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. 2012 Dec;122(12):4314-22.
doi: 10.1172/JCI63141. Epub 2012 Dec 3.

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

Claudia Bagni  1 , Flora Tassone, Giovanni Neri, Randi Hagerman
Affiliations

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

Claudia Bagni et al. J Clin Invest. 2012 Dec.

Abstract

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet expansion that inhibits expression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families.

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Figures

Figure 1
Figure 1. The four alleles of the human FMR1 gene.
According to the degree of CGG triplet expansion and the level of FMR1 mRNA transcription and translation changes, four alleles are generated: normal, PM, UFM, and FM.
Figure 2
Figure 2. Effects of receptor signaling pathways on FMRP-mediated regulation at synapses.
A complex cascade of molecules downstream of glutamate (NMDA, AMPA, mGluR5) and BDNF receptors modulates FMRP activity at synapses. FMRP is affected by mTOR and Mnk1 signaling pathways (89) that regulate phosphorylation of general eIF4E-binding proteins and consequently protein synthesis. FMRP can be phosphorylated by S6 kinase (S6K) (72) or dephosphorylated by protein phosphatase 2A (PP2A) (137). The phosphorylation status affects its RNA-binding properties as well as its translational regulation. Mechanistically, FMRP has been shown to interact with the initiation factor eIF4E and regulate translational through the specific eIF4E-binding protein CYFIP1 (52). Further studies are required to verify whether FMRP also binds general eIF4E-BPs and whether these signaling pathways affect the FMRP-CYFIP1 complex as well. FMRP may also affect translational elongation (58). In absence of FMRP, the upstream kinase phosphatidylinositol 3-kinase (PI3K) is upregulated, leading to the increased mTOR phosphorylation and activity observed in patients with FXS as well as in the Fmr1 KO mouse (87, 89), culminating in an increased protein synthesis. Similar and possibly convergent effects are due to an upregulation of ERK (, –89) and TrkB (85) signaling. In absence of FMRP, there is an increase of a subset of locally synthesized proteins (Arc, Map1B, αCAMKII, postsynaptic density-95 [PSD-95], MMP9, GSK-3β, among others). The increased Arc level contributes to an increased AMPA internalization and reduced AMPA in the membrane. At the same time, Arc, Map1B, PSD-95, and other dysregulated proteins involved in cytoskeleton scaffolding and remodeling may contribute to the FXS dysmorphic spine as well.
Figure 3
Figure 3. Toward a therapy for FXS.
(A) Epigenetic-modifying compounds that may reactivate FMR1 gene expression. (B) Compounds used in clinical trials and affecting dysregulated molecules and pathways are shown. Lack of FMRP leads to a dysregulated synthesis of molecules with key functions at synapses, such as increased levels of Arc, αCAMKII, MMP9, GSK-3β, mGluR, and NMDA and decreased GABA and AMPA receptor activity. Arrows and inhibition symbols do not necessarily represent direct interactions.
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