Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Department of Biology, University of Waterloo, Waterloo, Ontario, N2L 3G1, Canada.
Sci Rep. 2018 May 25;8(1):8096. doi: 10.1038/s41598-018-25903-w.
Post-translational modifications (PTMs) are key modulators of protein function. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin (HTT) gene. A spectrum of PTMs have been shown to modify the normal functions of HTT, including proteolysis, phosphorylation and lipidation, but the full contribution of these PTMs to the molecular pathogenesis of HD remains unclear. In this study, we examine all commonly occurring missense mutations in HTT to identify potential human modifiers of HTT PTMs relevant to HD biology. We reveal a SNP that modifies post-translational myristoylation of HTT, resulting in downstream alterations to toxic HTT proteolysis in human cells. This is the first SNP shown to functionally modify a PTM in HD and the first validated genetic modifier of post-translational myristoylation. This SNP is a high-priority candidate modifier of HD phenotypes and may illuminate HD biology in human studies.
翻译后修饰（PTMs）是蛋白质功能的关键调节因子。亨廷顿病（HD）是一种常染色体显性遗传的神经退行性疾病，由亨廷顿蛋白（HTT）基因中CAG三核苷酸重复序列扩增引起。一系列翻译后修饰已被证明可改变HTT的正常功能，包括蛋白水解、磷酸化和脂酰化，但这些翻译后修饰对HD分子发病机制的全部作用仍不清楚。在本研究中，我们检测了HTT中所有常见的错义突变，以确定与HD生物学相关的HTT翻译后修饰的潜在人类调节因子。我们发现了一个单核苷酸多态性（SNP），它可修饰HTT的翻译后豆蔻酰化，导致人类细胞中有毒性的HTT蛋白水解发生下游改变。这是首个被证明在功能上修饰HD中翻译后修饰的SNP，也是首个经证实的翻译后豆蔻酰化的遗传调节因子。该SNP是HD表型的高优先级候选调节因子，可能为人类研究中的HD生物学提供启示。
