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. 2013 Jan 29:14:18.
doi: 10.1186/1471-2350-14-18.

Genome-wide analysis validates aberrant methylation in fragile X syndrome is specific to the FMR1 locus

Reid S Alisch  1 , Tao Wang, Pankaj Chopra, Jeannie Visootsak, Karen N Conneely, Stephen T Warren
Affiliations

Genome-wide analysis validates aberrant methylation in fragile X syndrome is specific to the FMR1 locus

Reid S Alisch et al. BMC Med Genet. .

Abstract

Background: Fragile X syndrome (FXS) is a common form of inherited intellectual disability caused by an expansion of CGG repeats located in the 5' untranslated region (UTR) of the FMR1 gene, which leads to hypermethylation and silencing of this locus. Although a dramatic increase in DNA methylation of the FMR1 full mutation allele is well documented, the extent to which these changes affect DNA methylation throughout the rest of the genome has gone unexplored.

Methods: Here we examined genome-wide methylation in both peripheral blood (N = 62) and induced pluripotent stem cells (iPSCs; N = 10) from FXS individuals and controls.

Results: We not only found the expected significant DNA methylation differences in the FMR1 promoter and 5' UTR, we also saw that these changes inverse in the FMR1 gene body. Importantly, we found no other differentially methylated loci throughout the remainder of the genome, indicating the aberrant methylation of FMR1 in FXS is locus-specific.

Conclusions: This study provides a comprehensive methylation profile of FXS and helps refine our understanding of the mechanisms behind FMR1 silencing.

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Figures

Figure 1
Figure 1
FXS-associated differentially methylated loci.(A) Modified Manhattan plot of FXS-associated methylation levels in the peripheral blood: loci are displayed with the –log10(P-value) generated by the linear mixed-effect model (y-axis). Horizontal lines reflect cutoffs for FDR <0.05 (blue line) and Bonferroni-adjusted P-value <0.05 (red line). FMR1 annotated loci are shown in red; otherwise, loci are colored black or gray on alternating chromosomes (x-axis). (B) Relative locations of FMR1 methylation. Top panel shows the methylation levels (y-axis) in FXS (orange squares) and control (blue crosses) individuals at several loci annotated in or near the FMR1 locus. Shown below are the relative CpG coverage (vertical black lines) and CpG island location (green rectangle). Bottom panel depicts a gene schematic of FMR1, indicating the relative location of the CGG repeat (expanded in FXS), the FMR1 transcription start site (TSS), and exons 1 and 2. The ideogram of the X chromosome (bottom) shows the relative location of FMR1 (red vertical bar), and the genomic position shown above is relative to HG-19 coordinates. (C and D)FMR1 promoter DNA methylation levels in peripheral blood and iPS cells. Top panel shows box and whisker plots of the methylation levels (y-axis) in FXS (orange) and control (blue) individuals at several loci annotated in the FMR1 promoter. Bottom panel is described in B.
See this image and copyright information in PMC

References

    1. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP. et al.Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991;65(5):905–914. doi: 10.1016/0092-8674(91)90397-H. - DOI - PubMed
    1. Wang T, Bray SM, Warren ST. New perspectives on the biology of fragile X syndrome. Curr Opin Genet Dev. 2012;22(3):256–263. doi: 10.1016/j.gde.2012.02.002. - DOI - PMC - PubMed
    1. Ashley CT, Sutcliffe JS, Kunst CB, Leiner HA, Eichler EE, Nelson DL, Warren ST. Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG-repeat. Nat Genet. 1993;4(3):244–251. doi: 10.1038/ng0793-244. - DOI - PubMed
    1. Coffee B, Ikeda M, Budimirovic DB, Hjelm LN, Kaufmann WE, Warren ST. Mosaic FMR1 deletion causes fragile X syndrome and can lead to molecular misdiagnosis: a case report and review of the literature. Am J Med Genet A. 2008;146A(10):1358–1367. doi: 10.1002/ajmg.a.32261. - DOI - PMC - PubMed
    1. De Boulle K, Verkerk AJ, Reyniers E, Vits L, Hendrickx J, Van Roy B, Van den Bos F, de Graaff E, Oostra BA, Willems PJ. A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nat Genet. 1993;3(1):31–35. doi: 10.1038/ng0193-31. - DOI - PubMed

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