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Review
. 2019 Apr 27;9(5):96.
doi: 10.3390/brainsci9050096.

Molecular Biomarkers in Fragile X Syndrome

Marwa Zafarullah  1 , Flora Tassone  2   3
Affiliations
Review

Molecular Biomarkers in Fragile X Syndrome

Marwa Zafarullah et al. Brain Sci. .

Abstract

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability (ID) and a known monogenic cause of autism spectrum disorder (ASD). It is a trinucleotide repeat disorder, in which more than 200 CGG repeats in the 5' untranslated region (UTR) of the fragile X mental retardation 1 (FMR1) gene causes methylation of the promoter with consequent silencing of the gene, ultimately leading to the loss of the encoded fragile X mental retardation 1 protein, FMRP. FMRP is an RNA binding protein that plays a primary role as a repressor of translation of various mRNAs, many of which are involved in the maintenance and development of neuronal synaptic function and plasticity. In addition to intellectual disability, patients with FXS face several behavioral challenges, including anxiety, hyperactivity, seizures, repetitive behavior, and problems with executive and language performance. Currently, there is no cure or approved medication for the treatment of the underlying causes of FXS, but in the past few years, our knowledge about the proteins and pathways that are dysregulated by the loss of FMRP has increased, leading to clinical trials and to the path of developing molecular biomarkers for identifying potential targets for therapies. In this paper, we review candidate molecular biomarkers that have been identified in preclinical studies in the FXS mouse animal model and are now under validation for human applications or have already made their way to clinical trials.

Keywords: ASD.; FMR1; FMRP; Fmr1 KO mouse; fragile X syndrome; intellectual disability; molecular biomarkers.

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Conflict of interest statement

F.T. received funds from Asuragen and Zynerba. The remaining authors have no disclosures.

Figures

Figure 1
Figure 1
Potential therapeutic targets for fragile X syndrome (FXS). Diagram of the mechanisms implicated in FXS leading to altered synaptic plasticity. The figure also shows the molecular pathways targeted or understudy, for the reversal of cognitive and behavioral impairments in FXS patients. Several types of drugs, modulators, and compounds (inhibitor, agonist, and antagonist) can interfere with different pathways disturbed in FXS and have been used in a number of pharmacological treatments some of which are currently under investigation and are indicated in the figure.
Figure 2
Figure 2
Candidate molecular biomarkers for FXS include a number of targets and substrates of several signaling pathways, in addition to fragile X mental retardation 1 (FMR1) molecular measures and metabolites, of which expression levels or activity have been found dysregulated in FXS animal models and in human FXS tissues. Fmr1 mRNA and fragile X mental retardation 1 protein (FMRP) expression, de novo protein synthesis, γ-aminobutyric acid (GABA) receptors (GABAA and GABAB), phosphoinositide 3-kinase (PI3K), extracellular-regulated kinase (ERK), matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase (S6K1), ion channels (KNa, BKCa, CaV, Kv, HCN1), bone morphogenetic protein receptor Type 2 (BMPR2), Diacylglycerol Kinase Kappa (Dgkκ), endocannabinoid system (eCS), amyloid-β protein precursor (APP), microRNA’s (miRNA’s), striatal-enriched protein tyrosine phosphatase (STEP), glycogen synthase kinase-3 (GSK-3) cytokine and chemokine profiles, metabotropic glutamate receptor (mGluRs).
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