Abstract
Fragile X syndrome, the leading heritable form of intellectual disability, is caused by hypermethylation and transcriptional silencing of large (CGG) repeat expansions (> 200 repeats) in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene. As a consequence of FMR1 gene silencing, there is little or no production of FMR1 protein (FMRP), an important element in normal synaptic function. Although the absence of FMRP has long been known to be responsible for the cognitive impairment in fragile X syndrome, the relationship between FMRP level and cognitive ability (IQ) is only imprecisely understood. To address this issue, a high-throughput, fluorescence resonance energy transfer (FRET) assay has been used to quantify FMRP levels in dermal fibroblasts, and the relationship between FMRP and IQ measures was assessed by statistical analysis in a cohort of 184 individuals with CGG-repeat lengths spanning normal (< 45 CGGs) to full mutation (> 200 CGGs) repeat ranges in fibroblasts. The principal findings of the current study are twofold: i) For those with normal CGG repeats, IQ is no longer sensitive to further increases in FMRP above an FMRP threshold of ~70% of the mean FMRP level; below this threshold, IQ decreases steeply with further decreases in FMRP; and ii) For the current cohort, a mean IQ of 85 (lower bound for the normal IQ range) is attained for FMRP levels that are only ~35% of the mean FMRP level among normal CGG-repeat controls. The current results should help guide expectations for efforts to induce FMR1 gene activity and for the levels of cognitive function expected for a given range of FMRP levels.
Highlights
Fragile X syndrome (FXS) is the leading heritable form of intellectual disability and the leading monogenic form of autism spectrum disorder (ASD)
The distributions of FMR1 protein (FMRP) levels across allele classes are displayed in Fig 1, where all FMRP values for normal or gray-zone (~46–54 CGG repeats) alleles for the current, relatively small dataset, are well above the threshold value for the normal full-scale IQ (FSIQ) range; the sole exception is a normal CGG-repeat allele that harbors a point mutation in the FMRP coding sequence [80]
FM alleles are all associated with FMRP levels below the threshold level corresponding to FSIQ = 85 in the fitting model represented in Fig 2, in keeping with the general observation that all males with FM alleles have some degree of cognitive impairment
Summary
Fragile X syndrome (FXS) is the leading heritable form of intellectual disability and the leading monogenic form of autism spectrum disorder (ASD). FXS is caused by expansion of a 50 noncoding trinucleotide (CGG) beyond ~200 repeats (full mutation; FM) in the fragile X mental retardation 1 (FMR1) gene. These large CGG-repeat expansions generally lead to hypermethylation of the promoter and CGG-repeat regions, with attendant transcriptional silencing and little or no expression of the FMR1 protein (FMRP) [5,6,7,8]. Reduction or absence of FMRP, with resultant effects on brain morphology and function [29,30,31], is thought to be directly responsible for the cognitive and behavioral problems that are core features of the FXS phenotype [1]
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