PT  - JOURNAL ARTICLE
AU  - DDO Martin
AU  - C Kay
AU  - JA Collins
AU  - YT Nguyen
AU  - RA Slama
AU  - MR Hayden
TI  - A human huntingtin SNP alters post-translational modification and pathogenic proteolysis of the protein causing Huntington disease
AID  - 10.1101/129536
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 129536
4099  - http://biorxiv.org/content/early/2017/05/17/129536.short
4100  - http://biorxiv.org/content/early/2017/05/17/129536.full
AB  - 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.