Mouse models of fragile X-related disorders

Abstract

The fragile X-related disorders are an important group of hereditary disorders that are caused by expanded CGG repeats in the 5' untranslated region of the FMR1 gene or by mutations in the coding sequence of this gene. Two categories of pathological CGG repeats are associated with these disorders, full mutation alleles and shorter premutation alleles. Individuals with full mutation alleles develop fragile X syndrome, which causes autism and intellectual disability, whereas those with premutation alleles, which have shorter CGG expansions, can develop fragile X-associated tremor/ataxia syndrome, a progressive neurodegenerative disease. Thus, fragile X-related disorders can manifest as neurodegenerative or neurodevelopmental disorders, depending on the size of the repeat expansion. Here, we review mouse models of fragile X-related disorders and discuss how they have informed our understanding of neurodegenerative and neurodevelopmental disorders. We also assess the translational value of these models for developing rational targeted therapies for intellectual disability and autism disorders.

Keywords: FMR1; Fragile X syndrome; Fragile X-associated tremor/ataxia syndrome; Mouse models.

Fig. 1.

The structure of the FMR1 gene and FMRP protein. (A) Schematic of the human FMR1 gene showing its potential alternative splicing sites. (B) Schematic showing the transcription and translation of FMR1 alleles. Most individuals carry 5-54 CGG repeats in their FMR1 gene, which is considered wild-type and is expressed normally (top). Individuals with CGG repeats in the range of 55-200 repeats (shown in blue) carry so-called premutation (PM) alleles, which are associated with elevated FMR1 mRNA levels and a moderate decrease in FMRP production (middle). Individuals with >200 CGG units repeats (shown in red) carry full-mutation (FM) alleles. In FM, FMR1 transcription is silenced due to promoter hypermethylation (bottom). (C) The human FMRP protein that is encoded by FMR1. Its functional domains include a Tudor methyl-lysine- and methyl-arginine-binding domain, a nuclear localization signal (NLS), two K homology (KH) domains, a nuclear export signal (NES) and an arginine-glycine-rich (RGG) domain.

Fig. 2.

FMRP function in neurons. FMRP is synthesized in the cytoplasm and enters the nucleus via its nuclear localization signal (NLS). In the nucleus, FMRP binds to target mRNAs and other proteins, forming a ribonucleoprotein (RNP) particle. The FMRP-RNP particle is transported back to the cytoplasm via the nuclear export signal (NES) of FMRP. FMRP-RNP particles regulate protein synthesis in the cytoplasm of a neuron. Some FMRP-RNP particles are also packed into mRNA-granules and transported into the dendrites of the neuron. During transport, FMRP acts as a translational repressor of the target mRNAs within the granules. Upon synaptic stimulation of group I mGluRs, FMRP allows the translation of its mRNA targets. The translated proteins are involved in the cyclic internalization of AMPA receptors and other neuronal processes. RBP, RNA-binding protein.

Fig. 3.

Two models of expanded CGG repeat toxicity. (A) The CGG repeat-mediated RNA toxicity and sequestration model assumes that RNA-binding proteins (RBPs) are sequestered through their interactions with the expanded CGG repeat-containing FMR1 mRNA. These proteins in turn recruit other essential cellular proteins and sequester them, such that these essential proteins are unavailable for their normal cellular functions. (B) The toxic polypeptide model assumes that the ribosome translation initiation complex stalls near the CGG repeat hairpin formed on the FMR1 mRNA. This drives the repeat-associated non-AUG (RAN) translation of FMR1 mRNA using a nearby AUG start site. This results in a frame shift and the production of the polyglycine-containing polypeptide (FMRpolyG), among other polypeptides, which interfere with normal cellular function via an unknown toxic mechanism.

Fig. 4.

Summary of FXS mouse models. (A) The general phenotypes, limitations and future research directions for FXS knock-out mouse models, which do not express FMRP and are therefore aimed at recapitulating the full mutation in patients. (B) The phenotypes, limitations and future research directions for the FXTAS knock-in mouse model. AONs, antisense oligonucleotides; FM, full mutation; Fmr1, fragile X messenger ribonucleoprotein 1 gene; Fmrp, fragile X messenger ribonucleoprotein; LTD, long-term depression; PM, premutation; RAN translation, repeat associated non-AUG translation.

Fig. 5.

Pathways involved in fragile X syndrome and synaptic targets of therapeutic interventions. Several types of drugs can interact with neuronal receptors, which might rescue the disturbed synaptic transmission in FXS. These include NMDA, AMPA, mGluR5, GABA and muscarinic receptors. MPEP, 2-methyl-6-(phenylethynyl)pyridine; THIP, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol.