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Brain. 2014 Sep;137(Pt 9):2444-55. doi: 10.1093/brain/awu174. Epub 2014 Jun 26.

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

Author information

1
1 Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Univ Paris 06, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013, Paris, France2 INSERM, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013, Paris, France3 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Biostatistics Unit, Paris, F-75013, France sophie.tezenas@psl.aphp.fr alexis.brice@upmc.fr.
2
4 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Genetics and Cytogenetics, F-75013, Paris, France5 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
3
6 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
4
7 Department of Neurology, University of Utah, Salt Lake City, USA.
5
8 Department of Neurology, University of Tokyo, Graduate School of Medicine, Tokyo, Japan.
6
9 University of Torino, Department of Medical Sciences, and Medical Genetics Unit, Az. Osp. 'Città della Salute e della Scienza', Torino, Italy.
7
5 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
8
10 Institute of Psychiatry and Neurology Warsaw, Sobieskiego 9, 02-957 Warsaw, Poland.
9
11 Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany12 German Centre of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
10
13 SOSD Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS, Istituto Neurologico 'Carlo Besta', Milan, Italy.
11
14 Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radbound University Medical Centre, Nijmegen, The Netherlands.
12
15 Neurologic Division I, Department of Neuroscience and Mental Health, AOU Città della Salute e della Scienza, Torino, Italy.
13
16 Institute of Neurology, Department of Molecular Neuroscience, UCL, Queen Square, London, UK.
14
17 Department of Neurological Sciences, Federico II University, Naples, Italy.
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18 Department of Neurology, St. Josef Hospital, University Hospital of Bochum, Bochum, Germany.
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19 Department of Neurology, University Hospital of Bonn, Bonn, Germany.
17
20 Department of Neurology, University Hospital 'Marqués de Valdecilla', UC, IDIVAL and CIBERNED, 39008 Santander, Spain.
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21 Department of Neurology, ULB-Hôpital Erasme, Université Libre de Bruxelles, CP 231, Campus Plaine, ULB, Brusssels, Belgium.
19
22 Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
20
23 Department of Medical Genetics, and Szentagothai Research Centre, University Pécs, Hungary.
21
24 Department of Neurology, University Clinic Essen, University of Duisburg-Essen, Essen, Germany.
22
25 Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal Child Health, University of Genova, and U.O. Medical Genetics of IRCCS AOU S. Martino Institute, Genova, Italy.
23
26 Department of Neurology and McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.
24
4 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Genetics and Cytogenetics, F-75013, Paris, France.
25
4 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Genetics and Cytogenetics, F-75013, Paris, France5 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France sophie.tezenas@psl.aphp.fr alexis.brice@upmc.fr.
26
4 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Genetics and Cytogenetics, F-75013, Paris, France5 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France27 Ecole Pratique des Hautes Etudes, heSam Université, laboratoire de neurogénétique, ICM, Groupe Hospitalier Pitié-Salpêtrière, F-75013 Paris, France.

Abstract

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.

KEYWORDS:

age at onset; modifier; spinocerebellar ataxia; trinucleotide repeat

PMID:
24972706
PMCID:
PMC4132646
DOI:
10.1093/brain/awu174
[Indexed for MEDLINE]
Free PMC Article

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