Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients

被引:113
作者
Lee, Teresa [1 ]
Li, Yun R. [1 ]
Ingre, Caroline [2 ]
Weber, Markus [4 ,5 ]
Grehl, Torsten [6 ]
Gredal, Ole [7 ]
de Carvalho, Mamede [8 ]
Meyer, Thomas [9 ]
Tysnes, Ole-Bjorn [10 ]
Auburger, Georg [11 ]
Gispert, Suzana [11 ]
Bonini, Nancy M. [12 ]
Andersen, Peter M. [2 ,3 ]
Gitler, Aaron D. [1 ]
机构
[1] Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA
[2] Umea Univ, Dept Neurol, S-90187 Umea, Sweden
[3] Univ Ulm, Dept Neurol, D-7900 Ulm, Germany
[4] Kantonspital St Gallen, Neuromuscular Dis Unit, St Gallen, Switzerland
[5] Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland
[6] Ruhr Univ Bochum, Univ Hosp Bergmannsheil, Dept Neurol, Bochum, Germany
[7] Rehabil Ctr Neuromuscular Dis, Copenhagen, Denmark
[8] Fac Med, Inst Mol Med, Neuromuscular Unit, Lisbon, Portugal
[9] Charite, Dept Neurol, Berlin, Germany
[10] Haukeland Hosp, Dept Neurol, N-5021 Bergen, Norway
[11] Goethe Univ Frankfurt, Dept Neurol, Frankfurt, Germany
[12] Univ Penn, Howard Hughes Med Inst, Dept Biol, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院;
关键词
AMYOTROPHIC-LATERAL-SCLEROSIS; GENOME-WIDE ASSOCIATION; SPINOCEREBELLAR ATAXIA; TRINUCLEOTIDE REPEAT; MUTATIONS; PROTEIN; GENE; TYPE-2; DEGENERATION; MANAGEMENT;
D O I
10.1093/hmg/ddr045
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease primarily affecting motor neurons. We recently identified intermediate-length polyglutamine (polyQ) expansions (27-33 Qs) in ataxin 2 as a genetic risk factor for sporadic ALS in North American ALS patients. To extend these findings, we assessed the ataxin 2 polyQ repeat length in 1294 European ALS patients and 679 matched healthy controls. We observed a significant association between polyQ expansions and ALS (> 30 Qs; P = 6.2 x 10(-3)). Thus, intermediate-length ataxin 2 polyQ repeat expansions are associated with increased risk for ALS also in the European cohort. The specific polyQ length cutoff, however, appears to vary between different populations, with longer repeat lengths showing a clear association. Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the disease.
引用
收藏
页码:1697 / 1700
页数:4
相关论文
共 33 条
  • [1] DAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1
    Al-Ramahi, Ismael
    Perez, Alma M.
    Lim, Janghoo
    Zhang, Minghang
    Sorensen, Rie
    de Haro, Maria
    Branco, Joana
    Pulst, Stefan M.
    Zoghbi, Huda Y.
    Botas, Juan
    [J]. PLOS GENETICS, 2007, 3 (12): : 2551 - 2564
  • [2] Good practice in the management of amyotrophic lateral sclerosis: Clinical guidelines. An evidence-based review with good practice points. EALSC Working Group
    Andersen, Peter Munch
    Borasio, Gian Domenico
    Dengler, Reinhard
    Hardiman, Orla
    Kollewe, Katja
    Leigh, Peter Nigel
    Pradat, Pierre-Francois
    Silani, Vincenzo
    Tomik, Barbara
    [J]. AMYOTROPHIC LATERAL SCLEROSIS, 2007, 8 (04): : 195 - 213
  • [3] Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation - A clinical and genealogical study of 36 patients
    Andersen, PM
    Forsgren, L
    Binzer, M
    Nilsson, P
    AlaHurula, V
    Keranen, ML
    Bergmark, L
    Saarinen, A
    Haltia, T
    Tarvainen, I
    Kinnunen, E
    Udd, B
    Marklund, SL
    [J]. BRAIN, 1996, 119 : 1153 - 1172
  • [4] Analysis of genome-wide copy number variation in Irish and Dutch ALS populations
    Cronin, Simon
    Blauw, Hylke M.
    Veldink, Jan H.
    van Es, Michael A.
    Ophoff, Roel A.
    Bradley, Daniel G.
    van den Berg, Leonard H.
    Hardiman, Orla
    [J]. HUMAN MOLECULAR GENETICS, 2008, 17 (21) : 3392 - 3398
  • [5] A genome-wide association study of sporadic ALS in a homogenous Irish population
    Cronin, Simon
    Berger, Stephen
    Ding, Jinhui
    Schymick, Jennifer C.
    Washecka, Nicole
    Hernandez, Dena G.
    Greenway, Matthew J.
    Bradley, Daniel G.
    Traynor, Bryan J.
    Hardiman, Orla
    [J]. HUMAN MOLECULAR GENETICS, 2008, 17 (05) : 768 - 774
  • [6] SOD1 gene mutations in ALS patients from British Columbia, Canada: Clinical features, neurophysiology and ethical issues in management
    Eisen, Andrew
    Mezei, Michelle M.
    Stewart, Heather G.
    Fabros, Marife
    Gibson, Gillan
    Andersen, Peter M.
    [J]. AMYOTROPHIC LATERAL SCLEROSIS, 2008, 9 (02): : 108 - 119
  • [7] Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS
    Elden, Andrew C.
    Kim, Hyung-Jun
    Hart, Michael P.
    Chen-Plotkin, Alice S.
    Johnson, Brian S.
    Fang, Xiaodong
    Armakola, Maria
    Geser, Felix
    Greene, Robert
    Lu, Min Min
    Padmanabhan, Arun
    Clay-Falcone, Dana
    McCluskey, Leo
    Elman, Lauren
    Juhr, Denise
    Gruber, Peter J.
    Rueb, Udo
    Auburger, Georg
    Trojanowski, John Q.
    Lee, Virginia M. -Y.
    Van Deerlin, Vivianna M.
    Bonini, Nancy M.
    Gitler, Aaron D.
    [J]. NATURE, 2010, 466 (7310) : 1069 - U77
  • [8] Progressive disruption of cellular protein folding in models of polyglutamine diseases
    Gidalevitz, T
    Ben-Zvi, A
    Ho, KH
    Brignull, HR
    Morimoto, RI
    [J]. SCIENCE, 2006, 311 (5766) : 1471 - 1474
  • [9] Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats
    Imbert, G
    Saudou, F
    Yvert, G
    Devys, D
    Trottier, Y
    Garnier, JM
    Weber, C
    Mandel, JL
    Cancel, G
    Abbas, N
    Durr, A
    Didierjean, O
    Stevanin, G
    Agid, Y
    Brice, A
    [J]. NATURE GENETICS, 1996, 14 (03) : 285 - 291
  • [10] Spinocerebellar ataxia type 2 with levodopa-responsive parkinsonism culminating in motor neuron disease
    Infante, J
    Berciano, J
    Volpini, V
    Corral, J
    Polo, JM
    Pascual, J
    Combarros, O
    [J]. MOVEMENT DISORDERS, 2004, 19 (07) : 848 - 852