Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes - Institut Pierre Louis d'Epidémiologie et de Santé Publique
Article Dans Une Revue Brain - A Journal of Neurology Année : 2014

Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes

1 iPLESP - Institut Pierre Louis d'Epidémiologie et de Santé Publique
2 CHU Pitié-Salpêtrière [AP-HP]
3 ICM - Institut du Cerveau = Paris Brain Institute
4 Eberhard Karls Universität Tübingen = University of Tübingen
5 University of Utah
6 UTokyo - The University of Tokyo
7 UNITO - Università degli studi di Torino = University of Turin
8 Institute of Psychiatry and Neurology [Warsaw]
9 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
10 Fondazione IRCCS Istituto Neurologico "Carlo Besta"
11 Radboud University Medical Center [Nijmegen]
12 A.O.U - Città della Salute e della Scienza di Torino
13 UCL - University College of London [London]
14 University of Naples Federico II = Università degli studi di Napoli Federico II
15 St. Josef Hospital [Bochum, Germany]
16 University Hospital Bonn
17 Marqués de Valdecilla University Hospital [Santander]
18 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
19 ULB - Université libre de Bruxelles
20 Hôpital Erasme [Bruxelles]
21 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
22 University of Pecs
23 AöR - University Hospital Essen
24 Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
25 UniGe - Università degli studi di Genova = University of Genoa
26 UF - University of Florida [Gainesville]
27 HESAM - HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université
Bela Melegh
  • Fonction : Auteur
Jun Goto
  • Fonction : Auteur

Résumé

Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Dates et versions

hal-04688293 , version 1 (04-09-2024)

Identifiants

Citer

Sophie Tezenas Du Montcel, Alexandra Durr, Peter Bauer, Karla P Figueroa, Yaeko Ichikawa, et al.. Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes. Brain - A Journal of Neurology , 2014, 137 (9), pp.2444-55. ⟨10.1093/brain/awu174⟩. ⟨hal-04688293⟩
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