ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization
Authors: Tazelaar Gijs H P , Boeynaems Steven , De Decker Mathias , van Vugt Joke J F A , Kool Lindy , Goedee H Stephan , McLaughlin Russell L , Sproviero William , Iacoangeli Alfredo , Moisse Matthieu , Jacquemyn Maarten , Daelemans Dirk , Dekker Annelot M , van der Spek Rick A , Westeneng Henk-Jan , Kenna Kevin P , Assialioui Abdelilah , Da Silva Nica ,   Project MinE ALS Sequencing Consortium, Akçimen Fulya , Al Khleifat Ahmad , Al-Chalabi Ammar , Andersen Peter , Basak A Nazli , Bauer Denis C , Blair Ian , Brands William J , Byrne Ross P , Calvo Andrea , Gonzalez Yolanda Campos , Chio Adriano , Cooper-Knock Jonothan , Corcia Philippe , Couratier Philippe , de Carvalho Mamede , Dekker Annelot M , Drory Vivian E , Eitan Chen , Redondo Alberto Garcia , Gellera Cinzia , Glass Jonathan D , Gotkine Marc , Hardiman Orla , Hornstein Eran , Iacoangeli Alfredo , Kenna Kevin P , Kenna Brandon , Kiernan Matthew C , Kocoglu Cemile , Kooyman Maarten , Landers John E , Alonso Victoria López , McLaughlin Russell L , Middelkoop Bas , Mill Jonathan , Mitne-Neto Miguel , Moisse Matthieu , Mora Pardina Jesus S , Morrison Karen E , Pinto Susana , Gromicho Marta , Panadés Monica Povedano , Pulit Sara L , Ratti Antonia , Robberecht Wim , Schellevis Raymond D , Shatunov Aleksey , Shaw Christopher E , Shaw Pamela J , Silani Vincenzo , Sproviero William , Staiger Christine , Tazelaar Gijs H P , Ticozzi Nicola , Tunca Ceren , Twine Nathalie A , van Damme Philip , van den Berg Leonard H , van der Spek Rick A , van Doormaal Perry T C , van Eijk Kristel R , van Es Michael A , van Rheenen Wouter , van Vugt Joke J F A , Veldink Jan H , Visscher Peter M , Vourc’h Patrick , Weber Markus , Williams Kelly L , Wray Naomi , Yang Jian , Zatz Mayana , Zhang Katharine , Povedano Mónica , Pardina Jesus S Mora , Hardiman Orla , Salachas François , Millecamps Stéphanie , Vourc’h Patrick , Corcia Philippe , Couratier Philippe , Morrison Karen E , Shaw Pamela J , Shaw Christopher E , Pasterkamp R Jeroen , Landers John E , Van Den Bosch Ludo , Robberecht Wim , Al-Chalabi Ammar , van den Berg Leonard H , Van Damme Philip , Veldink Jan H , van Es Michael A 
Published: May 2020

Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 × 10−7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.