Author:
,Lee Jong-Min,Correia Kevin,Loupe Jacob,Kim Kyung-Hee,Barker Douglas,Hong Eun Pyo,Chao Michael J,Long Jeffrey D.,Lucente Diane,Vonsattel Jean-Paul,Mouro Pinto Ricardo,Abu Elneel Kawther,Ramos Eliana Marisa,Mysore Jayalakshmi Srinidhi,Gillis Tammy,Wheeler Vanessa C.,MacDonald Marcy E.,Gusella James F,Massey Thomas,McAllister Branduff,Medway Christopher,Stone Timothy C,Hall Lynsey,Jones Lesley,Holmans Peter,Kwak Seung,Ehrhardt Anka,Sampaio Cristina,Ciosi Marc,Maxwell Alastair,Chatzi Afroditi,Monckton Darren G,Orth Michael,Landwehrmeyer G. Bernhard,Paulsen Jane S,Dorsey E. Ray,Shoulson Ira,Myers Richard H
Abstract
SUMMARYThe 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”.
Publisher
Cold Spring Harbor Laboratory
Cited by
4 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献