Elevated FMR1-mRNA and lowered FMRP - A double-hit mechanism for psychiatric features in men with FMR1 premutations
Andrea Schneider1,2, Tri Indah Winarni3, Ana María Cabal-Herrera4,5
1Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Health, Sacramento, CA, USA. anschneider@ucdavis.edu.
Abstract:
Fragile X syndrome (FXS) is caused by a full mutation of the FMR1 gene (>200 CGG repeats and subsequent methylation), such that there is little or no FMR1 protein (FMRP) produced, leading to intellectual disability (ID). Individuals with the premutation allele (55-200 CGG repeats, generally unmethylated) have elevated FMR1 mRNA levels, a consequence of enhanced transcription, resulting in neuronal toxicity and a spectrum of premutation-associated disorders, including the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Here we described 14 patients who had both lowered FMRP and elevated FMR1 mRNA levels, representing dual mechanisms of clinical involvement, which may combine features of both FXS and FXTAS. In addition, the majority of these cases show psychiatric symptoms, including bipolar disorder, and/or psychotic features, which are rarely seen in those with just FXS.
Insights
Fragile X syndrome (FXS) involves low FMR1 protein (FMRP). Premutation carriers have high FMR1 mRNA. This study found patients with both low FMRP and high FMR1 mRNA, showing dual mechanisms and unique symptoms.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Fragile X syndrome (FXS) results from a full FMR1 gene mutation, causing low FMRP and intellectual disability.
- FMR1 premutation alleles lead to elevated FMR1 mRNA, neuronal toxicity, and fragile X-associated tremor/ataxia syndrome (FXTAS).
Purpose of the Study:
- To describe 14 patients exhibiting both low FMRP and elevated FMR1 mRNA levels.
- To investigate the clinical implications of dual molecular mechanisms in Fragile X spectrum disorders.
Main Methods:
- Clinical case description of 14 patients.
- Molecular analysis of FMR1 gene status (CGG repeats, methylation).
- Assessment of FMRP levels and FMR1 mRNA expression.
Main Results:
- All 14 patients presented with both low FMRP and elevated FMR1 mRNA.
- These patients displayed a combination of FXS and FXTAS features.
- A majority of cases exhibited psychiatric symptoms, including bipolar disorder and/or psychotic features.
Conclusions:
- Dual molecular mechanisms (low FMRP and high FMR1 mRNA) can occur in the Fragile X spectrum.
- This dual mechanism may lead to combined FXS and FXTAS phenotypes.
- Associated psychiatric symptoms are more prevalent in individuals with this dual molecular profile.
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