Abstract
Variability among individuals in the severity of fragile X syndrome (FXS) is influenced by epigenetic methylation mosaicism, which may also be common in other complex disorders. The epigenetic signal of dense promoter DNA methylation is usually associated with gene silencing, as was initially reported for FMR1 alleles in individuals with FXS. A paradox arose when significant levels of FMR1 mRNA were reported for some males with FXS who had been reported to have predominately methylated alleles. We have used hairpin-bisufite PCR, validated with molecular batch-stamps and barcodes, to collect and assess double-stranded DNA methylation patterns from these previously studied males. These patterns enable us to distinguish among three possible forms of methylation mosaicism, any one of which could explain FMR1 expression in these males. Our data indicate that cryptic inter-cell mosaicism in DNA methylation can account for the presence of FMR1 mRNA in some individuals with FXS.
Highlights
Epigenetic mosaicism strongly influences the variable phenotypes characteristic of at least two neurodevelopmental disorders: fragile X syndrome (FXS) and Rett syndrome [1,2,3,4,5,6]
We collected double-stranded methylation patterns from DNA of nine males with full mutation alleles reported to be fully methylated, using a subset of the samples that Tassone and colleagues used in their 2001 study [16]
Due to the detection limits of the Southern hybridization approach, an alternative possibility is that these samples contained alleles with previously unexamined types of methylation mosaicism that could be permissive for FMR1 transcription
Summary
Epigenetic mosaicism strongly influences the variable phenotypes characteristic of at least two neurodevelopmental disorders: fragile X syndrome (FXS) and Rett syndrome [1,2,3,4,5,6]. Dense methylation of promoter regions is a common feature of silenced genes [12] Such silencing was initially reported to hold for abnormally methylated FMR1 alleles in individuals with FXS [13]. A paradox arose when Tassone and colleagues reported significant levels of FMR1 mRNA in the majority of individuals from a cohort of males with FXS found to have methylated, full mutation FMR1 alleles, and to lack subpopulations of premutation alleles [16]. These individuals showed no evidence of correspondence between levels of FMR1 mRNA and the severity of the fragile X phenotype. Even in the presence of an unmethylated, full mutation allele, these individuals do not express appreciable levels of FMR1-encoded protein, FMRP, and do not have phenotypes markedly different from those of males who lack FMR1 mRNA
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