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© 1992 Oxford University Press

OTHER

Methylation analysis of CGG sites in the CpG island of the human FMR1 gene

R.Scott Hansen1,*, Stanley M. Gartler1,2, C.Ronald Scott3, Shi-Han Chen3 and Charles M. xLaird2,4

1Departments of Medicine, University of Washington Seattle, WA 98195, USA 2Departments of Genetics, University of Washington Seattle, WA 98195, USA 3Departments of Pediatrics, University of Washington Seattle, WA 98195, USA 4Departments of Zoology, University of Washington Seattle, WA 98195, USA

*To whom correspondence should be addressed at: Department of Genetics, SK-50, University of Washington, Seattle, WA 9815, USA

Received August 18, 1992; Revised September 23, 1992; Accepted September 23, 1992

The fragile-X syndrome of mental retardation is associated with an expansion in the number of CGG repeats present in the FMR1 gene. The repeat region is within sequences characteristic of a CpG island. Methylation of CpG dinucleotides that are 5' to the CGG repeat has been shown to occur on the inactive X chromosome of normal females and on the X chromosome of affected fragile-X males, and is correlated with silencing of the FMR1 gene. The methylation status of CpG sites 3' to the repeat and within the repeat itself has not previously been reported. We have used two methylation-sensitive restriction enzymes, Acil and Fnu4HI, to further characterize the methylation pattern of the FMR1 CpG island in normal individuals and in those carrying fragile-X mutations. Our results indicate that: (i) CpG dinucleotides on the 3' side of the CGG repeat are part of the CpG island that is methylated during inactivation of a normal X chromosome in females; (ii) the CGG repeats are also part of the CpG island and are extensively methylated as a result of normal X-chromosome inactivation; (iii) similar to normal males, unaffected fragile-X males with small CGG expansions are unmethylated in the CpG island; for affected males, the patterns of methylation are similar to those of a normal, inactive X chromosome; (iv) in contrast to the partial methylation observed for certain sites in lymphocyte DNA, complete methylation was observed in DNA from cell lines containing either a normal inactive X chromosome or a fragile-X chromosome from an affected male. Our data are consistent with the hypothesis that hypermethylation and silencing of the FMR1 gene in affected fragile-X individuals result from the normal process of X-chromosome inactivation and the abnormal failure to reverse it prior to female meiosis.


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