Hypomethylation of an Expanded FMR1 Allele Is Not Associated with a Global DNA Methylation Defect

Hypomethylation of an Expanded FMR1 Allele Is Not Associated with a Global DNA Methylation Defect

The vast majority of fragile-X full mutations are heavily methylated throughout the expanded CGG repeat and the surrounding CpG island. Hypermethylation initiates and/or stabilizes transcriptional inactivation of the FMR1 gene, which causes the fragile X–syndrome phenotype characterized, primarily,...

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Bibliographic Details
Published in:American journal of human genetics Vol. 65; no. 5; pp. 1375 - 1386
Main Authors: Burman, Robert W., Yates, Phillip A., Green, Lindsay D., Jacky, Peter B., Turker, Mitchell S., Popovich, Bradley W.
Format: Journal Article
Language:English
Published: Chicago, IL Elsevier Inc 01-11-1999
University of Chicago Press
The American Society of Human Genetics
Subjects:
Adult
Alleles
Alu Elements
Animals
Biological and medical sciences
Cells, Cultured
CGG
Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...)
CpG Islands - genetics
Deoxyribonucleases, Type II Site-Specific - metabolism
DNA Methylation
DNA Restriction Enzymes - metabolism
FMR1
Fragile X
Fragile X Mental Retardation Protein
Fragile X Syndrome - genetics
Humans
Hypomethylation
Male
Medical genetics
Medical sciences
Methylation
Mice
Nerve Tissue Proteins - genetics
Repetitive elements
Restriction Mapping
RNA-Binding Proteins
Trinucleotide Repeats - genetics
X Chromosome - genetics
CGG
Hypomethylation
Methylation
FMR1
Fragile X
Repetitive elements
Human
Chromosome fragility
Repeated sequence
Rodentia
Genetic determinism
Genetic transfer
Case study
Vertebrata
Mammalia
Cell line
Mouse
Animal
Genetics
Fragile X syndrome
Tumor cell
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Description
Summary:The vast majority of fragile-X full mutations are heavily methylated throughout the expanded CGG repeat and the surrounding CpG island. Hypermethylation initiates and/or stabilizes transcriptional inactivation of the FMR1 gene, which causes the fragile X–syndrome phenotype characterized, primarily, by mental retardation. The relation between repeat expansion and hypermethylation is not well understood nor is it absolute, as demonstrated by the identification of nonretarded males who carry hypomethylated full mutations. To better characterize the methylation pattern in a patient who carries a hypomethylated full mutation of ∼60–700 repeats, we have evaluated methylation with the McrBC endonuclease, which allows analysis of numerous sites in the FMR1 CpG island, including those located within the CGG repeat. We report that the expanded-repeat region is completely free of methylation in this full-mutation male. Significantly, this lack of methylation appears to be specific to the expanded FMR1 CGG-repeat region, because various linked and unlinked repetitive-element loci are methylated normally. This finding demonstrates that the lack of methylation in the expanded CGG-repeat region is not associated with a global defect in methylation of highly repeated DNA sequences. We also report that de novo methylation of the expanded CGG-repeat region does not occur when it is moved via microcell-mediated chromosome transfer into a de novo methylation-competent mouse embryonal carcinoma cell line.
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ISSN:0002-9297
1537-6605
DOI:10.1086/302628