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研究发现调控肌萎缩性脊髓侧索硬化症的新基因
作者:小柯机器人 发布时间:2019/11/26 15:26:14

美国哈佛大学-麻省理工学院博德研究所Benjamin M. Neale组和Sali M. K. Farhan组合作,在肌萎缩性脊髓侧索硬化症(ALS)的外显子组测序中,发现一种新的热休克蛋白编码基因-DNAJC7。11月25日,《自然—神经科学》在线发表了这一成果。

为了发现ALS的新基因,研究人员分析了3,864例病例和7,839个遗传匹配的对照外显子组数据。研究人员在ALS病例中观察到显著过量的稀有蛋白截短变异体,这些变异集中在受限基因中。

通过基因水平的分析,研究人员测定了已知的ALS基因,如SOD1、NEK1和FUS。研究人员还观察到高度受限基因DNAJC7中存在多个截然不同的蛋白截短变体。

DNAJC7的信号强度明显高于全基因组的显著性,免疫印迹表明,携带p.Arg156Ter变体的ALS患者其成纤维细胞中缺少DNAJC7蛋白。DNAJC7编码热休克蛋白家族成员HSP40,它与HSP70蛋白合作通过调控新生多肽的折叠和降解蛋白质的清除来促进蛋白质稳态。

当这些过程不受调控时,细胞内会发生异常蛋白的错误折叠和积累并导致蛋白聚合,这是神经退行性疾病的病理学标志。该研究揭示了DNAJC7是调控ALS的新基因。

附:英文原文

Title: Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7 , encoding a heat-shock protein

Author: Sali M. K. Farhan, Daniel P. Howrigan, Liam E. Abbott, Joseph R. Klim, Simon D. Topp, Andrea E. Byrnes, Claire Churchhouse, Hemali Phatnani, Bradley N. Smith, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Aleksey Shatunov, Alfredo Iacoangeli, Ahmad Al Khleifat, Daniel A. Mordes, Sulagna Ghosh, Kevin Eggan, Rosa Rademakers, Jacob L. McCauley, Rebecca Schle, Stephan Zchner, Michael Benatar, J. Paul Taylor, Michael Nalls, Marc Gotkine, Pamela J. Shaw, Karen E. Morrison, Ammar Al-Chalabi, Bryan Traynor, Christopher E. Shaw, David B. Goldstein, Matthew B. Harms, Mark J. Daly, Benjamin M. Neale

Issue&Volume: 2019-11-25

Abstract: To discover novel genes underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry-matched controls. We observed a significant excess of rare protein-truncating variants among ALS cases, and these variants were concentrated in constrained genes. Through gene level analyses, we replicated known ALS genes including SOD1, NEK1 and FUS. We also observed multiple distinct protein-truncating variants in a highly constrained gene, DNAJC7. The signal in DNAJC7 exceeded genome-wide significance, and immunoblotting assays showed depletion of DNAJC7 protein in fibroblasts in a patient with ALS carrying the p.Arg156Ter variant. DNAJC7 encodes a member of the heat-shock protein family, HSP40, which, along with HSP70 proteins, facilitates protein homeostasis, including folding of newly synthesized polypeptides and clearance of degraded proteins. When these processes are not regulated, misfolding and accumulation of aberrant proteins can occur and lead to protein aggregation, which is a pathological hallmark of neurodegeneration. Our results highlight DNAJC7 as a novel gene for ALS.

DOI: 10.1038/s41593-019-0530-0

Source: https://www.nature.com/articles/s41593-019-0530-0

期刊信息

Nature Neuroscience:《自然—神经科学》,创刊于1998年。隶属于施普林格·自然出版集团,最新if:21.126
官方网址:https://www.nature.com/neuro/
投稿链接:https://mts-nn.nature.com/cgi-bin/main.plex