Investigation of C9orf72 in 4 neurodegenerative disorders
Author
- Xi, Zhengrui;
- Zinman, Lorne;
- Grinberg, Yakov;
- Moreno, Danielle;
- Sato, Christine;
- Bilbao, Juan M.;
- Ghani, Mahdi;
- Hernańdez, Isabel;
- Ruiz, Agustín;
- Boada, Mercè;
- Morón, Francisco J.;
- Lang, Anthony E.;
- Marras, Connie;
- Bruni, Amalia;
- Colao, Rosanna;
- Maletta, Raffaele G.;
- Puccio, Gianfranco;
- Rainero, Innocenzo;
- Pinessi, Lorenzo;
- Galimberti, Daniela;
- Morrison, Karen E.;
- Moorby, Catriona;
- Stockton, Joanne D.;
- Masellis, Mario;
- Black, Sandra E.;
- Hazrati, Lili-Naz;
- Liang, Yan;
- Haersma de With, Jan van;
- Fornazzari, Luis;
- Villagra, Roque;
- Rojas-Garcia, Ricardo;
- Clarimón, Jordi;
- Mayeux, Richard;
- Robertson, Janice;
- St George-Hyslop, Peter;
- Rogaeva, Ekaterina;
Abstract
Objective: To estimate the allele frequency of C9orf72 (G4C 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.
Indexation
Artículo de publicación SCOPUS
Identifier
URI: https://repositorio.uchile.cl/handle/2250/160035
DOI: 10.1001/archneurol.2012.2016
ISSN: 00039942
15383687
Quote Item
Archives of Neurology, Volumen 69, Issue 12, 2012, Pages 1583-1590
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