Abstract
Fragile X tremor ataxia syndrome (FXTAS) is a late-onset disorder manifesting in a proportion of FMR1 premutation individuals (PM: 55-199 CGG triplet expansions). FXTAS is associated with elevated levels of FMR1 mRNA which are toxic. In this study, relationships between neurocognitive and intra-step gait variability measures with mRNA levels, measured in blood samples, were examined in 35 PM and 35 matched control females. The real-time PCR assays measured FMR1 mRNA, and previously used internal control genes: β-Glucuronidase (GUS), Succinate Dehydrogenase 1 (SDHA) and Eukaryotic Translation Initiation Factor 4A (EI4A2). Although there was significant correlation of gait variability with FMR1 mRNA levels (p = 0.004) when normalized to GUS (FMR1/GUS), this was lost when FMR1 was normalized to SDHA and EI4A2 (2IC). In contrast, GUS mRNA level normalized to 2IC showed a strong correlation with gait variability measures (p < 0.007), working memory (p = 0.001) and verbal intelligence scores (p = 0.008). PM specific changes in GUS mRNA were not mediated by FMR1 mRNA. These results raise interest in the role of GUS in PM related disorders and emphasise the importance of using appropriate internal control genes, which have no significant association with PM phenotype, to normalize FMR1 mRNA levels.
Highlights
Fragile X tremor ataxia syndrome (FXTAS) is a late-onset disorder manifesting in a proportion of FMR1 premutation individuals (PM: 55-199 CGG triplet expansions)
Since increase in CGG triplet expansion has been associated with an increase in FMR1 mRNA toxicity, mitochondrial dysfunction and elevated apoptosis[8], it is not unreasonable to postulate that CGG triplet repeat size has an impact on the expression profile of many genes
We postulated that normalising FMR1 mRNA to GUS mRNA levels in blood should impact the correlation that is understood to exist between FMR1 mRNA levels and PM specific phenotypes, as opposed to the correlation with FMR1 mRNA expression when normalised to that of other internal control genes
Summary
Fragile X tremor ataxia syndrome (FXTAS) is a late-onset disorder manifesting in a proportion of FMR1 premutation individuals (PM: 55-199 CGG triplet expansions). Since increase in CGG triplet expansion has been associated with an increase in FMR1 mRNA toxicity, mitochondrial dysfunction and elevated apoptosis[8], it is not unreasonable to postulate that CGG triplet repeat size has an impact on the expression profile of many genes This is consistent with genome wide gene expression analysis showing that multiple pathways are affected by a PM expansion, including glycoprotein biosynthesis, which is mediated through the β-glucuronidase (GUS) pathway[15]. This study, examined relationships of FMR1 and GUS mRNA levels in blood samples (with reverse transcription real-time quantitative RT-PCR [RT-qPCR] normalized to different internal controls) and gait stepping and working memory measures previously described to reflect PM-specific neurocognitive phenotypes[16]
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