The FMRP regulon: from targets to disease convergence

Abstract

The fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates mRNA metabolism. FMRP has been largely studied in the brain, where the absence of this protein leads to fragile X syndrome, the most frequent form of inherited intellectual disability. Since the identification of the FMRP gene in 1991, many studies have primarily focused on understanding the function/s of this protein. Hundreds of potential FMRP mRNA targets and several interacting proteins have been identified. Here, we report the identification of FMRP mRNA targets in the mammalian brain that support the key role of this protein during brain development and in regulating synaptic plasticity. We compared the genes from databases and genome-wide association studies with the brain FMRP transcriptome, and identified several FMRP mRNA targets associated with autism spectrum disorders, mood disorders and schizophrenia, showing a potential common pathway/s for these apparently different disorders.

Keywords: FMRP; RNA-binding proteins; autism; fragile X syndrome; local protein synthesis; major depressive disorders; schizophrenia; synaptic plasticity.

Figure 1

FMRP exon structure comprising its functional domains. Upper frame: The red box at the N-terminus of exon 1 indicates the location of the CGG triplet repeat within the 5′ UTR of the mRNA. The four RNA binding domains are: the N-terminus, the two K homology domains (KH1 and KH2) and the RGG box. Middle frame: FMRP domains interacting with NUFIP1, CYFIP1, CYFIP2, FXR1P, FXR2P, TDRD3, and SMN proteins. The FMRP amino acid sequence involved in these interactions is shown between the brackets. The nuclear localization signal (NLS) and the nuclear export signal (NES) are also indicated. Lower frame: The FMRP RNA binding domains and the RNA/mRNA targets directly bound are indicated.

Figure 2

Venn diagram of FMRP mRNA targets associated with autistic spectrum disorder (ASD), schizophrenia (SCZ) and mood disorder (MD). FMRP neuronal target genes (1169) were compared with de novo gene disruptions (nonsense, splice and frameshifts) reported in GWAS are associated with ASD, as previously described (Iossifov et al., ; Neale et al., ; O'roak et al., ; Sanders et al., 2012), the 528 genes from the SFARI (https://sfari.org/resources/sfari-base) and the 304 genes from the AutDB databases (http://autism.mindspec.org/autdb/Welcome.do). Approximately 120 FMRP target genes were associated with ASD (in black). Among the 120 target genes, included 35 genes were identified from the GWAS (in red) and 100 genes were identified from the two databases (in black). Fifteen genes showed overlap between the GWAS, the SFARI, and AutDB databases (in black/red color). The 1169 FMRP target genes were compared with the genes associated with SCZ and MD in the NHGRI GWAS database (http://www.genome.gov/gwastudies/) and 26 common FMRP targets were shown.