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ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization
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 polyal...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425293/ https://www.ncbi.nlm.nih.gov/pubmed/32954321 http://dx.doi.org/10.1093/braincomms/fcaa064 |
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author | 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 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 |
author_facet | 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 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 |
author_sort | Tazelaar, Gijs H P |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7425293 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-74252932020-09-17 ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization 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 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 Brain Commun Original Article 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. Oxford University Press 2020-05-19 /pmc/articles/PMC7425293/ /pubmed/32954321 http://dx.doi.org/10.1093/braincomms/fcaa064 Text en © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Article 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 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 ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization |
title |
ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and
contribute to TDP-43 mislocalization |
title_full |
ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and
contribute to TDP-43 mislocalization |
title_fullStr |
ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and
contribute to TDP-43 mislocalization |
title_full_unstemmed |
ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and
contribute to TDP-43 mislocalization |
title_short |
ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and
contribute to TDP-43 mislocalization |
title_sort | atxn1 repeat expansions confer risk for amyotrophic lateral sclerosis and
contribute to tdp-43 mislocalization |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425293/ https://www.ncbi.nlm.nih.gov/pubmed/32954321 http://dx.doi.org/10.1093/braincomms/fcaa064 |
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