PDF(Pubmed)
Abstract：
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.
摘要：
遗传性痉挛性旁路（HSP）是临床上异质性的运动神经元疾病，发病年龄和严重程度各不相同。尽管数十种基因的变异与HSP有关，儿童发生HSP的大部分遗传基础仍无法解释.这里,我们重新分析了来自遗传病因未知的HSP兄弟姐妹的临床外显子组测序数据，并确定了遗传的无义突变（c.523C>T[p.Arg175Ter]）在高度保守的RAB1A中。预测突变产生具有完整的RABGTP酶结构域但没有适当的亚细胞蛋白质定位所需的两个C末端半胱氨酸残基的截短蛋白质。额外的RAB1A突变，包括两个移码突变和一个马赛克错义突变（c.83T>C[p。Leu28Pro]),在三个具有相似神经发育表现的个体中发现。在救援实验中，全长的生产，但不是截断的，RAB1a在Rab1耗竭细胞中拯救高尔基体结构和细胞增殖。相比之下,错义变体RAB1a破坏高尔基结构，尽管完整的Rab1表达，提示马赛克错义突变的显性负功能。在培养的人胚胎干细胞衍生的神经元中敲除RAB1A导致神经元乔化受损。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的相似临床表现暗示RAB1A的丧失在这种微缺失综合征的神经发育表现的发病机理中。我们的研究确定了RAB1A相关的神经认知障碍，伴有言语和运动延迟，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有关。
