PMS1 as a target for splice modulation to prevent somatic CAG repeat expansion in Huntington's disease.

ABSTRACT: Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder whose motor, cognitive, and behavioral manifestations are caused by an expanded, somatically unstable CAG repeat in the first exon of HTT that lengthens a polyglutamine tract in huntingtin. Genome-wide association studies (GWAS) have revealed DNA repair genes that influence the age-at-onset of HD and implicate somatic CAG repeat expansion as the primary driver of disease timing. To prevent the consequent neuronal damage, small molecule splice modulators (e.g., branaplam) that target HTT to reduce the levels of huntingtin are being investigated as potential HD therapeutics. We found that the effectiveness of the splice modulators can be influenced by genetic variants, both at HTT and other ge

SUBMITTER: McLean ZL 

PROVIDER: S-EPMC10402039 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature