ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

Gijs H. P. Tazelaar; Steven Boeynaems; Mathias De Decker; Joke J. F. A. van Vugt; Lindy Kool; H. Stephan Goedee; Russell L. McLaughlin; William Sproviero; Alfredo Iacoangeli; Matthieu Moisse; Maarten Jacquemyn; Dirk Daelemans; Annelot M. Dekker; Rick A. van der Spek; Henk-Jan Westeneng; Kevin P. Kenna; Abdelilah Assialioui; Nica Da Silva; Project MinE ALS Sequencing Consortium; Mónica Povedano; Jesus S. Mora Pardina; Orla Hardiman; François Salachas; Stéphanie Millecamps; Patrick Vourc'h; Philippe Corcia; Philippe Couratier; Karen E. Morrison; Pamela J. Shaw; Christopher E. Shaw; R. Jeroen Pasterkamp; John E. Landers; Ludo Van Den Bosch; Wim Robberecht; Ammar Al-Chalabi; Leonard H. van den Berg; Philip Van Damme; Jan H. Veldink; Michael A. van Es

doi:10.1093/braincomms/fcaa064

ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

Gijs H. P. Tazelaar, Steven Boeynaems, Mathias De Decker, Joke J. F. A. van Vugt, Lindy Kool, H. Stephan Goedee, Russell L. McLaughlin, William Sproviero, Alfredo Iacoangeli, Matthieu Moisse, Maarten Jacquemyn, Dirk Daelemans, Annelot M. Dekker, Rick A. van der Spek, Henk-Jan Westeneng, Kevin P. Kenna, Abdelilah Assialioui, Nica Da Silva, Project MinE ALS Sequencing Consortium, Mónica PovedanoJesus S. Mora Pardina, Orla Hardiman, François Salachas, Stéphanie Millecamps, Patrick Vourc'h, Philippe Corcia, Philippe Couratier, Karen E. Morrison, Pamela J. Shaw, Christopher E. Shaw, R. Jeroen Pasterkamp, John E. Landers, Ludo Van Den Bosch, Wim Robberecht, Ammar Al-Chalabi, Leonard H. van den Berg, Philip Van Damme, Jan H. Veldink, Michael A. van Es

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Abstract

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.

Original language	English
Article number	fcaa064
Pages (from-to)	1-13
Number of pages	13
Journal	Brain Communications
Volume	2
Issue number	2
DOIs	https://doi.org/10.1093/braincomms/fcaa064
Publication status	Published - 2020

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

amyotrophic lateral sclerosis
trinucleotide repeat expansions
DNA repeat expansion
genetic association study

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10.1093/braincomms/fcaa064Licence: CC BY-NC

Publisher version (open access)Final published version, 1.03 MBLicence: CC BY-NC

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Tazelaar, G. H. P., Boeynaems, S., De Decker, M., van Vugt, J. J. F. A., Kool, L., Goedee, H. S., McLaughlin, R. L., Sproviero, W., Iacoangeli, A., Moisse, M., Jacquemyn, M., Daelemans, D., Dekker, A. M., van der Spek, R. A., Westeneng, H.-J., Kenna, K. P., Assialioui, A., Da Silva, N., Project MinE ALS Sequencing Consortium, ... van Es, M. A. (2020). ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization. Brain Communications, 2(2), 1-13. Article fcaa064. https://doi.org/10.1093/braincomms/fcaa064

@article{a993af60a26f4c4ba54b779f76e4fbf8,

title = "ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization",

abstract = "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.",

keywords = "amyotrophic lateral sclerosis, trinucleotide repeat expansions, DNA repeat expansion, genetic association study",

author = "Tazelaar, {Gijs H. P.} and Steven Boeynaems and {De Decker}, Mathias and {van Vugt}, {Joke J. F. A.} and Lindy Kool and Goedee, {H. Stephan} and McLaughlin, {Russell L.} and William Sproviero and Alfredo Iacoangeli and Matthieu Moisse and Maarten Jacquemyn and Dirk Daelemans and Dekker, {Annelot M.} and {van der Spek}, {Rick A.} and Henk-Jan Westeneng and Kenna, {Kevin P.} and Abdelilah Assialioui and {Da Silva}, Nica and {Project MinE ALS Sequencing Consortium} and Fulya Akcimen and {Al Khleifat}, Ahmad and Peter Andersen and Basak, {A. Nazli} and Bauer, {Denis C.} and Ian Blair and Brands, {William J.} and Byrne, {Ross P.} and Andrea Calvo and {Campos Gonzalez}, Yolanda and Adriano Chio and Johnathan Cooper-Knock and {de Carvalho}, Mamede and Drory, {Vivian E.} and Chen Eitan and {Garc{\'i}a Redondo}, Alberto and Cinzia Gellera and Glass, {Jonathan D.} and Marc Gotkine and Eran Hornstein and Brandon Kenna and Kiernan, {Matthew C.} and Cemile Kocoglu and Maarten Kooyman and {L{\'o}pez Alonso}, Victoria and Bas Middelkoop and Jonathan Mill and Miguel Mitne-Neto and Susana Pinto and Marta Gromicho and Pulit, {Sara L.} and Antonia Ratti and Schellevis, {Raymond D.} and Aleksey Shatunov and Vincenzo Silani and Christine Staiger and Nicola Ticozzi and Ceren Tunca and Twine, {Nathalie A.} and {van Doormaal}, {Perry T. C.} and {van Eijk}, {Kristel R.} and {van Rheenen}, Wouter and Visscher, {Peter M.} and Markus Weber and Williams, {Kelly L.} and Naomi Wray and Jian Yang and Mayana Zatz and Katharine Zhang and M{\'o}nica Povedano and Pardina, {Jesus S. Mora} and Orla Hardiman and Fran{\c c}ois Salachas and St{\'e}phanie Millecamps and Patrick Vourc'h and Philippe Corcia and Philippe Couratier and Morrison, {Karen E.} and Shaw, {Pamela J.} and Shaw, {Christopher E.} and Pasterkamp, {R. Jeroen} and Landers, {John E.} and {Van Den Bosch}, Ludo and Wim Robberecht and Ammar Al-Chalabi and {van den Berg}, {Leonard H.} and {Van Damme}, Philip and Veldink, {Jan H.} and {van Es}, {Michael A.}",

