Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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, Medway, Christopher, Stone, Timothy, Hall, Lynsey, Jones, Lesley, Holmans, Peter, 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) , 887-900.e14. 10.1016/j.cell.2019.06.036

[img]
Preview
PDF - Published Version
Available under License Creative Commons Attribution.

Download (6MB) | Preview

Abstract

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)
Publisher: Elsevier
ISSN: 0092-8674
Date of First Compliant Deposit: 18 July 2019
Date of Acceptance: 16 July 2019
Last Modified: 29 Aug 2019 08:27
URI: http://orca.cf.ac.uk/id/eprint/124280

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics