高度保守的RAB1A中发现了遗传性无义突变 (c.523C>T [p.Arg175Ter]) 。预计该突变会产生具有完整 RAB GTPase 结构域的截短蛋白，但没有正确亚细胞蛋白定位所需的两个 C 端半胱氨酸残基。在具有相似神经发育表现的三个个体中发现了其他RAB1A突变，包括两个移码突变和一个嵌合错义突变(c.83T>C [p.Leu28Pro])。在挽救实验中，生产全长而非截短的RAB1a可以挽救Rab1耗尽的细胞中的高尔基体结构和细胞增殖。相比之下，尽管 Rab1表达完整，错义变体 RAB1a 却破坏了高尔基体结构，这表明嵌合错义突变具有显性失活功能。在培养的人胚胎干细胞衍生的神经元中敲除RAB1A会导致神经元树枝化受损。最后， RAB1A位于 2p14-p15 微缺失综合征基因座内。具有RAB1A功能丧失突变和 2p14-p15 微缺失综合征的个体具有相似的临床表现，表明RAB1A缺失参与了这种微缺失综合征神经发育表现的发病机制。我们的研究确定了一种与语言和运动延迟相关的RAB1A相关神经认知障碍，证明了 RAB1a 在神经元分化中的重要作用，并暗示RAB1A与 2p14-p15 微缺失综合征相关的神经发育后遗症的病因学有关。