Chunk #16 — 3. Overview of Monogenic Mouse Models of ASDs — 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten — 3.2.1 Fmr1 (Fragile X syndrome)
Fragile X syndrome (FXS), primarily affecting males, also has phenotypic overlap with ASDs and is caused by extended CGG trinucleotide repeats in the 5′ untranslated region of FMR1 (Verkerk et al., 1991; Pieretti et al., 1991). Such mutations lead to hypermethylation of the FMR1 promoter, which transcriptionally silences the fragile X mental retardation protein (FMRP), an RNA binding protein involved in suppressing activity-dependent translation of synaptic proteins, many of which have been independently implicated in ASDs (Darnell et al., 2011). Under normal conditions, FMRP is dephosphorylated after activation of metabotropic glutamate receptors (mGluRs), leading to de-repression of local translation (reviewed in Bassell and Warren, 2008). Extended CGG repeats in Fmr1 in mice do not recapitulate the hypermethylation and transcriptional silencing of FMRP that is characteristic of human fragile X (Brouwer et al., 2007). However, researchers have mimicked the molecular consequences of the human mutation by deleting exon 5 (The Dutch-Belgian Fragile X Consortium, 1994) or exon 1 (Mientjes et al., 2006) of Fmr1. Almost all data related to fragile X syndrome mouse models in the literature have been generated from
