title: Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes.
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.
authors: 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.
authors: Sophie
authors: S
authors: Tezenas du Montcel
authors: 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.
authors: Alexandra
authors: A
authors: Durr
authors: 6 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Peter
authors: P
authors: Bauer
authors: 7 Department of Neurology, University of Utah, Salt Lake City, USA.
authors: Karla P
authors: KP
authors: Figueroa
authors: 8 Department of Neurology, University of Tokyo, Graduate School of Medicine, Tokyo, Japan.
authors: Yaeko
authors: Y
authors: Ichikawa
authors: 9 University of Torino, Department of Medical Sciences, and Medical Genetics Unit, Az. Osp. 'Città della Salute e della Scienza', Torino, Italy.
authors: Alessandro
authors: A
authors: Brussino
authors: 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.
authors: Sylvie
authors: S
authors: Forlani
authors: 10 Institute of Psychiatry and Neurology Warsaw, Sobieskiego 9, 02-957 Warsaw, Poland.
authors: Maria
authors: M
authors: Rakowicz
authors: 11 Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany12 German Centre of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors: Ludger
authors: L
authors: Schöls
authors: 13 SOSD Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS, Istituto Neurologico 'Carlo Besta', Milan, Italy.
authors: Caterina
authors: C
authors: Mariotti
authors: 14 Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radbound University Medical Centre, Nijmegen, The Netherlands.
authors: Bart P C
authors: BP
authors: van de Warrenburg
authors: 15 Neurologic Division I, Department of Neuroscience and Mental Health, AOU Città della Salute e della Scienza, Torino, Italy.
authors: Laura
authors: L
authors: Orsi
authors: 16 Institute of Neurology, Department of Molecular Neuroscience, UCL, Queen Square, London, UK.
authors: Paola
authors: P
authors: Giunti
authors: 17 Department of Neurological Sciences, Federico II University, Naples, Italy.
authors: Alessandro
authors: A
authors: Filla
authors: 18 Department of Neurology, St. Josef Hospital, University Hospital of Bochum, Bochum, Germany.
authors: Sandra
authors: S
authors: Szymanski
authors: 19 Department of Neurology, University Hospital of Bonn, Bonn, Germany.
authors: Thomas
authors: T
authors: Klockgether
authors: 20 Department of Neurology, University Hospital 'Marqués de Valdecilla', UC, IDIVAL and CIBERNED, 39008 Santander, Spain.
authors: José
authors: J
authors: Berciano
authors: 21 Department of Neurology, ULB-Hôpital Erasme, Université Libre de Bruxelles, CP 231, Campus Plaine, ULB, Brusssels, Belgium.
authors: Massimo
authors: M
authors: Pandolfo
authors: 22 Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
authors: Sylvia
authors: S
authors: Boesch
authors: 23 Department of Medical Genetics, and Szentagothai Research Centre, University Pécs, Hungary.
authors: Bela
authors: B
authors: Melegh
authors: 24 Department of Neurology, University Clinic Essen, University of Duisburg-Essen, Essen, Germany.
authors: Dagmar
authors: D
authors: Timmann
authors: 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.
authors: Paola
authors: P
authors: Mandich
authors: 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.
authors: Agnès
authors: A
authors: Camuzat
authors: 8 Department of Neurology, University of Tokyo, Graduate School of Medicine, Tokyo, Japan.
authors: Jun
authors: J
authors: Goto
authors: 26 Department of Neurology and McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.
authors: Tetsuo
authors: T
authors: Ashizawa
authors: 4 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Genetics and Cytogenetics, F-75013, Paris, France.
authors: Cécile
authors: C
authors: Cazeneuve
authors: 8 Department of Neurology, University of Tokyo, Graduate School of Medicine, Tokyo, Japan.
authors: Shoji
authors: S
authors: Tsuji
authors: 7 Department of Neurology, University of Utah, Salt Lake City, USA.
authors: Stefan-M
authors: SM
authors: Pulst
authors: 9 University of Torino, Department of Medical Sciences, and Medical Genetics Unit, Az. Osp. 'Città della Salute e della Scienza', Torino, Italy.
authors: Alfredo
authors: A
authors: Brusco
authors: 6 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Olaf
authors: O
authors: Riess
authors: 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.
authors: Alexis
authors: A
authors: Brice
authors: 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.
authors: Giovanni
authors: G
authors: Stevanin
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D044466:Asian People / Q000208:ethnology / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020754:Spinocerebellar Ataxias / Q000175:diagnosis* / Q000208:ethnology / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D044465:White People / Q000208:ethnology / Q000235:genetics*; D055815:Young Adult
keywords: age at onset; modifier; spinocerebellar ataxia; trinucleotide repeat