Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes.
Brain. 2014-06-26; 137(9): 2444-2455
DOI: 10.1093/brain/awu174
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1. 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.
Tezenas du Montcel S(1), Durr A(2), Bauer P(3), Figueroa KP(4), Ichikawa Y(5),
Brussino A(6), Forlani S(7), Rakowicz M(8), Schöls L(9), Mariotti C(10), van de
Warrenburg BP(11), Orsi L(12), Giunti P(13), Filla A(14), Szymanski S(15),
Klockgether T(16), Berciano J(17), Pandolfo M(18), Boesch S(19), Melegh B(20),
Timmann D(21), Mandich P(22), Camuzat A(7); Clinical Research Consortium for
Spinocerebellar Ataxia (CRC-SCA); EUROSCA network, Goto J(5), Ashizawa T(23),
Cazeneuve C(24), Tsuji S(5), Pulst SM(4), Brusco A(6), Riess O(3), Brice A(25),
Stevanin G(26).
Collaborators: Ashizawa T, Figueroa K, Perlman S, Gomez C, Wilmot G, Schmahmann
J, Ying SH, Zesiewicz T, Paulson H, Shakkottai V, Bushara K, Kuo SH, Geschwind M,
Xia G, Mazzoni P, Pulst S, Subramony S, du Montcel ST, Durr A, Bauer P, Forlani
S, Rakowicz M, Sulek A, Schöls L, Mariotti C, van de Warrenburg BP, Giunti P,
Filla A, Szymanski S, Klockgether T, Berciano J, Pandolfo M, Boesch S, Bela M,
Baliko L, Hadzsiev K, Timmann D, Riess O, Brice A, Stevanin G.
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
.
(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.
(15)18 Department of Neurology, St. Josef Hospital, University Hospital of
Bochum, Bochum, Germany.
(16)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.
(18)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
.
(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.
Comment in
Brain. 2015 Dec;138(Pt 12):e398.
Brain. 2015 Dec;138(Pt 12):e399.
Brain. 2016 Aug;139(Pt 8):e41.
Brain. 2017 Jul 1;140(7):e42.
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
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DOI: 10.1093/brain/awu174
PMCID: PMC4132646
PMID: 24972706 [Indexed for MEDLINE]