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CAG repeat not polyglutamine length determines timing of Huntington’s disease onset

Lee, Jong-Min, Correia, Kevin, Loupe, Jacob, Kim, Kyung, Barker, Douglas, Hong, Eun Pyo, Chao, Michael, Long, Jeffery, Lucente, Diane, Vonsattel, Jean, Pinto, Richardo, Ehiana, Ramos, Mysore, Jayalakshmi, Gillis, Tammy, Wheeler, Vanessa, MacDonald, Marcy, Gusella, James, McAllister, Branduff, Massey, Thomas ORCID:, Medway, Christopher ORCID:, Stone, Timothy ORCID:, Hall, Lynsey, Jones, Lesley ORCID:, Holmans, Peter ORCID:, Kwark, Seung, Ehrhardt, Anka, Sampaio, Cristina, Ciosi, Marc, Maxwell, Alastair, Chatzi, Afroditi, Monckton, Darren, Orth, Michael, Landwehrmeyer, Bernhard and Paulsen, Jane 2019. CAG repeat not polyglutamine length determines timing of Huntington’s disease onset. Cell 178 (4) , 887-099.e14. 10.1016/j.cell.2019.06.036

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Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin’s polyglutamine segment, dictates the rate at which Huntington’s disease (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 the fundamental premise that polyglutamine length determines the rate of pathogenesis in the “polyglutamine disorders.”

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium Creative Commons Attribution (CC BY 4.0)
Publisher: Elsevier
ISSN: 0092-8674
Date of First Compliant Deposit: 18 July 2019
Date of Acceptance: 27 June 2019
Last Modified: 25 Nov 2022 10:47

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