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dc.contributor.author
Xi, Zhengrui
dc.contributor.author
Zhang, Ming
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Bruni, Amalia C.
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Maletta, Raffaele G.
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Colao, Rosanna
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Fratta, Pietro
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Polke, James M.
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Sweeny, Mary G.
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Mudanohwo, Ese
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Nacmias, Benedetta
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Sorbi, Sandro
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Tartaglia, Maria Carmela
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Rainero, Innocenzo
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Rubino, Elisa
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Pinessi, Lorenzo
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Galimberti, Daniela
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Surace, Ezequiel Ignacio
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McGoldrick, Philip
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McKeever, Paul
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Moreno, Danielle
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Sato, Christine
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Liang, Yan
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Keith, Julia
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Zinman, Lorne
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Robertson, Janice
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Rogaeva, Ekaterina
dc.date.available
2020-08-21T15:11:00Z
dc.date.issued
2015-05
dc.identifier.citation
Xi, Zhengrui; Zhang, Ming; Bruni, Amalia C.; Maletta, Raffaele G.; Colao, Rosanna; et al.; The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients.; Springer; Acta Neuropathologica; 5-2015; 1-13
dc.identifier.issn
0001-6322
dc.identifier.uri
http://hdl.handle.net/11336/112126
dc.description.abstract
The most common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a G4C2-repeat expansion in C9orf72. However, the lower limit for pathological repeats has not been established and expansions with different sizes could have different pathological consequences. One of the implicated disease mechanisms is haploinsufficiency. Previously, we identified expansion-specific hypermethylation at the 5´ CpG-island near the G4C2-repeat, but only in a fraction of carriers (up to 36 %). Here, we tested the hypothesis that the G4C2-repeat itself could be the main site of methylation. To evaluate (G4C2) n -methylation, we developed a novel assay, which was validated by an independent methylation-sensitive restriction enzyme assay. Notably, both assays are qualitative but not quantitative. Blood DNA was available for 270 unrelated individuals, including 71 expansion carriers. In addition, we investigated blood DNA from family members of 16 probands, and 38 DNA samples from multiple tissues of 10 expansion carriers. Finally, we tested DNA from different tissues of an ALS patient carrying a somatically unstable 90-repeat. We demonstrated that the G4C2-expansion is generally methylated in unrelated carriers of alleles >50 repeats (97 %), while small (<22 repeats) or intermediate (22-90 repeats) alleles were completely unmethylated. The presence of (G4C2) n -methylation does not separate the C9orf72-phenotypes (ALS vs. ALS/FTLD vs. FTLD), but has the potential to predict large vs. intermediate repeat length. Our results suggest that (G4C2) n -methylation might sometimes spread to the 5´-upstream region, but not vice versa. It is stable over time, since (G4C2) n -methylation was detected in carriers with a wide range of ages (24-74 years). It was identified in both blood and brain tissues for the same individual, implying its potential use as a biomarker. Furthermore, our findings may open up new perspectives for studying disease mechanisms, such as determining whether methylated and unmethylated repeats have the same ability to form a G-quadruplex configuration.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Springer
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
ALS
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FTD
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C9ORF72
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METHYLATION
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Genética Humana
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Medicina Básica
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dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients.
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2020-02-26T15:04:31Z
dc.journal.pagination
1-13
dc.journal.pais
Alemania
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dc.journal.ciudad
Berlin
dc.description.fil
Fil: Xi, Zhengrui. University of Toronto; Canadá
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Fil: Zhang, Ming. University of Toronto; Canadá
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Fil: Bruni, Amalia C.. No especifíca;
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Fil: Maletta, Raffaele G.. No especifíca;
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Fil: Colao, Rosanna. No especifíca;
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Fil: Fratta, Pietro. UCL Queen Square Institute of Neurology; Reino Unido
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Fil: Polke, James M.. National Hospital for Neurology and Neurosurgery; Reino Unido
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Fil: Sweeny, Mary G.. National Hospital for Neurology and Neurosurgery; Reino Unido
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Fil: Mudanohwo, Ese. National Hospital for Neurology and Neurosurgery; Reino Unido
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Fil: Nacmias, Benedetta. Universidad de Florencia
; Italia
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Fil: Sorbi, Sandro. Universidad de Florencia; Italia
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Fil: Tartaglia, Maria Carmela. University of Toronto; Canadá
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Fil: Rainero, Innocenzo. Università di Torino; Italia
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Fil: Rubino, Elisa. Università di Torino; Italia
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Fil: Pinessi, Lorenzo. Università di Torino; Italia
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Fil: Galimberti, Daniela. University of Milan; Italia
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Fil: Surace, Ezequiel Ignacio. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
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Fil: McGoldrick, Philip. University of Toronto; Canadá
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Fil: McKeever, Paul. University of Toronto; Canadá
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Fil: Moreno, Danielle. University of Toronto; Canadá
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Fil: Sato, Christine. University of Toronto; Canadá
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Fil: Liang, Yan. University of Toronto; Canadá
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Fil: Keith, Julia. No especifíca;
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Fil: Zinman, Lorne. No especifíca;
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Fil: Robertson, Janice. University of Toronto; Canadá
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Fil: Rogaeva, Ekaterina. University of Toronto; Canadá
dc.journal.title
Acta Neuropathologica
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1007/s00401-015-1401-8
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://link.springer.com/article/10.1007/s00401-015-1401-8?shared-article-renderer
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