Abstract
DNA methylation of the Fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary has been associated with executive dysfunction in female carriers of a FMR1 premutation (PM: 55–199 CGG repeats), whereas neuroanatomical changes have been associated with executive dysfunction in PM males. To our knowledge, this study for the first time examined the inter-relationships between executive function, neuroanatomical structure and molecular measures (DNA methylation and FMR1 mRNA levels in blood) in PM and control (<44 CGG repeats) females. In the PM group, FMR1 intron 1 methylation was positively associated with executive function and cortical thickness in middle and superior frontal gyri, and left inferior parietal gyrus. By contrast, in the control group, FMR1 intron 1 methylation was negatively associated with cortical thickness of the left middle frontal gyrus and superior frontal gyri. No significant associations were revealed for either group between FMR1 mRNA and neuroanatomical structure or executive function. In the PM group, the lack of any significant association between FMR1 mRNA levels and phenotypic measures found in this study suggests that either FMR1 expression is not well conserved between tissues, or that FMR1 intron 1 methylation is linked to neuroanatomical and cognitive phenotype in PM females via a different mechanism.
Highlights
Trinucleotide CGG repeat expansions of the Fragile X mental retardation 1 (FMR1) gene are related to a number of Fragile X-associated disorders
Does this study show that methylation of FMR1 intron 1 CpG sites is a useful biomarker of cortical thickness in PM females without Fragile X-associated tremor/ataxia syndrome (FXTAS), but it opens up the broader possibility that this may be the case for other disorders involving cortical thickness disruption, such as Alzheimer’s (PSEN1 mutations),[53] Parkinson’s,54,55 major depressive disorder[56] and social anxiety disorder.[57]
Overall, understanding how epigenetic changes influence neuroanatomy, executive function and clinical outcomes is highly important for both FMR1 PM- and Full mutation alleles (FM)-related disorders, and broader neurological disorders influenced by abnormal XCI
Summary
Trinucleotide CGG repeat expansions of the Fragile X mental retardation 1 (FMR1) gene are related to a number of Fragile X-associated disorders. Full mutation alleles (FM: greater than 200 CGG repeats) are associated with silencing of FMR1 through methylation of the promoter region located in the 5′ untranslated region,[1] resulting in a neurodevelopmental disorder known as Fragile X syndrome. The prevalence of Fragile X syndrome in the general population is ~ 1 in 4000.2 The more common FMR1 premutation (PM) expansion (55–199 CGG repeats), which is found in ~ 1 in 209 females and 1 in 430 males,[3] confers the risk of developing Fragile X-associated tremor/ataxia syndrome (FXTAS). Pertaining to working memory and response inhibition processes, has been reported in both PM males[8,9,10] and females without FXTAS,[11,12,13,14,15] and may represent either an independent PM phenotype or a precursor to FXTAS
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