note = "Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2020",

doi = "10.1093/braincomms/fcaa064",

language = "English",

volume = "2",

pages = "1--13",

journal = "Brain Communications",

issn = "2632-1297",

publisher = "Oxford University Press",

number = "2",

}

Tazelaar, GHP, Boeynaems, S, De Decker, M, van Vugt, JJFA, Kool, L, Goedee, HS, McLaughlin, RL, Sproviero, W, Iacoangeli, A, Moisse, M, Jacquemyn, M, Daelemans, D, Dekker, AM, van der Spek, RA, Westeneng, H-J, Kenna, KP, Assialioui, A, Da Silva, N, Project MinE ALS Sequencing Consortium, Povedano, M, Pardina, JSM, Hardiman, O, Salachas, F, Millecamps, S, Vourc'h, P, Corcia, P, Couratier, P, Morrison, KE, Shaw, PJ, Shaw, CE, Pasterkamp, RJ, Landers, JE, Van Den Bosch, L, Robberecht, W, Al-Chalabi, A, van den Berg, LH, Van Damme, P, Veldink, JH & van Es, MA 2020, 'ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization', Brain Communications, vol. 2, no. 2, fcaa064, pp. 1-13. https://doi.org/10.1093/braincomms/fcaa064

TY - JOUR

T1 - ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

AU - Tazelaar, Gijs H. P.

AU - Boeynaems, Steven

AU - De Decker, Mathias

AU - van Vugt, Joke J. F. A.

AU - Kool, Lindy

AU - Goedee, H. Stephan

AU - McLaughlin, Russell L.

AU - Sproviero, William

AU - Iacoangeli, Alfredo

AU - Moisse, Matthieu

AU - Jacquemyn, Maarten

AU - Daelemans, Dirk

AU - Dekker, Annelot M.

AU - van der Spek, Rick A.

AU - Westeneng, Henk-Jan

AU - Kenna, Kevin P.

AU - Assialioui, Abdelilah

AU - Da Silva, Nica

AU - Project MinE ALS Sequencing Consortium

AU - Akcimen, Fulya

AU - Al Khleifat, Ahmad

AU - Andersen, Peter

AU - Basak, A. Nazli

AU - Bauer, Denis C.

AU - Blair, Ian

AU - Brands, William J.

AU - Byrne, Ross P.

AU - Calvo, Andrea

AU - Campos Gonzalez, Yolanda

AU - Chio, Adriano

AU - Cooper-Knock, Johnathan

AU - de Carvalho, Mamede

AU - Drory, Vivian E.

AU - Eitan, Chen

AU - García Redondo, Alberto

AU - Gellera, Cinzia

AU - Glass, Jonathan D.

AU - Gotkine, Marc

AU - Hornstein, Eran

AU - Kenna, Brandon

AU - Kiernan, Matthew C.

AU - Kocoglu, Cemile

AU - Kooyman, Maarten

AU - López Alonso, Victoria

AU - Middelkoop, Bas

AU - Mill, Jonathan

AU - Mitne-Neto, Miguel

AU - Pinto, Susana

AU - Gromicho, Marta

AU - Pulit, Sara L.

AU - Ratti, Antonia

AU - Schellevis, Raymond D.

AU - Shatunov, Aleksey

AU - Silani, Vincenzo

AU - Staiger, Christine

AU - Ticozzi, Nicola

AU - Tunca, Ceren

AU - Twine, Nathalie A.

AU - van Doormaal, Perry T. C.

AU - van Eijk, Kristel R.

AU - van Rheenen, Wouter

AU - Visscher, Peter M.

AU - Weber, Markus

AU - Williams, Kelly L.

AU - Wray, Naomi

AU - Yang, Jian

AU - Zatz, Mayana

AU - Zhang, Katharine

AU - Povedano, Mónica

AU - Pardina, Jesus S. Mora

AU - Hardiman, Orla

AU - Salachas, François

AU - Millecamps, Stéphanie

AU - Vourc'h, Patrick

AU - Corcia, Philippe

AU - Couratier, Philippe

AU - Morrison, Karen E.

AU - Shaw, Pamela J.

AU - Shaw, Christopher E.

AU - Pasterkamp, R. Jeroen

AU - Landers, John E.

AU - Van Den Bosch, Ludo

AU - Robberecht, Wim

AU - Al-Chalabi, Ammar

AU - van den Berg, Leonard H.

AU - Van Damme, Philip

AU - Veldink, Jan H.

AU - van Es, Michael A.

N1 - Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - amyotrophic lateral sclerosis

KW - trinucleotide repeat expansions

KW - DNA repeat expansion

KW - genetic association study

UR - http://www.scopus.com/inward/record.url?scp=85094627397&partnerID=8YFLogxK

U2 - 10.1093/braincomms/fcaa064

DO - 10.1093/braincomms/fcaa064

M3 - Article

C2 - 32954321

SN - 2632-1297

VL - 2

SP - 1

EP - 13

JO - Brain Communications

JF - Brain Communications

IS - 2

M1 - fcaa064

ER -

ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

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