Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Nat Neurosci. 2019 Dec;22(12):1966-1974. doi: 10.1038/s41593-019-0530-0. Epub 2019 Nov 25.
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.
为了发现肌萎缩侧索硬化症（ALS）的新基因，我们对 3864 例病例和 7839 例匹配的对照组的外显子组进行了汇总。我们观察到 ALS 病例中存在显著过多的罕见蛋白截断变异，这些变异集中在受约束的基因中。通过基因水平分析，我们复制了已知的 ALS 基因，包括 SOD1、NEK1 和 FUS。我们还在一个高度受约束的基因 DNAJC7 中观察到多个不同的蛋白截断变异。DNAJC7 中的信号超过了全基因组显著性，免疫印迹检测显示在携带 p.Arg156Ter 变异的 ALS 患者的成纤维细胞中 DNAJC7 蛋白耗竭。DNAJC7 编码热休克蛋白家族的成员 HSP40，它与 HSP70 蛋白一起促进蛋白质的动态平衡，包括新合成多肽的折叠和降解蛋白的清除。当这些过程不受调节时，错误折叠和异常蛋白的积累可能发生，并导致蛋白聚集，这是神经退行性变的病理标志。我们的研究结果突出了 DNAJC7 作为 ALS 的一个新基因。
