Fig. 1.

A model for the pathogenic threshold in HD. A) HD pathogenesis is largely determined by an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat within exon 1 of the huntingtin (HTT) gene, which is translated into an expanded polyglutamine tract in the corresponding HTT protein. Wild-type HTT possesses 5– 35 CAG repeats (non-expanded HTT gene), and can undergo expansion into the disease range in the germline to create apparent de novo HD subjects, but ≥36 + repeats is associated with a significantly increased risk of developing HD (expanded HTT gene). B) An expanded HTT allele with 36 or more repeats is unstable and licenced to further expand in cells over the lifespan of the HD at-risk individual. HD symptoms would manifest and progress as increasing numbers of disease-relevant cells undergo somatic expansion beyond an unknown intracellular pathogenic threshold that renders the gene toxic in those cells. Figures created using BioRender.com. Figure 1A adapted from a figure by National Institute of General Medical Sciences, National Institutes of Health.