Abstract
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.
Highlights
Huntington disease (HD) is a debilitating neurodegenerative disease with no treatment to delay progression of the disease
While some Post-translational modifications (PTMs) of HTT have been shown to be protective against toxicity of mutant HTT, such as phosphorylation at S13/16 and S42110, others are crucial for HD pathogenesis or increase mutant HTT toxicity
To identify SNPs that could alter HTT PTMs and potentially modify HTT function, all common missense mutations (≥0.1% minor allele frequency; MAF) within HTT were curated from Phase 3 of the 1000 Genomes Project (1 KG) and from the Genome Aggregation Database
Summary
Huntington disease (HD) is a debilitating neurodegenerative disease with no treatment to delay progression of the disease. HD is caused by an expanded CAG repeat in the huntingtin gene (HTT) that translates into a polyglutamine tract at the N-terminus of the huntingtin protein (HTT)[1]. Age of onset may be accelerated or delayed by genetic modifiers, including a SNP at the transcription factor binding site of Nf-kB in the HTT promoter[7], and in genes related to DNA repair[8]. The HTT protein is a large monomeric protein whose function is intricately regulated by post-translational modifications including phosphorylation, acetylation, ubiquitination, proteolysis, and fatty acylation[9]. We sought to identify human SNPs that lead to missense mutations that may alter PTMs in HTT and, modify progression or pathogenic effects of the disease
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