Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK.
Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK.
Cell Rep. 2019 Feb 26;26(9):2298-2306.e5. doi: 10.1016/j.celrep.2019.02.006.
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding the glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C mutations in GLT8D1, which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site, and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro cytotoxicity and induces motor deficits in zebrafish consistent with ALS. Relative toxicity of mutations in model systems mirrors clinical severity. In conclusion, we have linked ALS pathophysiology to inherited mutations that diminish the activity of a glycosyltransferase enzyme.
肌萎缩侧索硬化症（ALS）是一种严重的神经退行性疾病，目前尚无有效的神经保护疗法。已知的遗传变异会损害包括 RNA 处理、轴突运输和蛋白质动态平衡在内的途径。我们在一个常染色体显性 ALS 家系中发现了编码糖基转移酶 GLT8D1 的基因突变，这些突变会导致疾病。对常染色体显性 ALS 家系的外显子组测序发现 GLT8D1 中的 p.R92C 突变与疾病共分离。对当地和国际队列的测序表明，在同一外显子中存在显著的 ALS 相关性，包括保守氨基酸中的其他罕见有害突变。这些突变与底物结合位点有关，R92C 和 G78W 改变均会损害 GLT8D1 酶的活性。突变的 GLT8D1 在体外具有细胞毒性，并在斑马鱼中引起运动缺陷，与 ALS 一致。在模型系统中，突变的相对毒性反映了临床严重程度。总之，我们已经将 ALS 的病理生理学与降低糖基转移酶酶活性的遗传突变联系起来。
