Hypomethylation of an expanded FMR1 allele is not associated with a global DNA methylation defect

Robert W. Burman, Phillip Yates, Lindsay D. Green, Peter B. Jacky, Mitchell Turker, Bradley W. Popovich

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1375-1386
Number of pages12
JournalAmerican Journal of Human Genetics
Volume65
Issue number5
DOIs
StatePublished - 1999

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DNA Methylation
Methylation
Alleles
Mutation
CpG Islands
Embryonal Carcinoma Stem Cells
Fragile X Syndrome
Gene Silencing
Intellectual Disability
Chromosomes
Phenotype
Cell Line

ASJC Scopus subject areas

  • Genetics

Cite this

Hypomethylation of an expanded FMR1 allele is not associated with a global DNA methylation defect. / Burman, Robert W.; Yates, Phillip; Green, Lindsay D.; Jacky, Peter B.; Turker, Mitchell; Popovich, Bradley W.

In: American Journal of Human Genetics, Vol. 65, No. 5, 1999, p. 1375-1386.

Research output: Contribution to journalArticle

Burman, Robert W. ; Yates, Phillip ; Green, Lindsay D. ; Jacky, Peter B. ; Turker, Mitchell ; Popovich, Bradley W. / Hypomethylation of an expanded FMR1 allele is not associated with a global DNA methylation defect. In: American Journal of Human Genetics. 1999 ; Vol. 65, No. 5. pp. 1375-1386.
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