Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

Abstract

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5'-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult "gain-of-function" syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

Keywords: FMR1; FMRP; FXAND; FXPOI; FXTAS; GABA; biomarker; blood; endocrine; miRNA; mitochondria; premutation; telomere; transcription.

Figure A1

Significant increase of protein carbonylation in the plasma of premutation carriers. Triangles ( Δ), female samples; circles (O), male samples. The mean is indicated as a horizontal bar. *, p < 0.05, Mann-Whitney U-test.

Figure A2

Relative expression of FMR1 and IRF2BPL genes in whole blood of controls and premutation donors. Triangles (Δ), female samples; circles (O), male samples. Of the four males of our cohort, only three were available for these assays. The mean is indicated (horizontal bar). *, p < 0.05, Mann-Whitney U-test. n.s., not significant.

Figure 1

Summary of the molecular mechanisms proposed for the PM of the FMR1 gene. Arrows indicate increases/decreases of RNA (FMR1 and the long non-coding RNAs ASFMR1/FMR4 and FMR6) or protein (FMRP) in PM carriers compared to controls. Pink ovals represent free proteins that interact/are sequestered/are aggregated by the CGG hairpin of the FMR1 mRNA and/or FMRpolyG peptide.