CGG repeat in the FMR1 gene: size matters

Abstract

The FMR1 gene contains a CGG repeat present in the 5'-untranslated region which can be unstable upon transmission to the next generation. The repeat is up to 55 CGGs long in the normal population. In patients with fragile X syndrome (FXS), a repeat length exceeding 200 CGGs (full mutation: FM) generally leads to methylation of the repeat and the promoter region, which is accompanied by silencing of the FMR1 gene. The absence of FMR1 protein, FMRP, seen in FM is the cause of the mental retardation in patients with FXS. The premutation (PM) is defined as 55-200 CGGs. Female PM carriers are at risk of developing primary ovarian insufficiency. Elderly PM carriers might develop a progressive neurodegenerative disorder called fragile X-associated tremor/ataxia syndrome (FXTAS). Although arising from the mutations in the same gene, distinct mechanisms lead to FXS (absence of FMRP), FXTAS (toxic RNA gain-of-function) and FXPOI. The pathogenic mechanisms thought to underlie these disorders are discussed. This review gives insight on the implications of all possible repeat length categories seen in fragile X families.

Figure 1. CGG repeat length, FMRP expression and clinical outcome

In unaffected individuals, the CGG repeat in the 5’ UTR ranges between 5-55, leading to normal FMR1 mRNA transcription and translation, and normal FMRP expression. The premutation repeat (55-200) results in elevated FMR1 mRNA transcription, but reduced FMRP expression. This increases the risk of developing FXTAS in males or FXPOI in females (111). A full mutation repeat (over 200) leads to silencing of the FMR1 gene due to hypermethylation. As a consequence FMRP is lacking resulting in fragile X syndrome (adapted from (112)).

Figure 2. Schematic model of the function of FMRP in neurons

FMRP is synthesised in the cytoplasm. Dimers of FMRP (yellow hexagons) enter the nucleus via the NLS domain. In the nucleus, FMRP binds to target mRNAs and other proteins, forming an RNP particle. The FMRP-RNP particle is transported back to the cytoplasm, via the NES of FMRP. In the cytoplasm, the FMRP-RNP particle can interact with members of the RNA-induced silencing complex (RISC; green circle) and also associate with ribosomes (red ovals). FMRP-RNP particles regulate protein synthesis (string of blue circles) in the cell body of the neuron. A proportion of the FMRP-RNP particles is packed in mRNA granules and is transported into dendrites. During transport, FMRP fulfils its major role as a translational repressor of target mRNAs. Upon synaptic stimulation of the group I mGluRs, FMRP allows translation of its mRNA targets. The proteins that are synthesised seem to be involved in the cyclic internalisation of AMPA receptors and other neuronal processes.

Figure 3. Therapeutic strategies for FXS

Schematic representation of a glutamatergic excitatory and GABAergic inhibitory synapse lacking FMRP. Several types of drugs can interact with different type of neuronal receptors which may result in rescue of the disturbed synaptic transmission found in FXS (adapted from (59)).

Figure 4. Inclusions in human and mouse brain

Paraffin sections of hippocampus from FXTAS patient (A) and KI mouse (B). The micrograph shows the presence of ubiquitin-positive intranuclear inclusions in neurons located in the CA3 region of the hippocampus using an indirect immunoperoxidase protocol.

Figure 4. Inclusions in human and mouse brain

Paraffin sections of hippocampus from FXTAS patient (A) and KI mouse (B). The micrograph shows the presence of ubiquitin-positive intranuclear inclusions in neurons located in the CA3 region of the hippocampus using an indirect immunoperoxidase protocol.

Figure 5. FMRP expression in human ovary

Parafin section of human ovary from a woman at age 20 years old. The micrograph shows FMRP expression in oocytes and granulosa cells during folliculogenesis using an indirect immunoperoxidase protocol. arrow = oocyte ; arrowhead = granulosa cells