Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

摘要

在神经退化疾病“肌萎缩性侧索硬化”(ALS)rn的近一半家族性病例中，疾病的遗传基础仍不rn知道。本文作者发现，profilin 1(PFNl)基因rn(它是将单体肌动蛋白转化成细丝状肌动蛋白rn所必需的)的突变会引起家族性ALS。现有数rn据表明，细胞骨架通道的改变有助于ALS的发rn病。对ALS中PFNl突变所做的观察对于家族rn性ALS病例的诊断性测试有直接意义，并且还rn为Als的治疗提供了一个新的潜在目标。rn突变速度受染色质结构影响rn癌症基因组的测序，为直接确定突变速度在rn整个人基因组中有何不同提供了一个机会。rnBenjamin Schuster-Boeckler平口Ben Lehner利用rn关于来自白血病、黑素瘤、肺癌和前列腺癌基rn因组的超过80,000个独特“单核苷酸变异体”rn位置的数据，来研究体细胞中(而不是生殖细rn胞中)突变速度的情况。他们发现，突变速度rn与染色质组织密切相关，说明将基因组组织成rn“异染色质类区域和常染色质类区域”的排列rn方式，对于人类体细胞中区域性突变速度差异rn具有支配性的影响。%Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.