Investigation of C9orf72 in 4 Neurodegenerative Disorders
Por:
Xi, ZR, Zinman, L, Grinberg, Y, Moreno, D, Sato, C, Bilbao, JM, Ghani, M, Hernandez, I, Ruiz, A, Boada, M, Moron, FJ, Lang, AE, Marras, C, Bruni, A, Colao, R, Maletta, RG, Puccio, G, Rainero, I, Pinessi, L, Galimberti, D, Morrison, KE, Moorby, C, Stockton, JD, Masellis, M, Black, SE, Hazrati, LN, Liang, Y, de With, JV, Fornazzari, L, Villagra, R, Rojas-Garcia, R, Clarimon, J, Mayeux, R, Robertson, J, St George-Hyslop, P, Rogaeva, E
Publicada:
1 dic 2012
Resumen:
Objective: To estimate the allele frequency of C9orf72 (G(4)C(2)) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD).
Design: The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes.
Setting: Hospitals specializing in neurodegenerative disorders.
Subjects: We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation.
Main Outcome Measure: The expansion frequency.
Results: Based on a prior cutoff (>30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD) was not associated with MAPT, APOE, or variability in the repeat flanking regions. Two patients with PD were carriers of 39 and 32 repeats with questionable pathological significance, since the 39-repeat allele does not segregate with PD. No expansion or intermediate alleles (20-29 repeats) were found among the G2019S carriers and AD cases with TAR DNA-binding protein 43-positive inclusions. Surprisingly, the frequency of the 10-repeat allele was marginally increased in all 4 neurodegenerative diseases compared with controls, indicating the presence of an unknown risk variation in the C9orf72 locus.
Conclusions: The C9orf72 expansion is a common cause of ALS and FTLD, but not of AD or PD. Our study raises concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic screening. Arch Neurol. 2012; 69(12): 1583-1590. Published online September 10, 2012. doi:10.1001/archneurol.2012.2016
Filiaciones:
Xi, ZR:
Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
Grinberg, Y:
Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
Moreno, D:
Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
Sato, C:
Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
Ghani, M:
Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
Hernandez, I:
Fundacio ACE, Memory Clin, Inst Catala Neurociencies Aplicades, Barcelona, Spain
Ruiz, A:
Fundacio ACE, Memory Clin, Inst Catala Neurociencies Aplicades, Barcelona, Spain
Boada, M:
Fundacio ACE, Memory Clin, Inst Catala Neurociencies Aplicades, Barcelona, Spain
Univ Autonoma Barcelona VHIR UAB, Hosp Univ Vall dHebron Inst Recerca, Barcelona, Spain
Moron, FJ:
Neocodex, Dept Struct Genom, Seville, Spain
Lang, AE:
Univ Toronto, Sunnybrook Hlth Sci Ctr, Div Neurol, Dept Med, Toronto, ON, Canada
Toronto Western Hosp, Morton & Gloria Shulman Movement Disorders Clin, Toronto, ON M5T 2S8, Canada
Toronto Western Hosp, Edmond J Safra Program Parkinsons Dis, Toronto, ON M5T 2S8, Canada
Marras, C:
Univ Toronto, Sunnybrook Hlth Sci Ctr, Div Neurol, Dept Med, Toronto, ON, Canada
Toronto Western Hosp, Morton & Gloria Shulman Movement Disorders Clin, Toronto, ON M5T 2S8, Canada
Toronto Western Hosp, Edmond J Safra Program Parkinsons Dis, Toronto, ON M5T 2S8, Canada
Bruni, A:
Azienda Sanit Prov Catanzaro, Reg Neurogenet Ctr, Lamezia Terme, Turin, Italy
Colao, R:
Azienda Sanit Prov Catanzaro, Reg Neurogenet Ctr, Lamezia Terme, Turin, Italy
Maletta, RG:
Azienda Sanit Prov Catanzaro, Reg Neurogenet Ctr, Lamezia Terme, Turin, Italy
Puccio, G:
Azienda Sanit Prov Catanzaro, Reg Neurogenet Ctr, Lamezia Terme, Turin, Italy
Rainero, I:
Univ Turin, Dept Neurosci, Turin, Italy
Pinessi, L:
Univ Turin, Dept Neurosci, Turin, Italy
Galimberti, D:
Univ Milan, Dept Neurol Sci, Ctr Dino Ferrari, Fdn CaGranda,IRCCS Osped Maggiore Policlin, Milan, Italy
Morrison, KE:
Univ Birmingham, Coll Med & Dent Sci, Sch Clin & Expt Med, Birmingham, W Midlands, England
Moorby, C:
Univ Birmingham, Coll Med & Dent Sci, Sch Clin & Expt Med, Birmingham, W Midlands, England
Stockton, JD:
Univ Birmingham, Coll Med & Dent Sci, Sch Clin & Expt Med, Birmingham, W Midlands, England
Masellis, M:
Univ Toronto, Sunnybrook Hlth Sci Ctr, Div Neurol, Dept Med, Toronto, ON, Canada
Sunnybrook Res Inst, LC Campbell Cognit Neurol Res Unit, Toronto, ON, Canada
Black, SE:
Univ Toronto, Sunnybrook Hlth Sci Ctr, Div Neurol, Dept Med, Toronto, ON, Canada
Sunnybrook Res Inst, LC Campbell Cognit Neurol Res Unit, Toronto, ON, Canada
Hazrati, LN:
Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
Liang, Y:
Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
de With, JV:
Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
Fornazzari, L:
Univ Toronto, St Michaels Hosp, Dept Psychiat, Sunnybrook Hlth Sci Ctr, Toronto, ON M5B 1W8, Canada
Villagra, R:
Univ Chile, Salvador Hosp, Santiago, Chile
Rojas-Garcia, R:
Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Madrid, Spain
Clarimon, J:
Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Madrid, Spain
Mayeux, R:
Columbia Univ, Gertrude H Sergievsky Ctr, Dept Neurol, Taub Inst Res Alzheimers Dis & Aging Brain,Coll P, New York, NY 10027 USA
Columbia Univ, Gertrude H Sergievsky Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, Dept Psychiat,Coll Phys & Surg, New York, NY 10027 USA
Columbia Univ, Gertrude H Sergievsky Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, Dept Med,Coll Phys & Surg, New York, NY 10027 USA
Robertson, J:
Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
St George-Hyslop, P:
Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
Univ Toronto, Sunnybrook Hlth Sci Ctr, Div Neurol, Dept Med, Toronto, ON, Canada
Univ Cambridge, Inst Med Res, Cambridge, England
Univ Cambridge, Dept Clin Neurosci, Cambridge, England
Rogaeva, E:
Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
Univ Toronto, Sunnybrook Hlth Sci Ctr, Div Neurol, Dept Med, Toronto, ON, Canada
Green Accepted, Green Published, Bronze
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