Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by loss of motor neurons. Human genetic studies have linked mutations in RNA-binding proteins as causative for this disease. The hnRNPA1 protein, a known pre-mRNA splicing factor, is mutated in some ALS patients. Here, two human cell models were generated to investigate how a mutation in the C-terminal low-complexity domain (LCD) of hnRNPA1 can cause splicing changes of thousands of transcripts that collectively are linked to the DNA damage response, cilium organization, and translation. We show that the hnRNPA1 D262V mutant protein binds to new binding sites on differentially spliced transcripts from genes that are linked to ALS. We demonstrate that this ALS-linked hnRNPA1 mutation alters normal RNA-dependent protein–protein interactions. Furthermore, cells expressing this hnRNPA1 mutant exhibit a cell aggregation phenotype, markedly reduced growth rates, changes in stress granule kinetics, and aberrant growth of neuronal processes. This study provides insight into how a single amino acid mutation in a splicing factor can alter RNA splicing networks of genes linked to ALS.

中文翻译：

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与肌萎缩侧索硬化症相关的剪接因子 hnRNPA1 低复杂性结构域的突变破坏了不同的神经元 RNA 剪接网络

肌萎缩侧索硬化症（ALS）是一种使人衰弱的神经退行性疾病，其特征是运动神经元丧失。人类遗传学研究已将 RNA 结合蛋白的突变与这种疾病的病因联系起来。 hnRNPA1 蛋白是一种已知的前 mRNA 剪接因子，在一些 ALS 患者中发生突变。在这里，生成了两个人类细胞模型来研究 hnRNPA1 C 端低复杂性结构域 (LCD) 中的突变如何导致数千个转录本的剪接变化，这些转录本共同与 DNA 损伤反应、纤毛组织和翻译相关。我们发现 hnRNPA1 D262V 突变蛋白与 ALS 相关基因的差异剪接转录本上的新结合位点结合。我们证明这种 ALS 相关的 hnRNPA1 突变改变了正常的 RNA 依赖性蛋白质-蛋白质相互作用。此外，表达这种 hnRNPA1 突变体的细胞表现出细胞聚集表型、生长速率显着降低、应激颗粒动力学变化以及神经元过程异常生长。这项研究深入了解剪接因子中的单个氨基酸突变如何改变与 ALS 相关的基因的 RNA 剪接网络。