Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion.
Am J Hum Genet
; 92(6): 981-9, 2013 Jun 06.
Article
em En
| MEDLINE
| ID: mdl-23731538
ABSTRACT
The G4C2 repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We tested the hypothesis that the repeat expansion causes aberrant CpG methylation near the G4C2 repeat, which could be responsible for the downregulation of gene expression. We investigated the CpG methylation profile by two methods using genomic DNA from the blood of individuals with ALS (37 expansion carriers and 64 noncarriers), normal controls (n = 76), and family members of 7 ALS probands with the expansion. We report that hypermethylation of the CpG island 5' of the G4C2 repeat is associated with the presence of the expansion (p < 0.0001). A higher degree of methylation was significantly correlated with a shorter disease duration (p < 0.01), associated with familial ALS (p = 0.009) and segregated with the expansion in 7 investigated families. Notably, we did not detect methylation for either normal or intermediate alleles (up to 43 repeats), bringing to question the current cutoff of 30 repeats for pathological alleles. Our study raises several important questions for the future investigation of large data sets, such as whether the degree of methylation corresponds to clinical presentation (ALS versus FTLD).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ilhas de CpG
/
Metilação de DNA
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Proteínas Supressoras de Tumor
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Esclerose Lateral Amiotrófica
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Proteínas de Membrana
Tipo de estudo:
Observational_studies
/
Risk_factors_studies
Limite:
Aged
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Humans
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Middle aged
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article