Abstract
Fragile X associated disorders are caused by a premutation allele in the fragile X mental retardation 1 gene (FMR1) and are hypothesized to result from the toxic effect of elevated levels of expanded FMR1 transcripts. Increased levels of FMR1 mRNA have indeed been reported in premutation carriers; however the mechanism by which expanded alleles lead to elevated levels of FMR1 mRNA in premutation carriers is unknown. Within the CGG repeat tract AGG interruptions are found, generally 1–3 present in normal/intermediate alleles (6–54 CGG repeats) and usually 0–1 in premutation alleles (55–200 CGG repeats). They are present at specific locations, generally occurring after 9 or 10 uninterrupted CGG repeats [(CGG)9AGG(CGG)9AGG(CGG)n ]. We evaluated both the number of AGG interruptions and the resulting length of the uninterrupted 3′ CGG repeat pure tract in premutation alleles derived from two large cohorts of male and female carriers to determine whether the presence of AGG interruptions or the length of a pure stretch of CGG repeats influence the levels of FMR1 mRNA in blood. Our findings indicate that neither the number of AGG interruptions, nor their position along the CGG tract have a significant affect on mRNA levels in premutation carriers. We also, as expected based on previous findings, observed a highly significant correlation between CGG repeat number (as both total length and length of pure CGG stretch) and FMR1 mRNA expression levels, in both males and females. Importantly, we did not observe any significant difference in FMR1 mRNA levels in premutation carriers based on age.
Highlights
Expansion of the CGG trinucleotide repeat in the 59 untranslated (UTR) region of the fragile X mental retardation 1 gene (FMR1) gene is causative for a number of disorders including fragile X syndrome (FXS), fragile X associated tremor ataxia syndrome (FXTAS) and FMR1 related primary ovarian insufficiency (FXPOI) [1]
Individuals with the premutation were previously thought to be clinically unaffected, it has become clear in the past decade that premutation carriers present with a number of clinical involvement including the fragile X-associated primary ovarian insufficiency (FXPOI) in approximately 20% of the females [22,23,24] and the fragile X-associated tremor ataxia syndrome (FXTAS) [25,26,27,28] which occurs in approximately 1/3 of the male carriers and less frequently in female carriers
The increased levels of FMR1 mRNA has led to the RNA gain- of- function model in which the FMR1 mRNA itself is causative of the clinical problems observed in carriers, including FXTAS
Summary
Expansion of the CGG trinucleotide repeat in the 59 untranslated (UTR) region of the FMR1 gene is causative for a number of disorders including fragile X syndrome (FXS), fragile X associated tremor ataxia syndrome (FXTAS) and FMR1 related primary ovarian insufficiency (FXPOI) [1]. A CGG expansion in the FMR1 gene has been associated with an increased incidence of several other clinical involvements ranging from anxiety to autism spectrum disorder (ASD) [2]. CGG repeats) result in transcriptional silencing of the FMR1 gene, absence of fragile X mental retardation 1 protein (FMRP) and fragile X syndrome. Intermediate (45–54 CGG repeats) and premutation alleles (55–200 CGG repeats) were originally characterized as having an increased risk of expansion in future generations, but having no phenotypic effect on the carrier of these alleles. Biological effects have been identified and studied [4,5,6], but more needs to be learned about the mechanism that leads to the clinical involvement in these transitional ranges
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