Jessica Dawson

Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by an expansion of a polyglutamine encoding CAG repeat in the huntingtin (HTT) gene. Disease severity in HD has been found to be best predicted by the number of pure CAG repeats, rather than the total number of glutamines encoded. However, there is still significant additional variation observed, which is heritable. Among the factors that modify the age of onset of HD, there are synonymous variants that either add or remove interruptions to the HTT CAG and CCG repeats. Recently, synonymous loss of interruption (LOI) variants have been identified as cis- acting modifiers that accelerate HD onset by 7 to 10 years. Interestingly, these LOI variants have not been associated with increased somatic expansion in bulk assessments of peripheral blood DNA in HD patients. This suggests that somatic expansion alone may not fully explain the disease-hastening effect associated with LOI variants unless there is a reversal of the effect in critical brain regions. In the case of another repeat expansion disorder, spinocerebellar ataxia type 8 (SCA8), sequence variants have been shown to affect the RNA structure, which in turn mediates differences in repeat-associated non-ATG (RAN) translation and accumulation of toxic products. In LOI variants, there is a reduction in mismatches or loop-outs in this secondary structure, which may lead to increased expression of RAN proteins, toxicity, and cell death, contributing to earlier disease onset. Despite these possibilities, the exact mechanism driving the modifier effect linked to LOI variants remains unknown. To address this knowledge gap, our study aims to investigate the LOI variants within the broader context of the HTT gene. Specifically, we seek to understand the relationship between somatic expansion in the brain and the production of toxic RAN proteins in patients with LOI variants. To accomplish this, we will leverage our clinical collaboration with the UBC Centre for Huntington Disease (CHD) Medical Clinic, which facilitates the collection of HD patient samples in the UBC HD Biobank. Through this research, we aim to contribute unique insights into clinically relevant disease modifiers in HD. By studying LOI variants, we hope to identify the underlying mechanisms and potential targets that can be used to delay the onset of HD. This study holds the potential to advance our understanding of HD pathology and provide valuable information for the development of therapeutic interventions.