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Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion.

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).

Pubmed ID: 23731538 RIS Download

Mesh terms: Aged | Amyotrophic Lateral Sclerosis | Base Sequence | Case-Control Studies | CpG Islands | DNA Methylation | DNA Repeat Expansion | Genetic Association Studies | Heterozygote | Humans | Linear Models | Membrane Proteins | Middle Aged | Molecular Sequence Data | Pedigree | Sequence Analysis, DNA | Tumor Suppressor Proteins

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UCSC Genome Browser

A collection of genomes which include reference sequences and working draft assemblies, as well as a variety of tools to explore these sequences. The Genome Browser zooms and scrolls over chromosomes, showing the work of annotators worldwide. The Gene Sorter shows expression, homology and other information on groups of genes that can be related in many ways. Blat quickly maps your sequence to the genome. The Table Browser provides access to the underlying database. VisiGene lets you browse through a large collection of in situ mouse and frog images to examine expression patterns. Genome Graphs allows you to upload and display genome-wide data sets. Also provided is a portal to the Encyclopedia of DNA Elements (ENCODE) and Neandertal projects.

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OMIM

Collection of human genes and genetic phenotypes, focusing on the relationship between phenotype and genotype. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and a variety of related genes. It is updated daily, and the entries contain copious links to other genetics resources.

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