Huntington's disease onset is determined by length of uninterrupted CAG, not encoded polyglutamine, and is modified by DNA maintenance mechanisms
Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium,
Eun Pyo Hong,
Michael J Chao,
Jeffrey D. Long,
Ricardo Mouro Pinto,
Kawther Abu Elneel,
Eliana Marisa Ramos,
Jayalakshmi Srinidhi Mysore,
Vanessa C Wheeler,
Marcy E MacDonald,
James F. Gusella,
Timothy C Stone,
Darren G. Monckton,
G. Bernhard Landwehrmeyer,
Jane S Paulsen,
E. Ray Dorsey,
Richard H Myers
Posted 24 Jan 2019
bioRxiv DOI: 10.1101/529768
Posted 24 Jan 2019
The effects of variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from huntingtin's polyglutamine segment, dictates the rate at which HD develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question a fundamental premise of the "polyglutamine disorders".
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