biostudies-literatureAldous SGUK Dementia Research InstituteMedical Research CouncilNCI NIH HHSCHDI FoundationDementia Research Institute LtdAlzheimer’s Society and Alzheimer’s Research UKNIHWellcome TrustNIH HHS1784-1798https://www.ebi.ac.uk/biostudies/studies/S-EPMC11068328biostudies-literatureUnknown147(5)The Huntington's disease mutation is a CAG repeat expansion in the huntingtin gene that results in an expanded polyglutamine tract in the huntingtin protein. The CAG repeat is unstable and expansions of hundreds of CAGs have been detected in Huntington's disease post-mortem brains. The age of disease onset can be predicted partially from the length of the CAG repeat as measured in blood. Onset age is also determined by genetic modifiers, which in six cases involve variation in DNA mismatch repair pathways genes. Knocking-out specific mismatch repair genes in mouse models of Huntington's disease prevents somatic CAG repeat expansion. Taken together, these results have led to the hypothesis that somatic CAG repeat expansion in Huntington's disease brains is required for pathogenesis. TherefoBrain : a journal of neurologyA CAG repeat threshold for therapeutics targeting somatic instability in Huntington's disease.PMC11068328UKDRI-1008/1P30 CA0133305P30CA13330R01 CA248536R01CA248536223082/Z/21/ZPhillips JLandles CBates GPSmith EJGreene JRBenn CLOsborne GFJin BZhang YHirst MBEdelmann WCanibano-Pico MAldous SGNita IMBond BCfalseA CAG repeat threshold for therapeutics targeting somatic instability in Huntington's disease.The Huntington's disease mutation is a CAG repeat expansion in the huntingtin gene that results in an expanded polyglutamine tract in the huntingtin protein. The CAG repeat is unstable and expansions of hundreds of CAGs have been detected in Huntington's disease post-mortem brains. The age of disease onset can be predicted partially from the length of the CAG repeat as measured in blood. Onset age is also determined by genetic modifiers, which in six cases involve variation in DNA mismatch repair pathways genes. Knocking-out specific mismatch repair genes in mouse models of Huntington's disease prevents somatic CAG repeat expansion. Taken together, these results have led to the hypothesis that somatic CAG repeat expansion in Huntington's disease brains is required for pathogenesis. Therefo2024-01-01T00:00:00Z2024 May2026-06-03T20:04:00.054Z2026-05-01T03:10:44.914ZS-EPMC110683283838708010.1093/brain/awae063