Fragile X Syndrome (Homo sapiens)

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P463970339137127565179259928292175128744129426295959436, 6019128712874715, 25512945641550672564295825367287125295151953636, 955856229676967617794515112, 806867865194Anterior cingulate cortexDefective cAMP productionNMDA ReceptorPoolFXS:loss of FMRPNMDARsubunitsGABA A Receptor SubunitsOther targetsBasolateral Amygdalastalled polyribosomesNMDARinternalization3173RISC ComplexGABAergic synapse components64Dysregulated metabolic homeostasis24, 38TSC complex PKAeIF4F complexmGluR-LTD6Receptor subunitsHippocampus CA146AMPA ReceptorEnteric innervation of the ileum1upregulationTrkB ReceptorLTD proteins17ClathrinNMDA ReceptorAMPAR internalizationAMPA Receptor PoolDysregulation of GABAergic synaptic transmissiondeletionrelease of Ca2+Lipid and glucose metabolsim38AP-2Group I mGluR67mTORC181GDPHOMER1EEF1A1EPS8L1GRIN2AGRM5KCNC1CNR1BDNF-TrkB SignallingGRIN2AFYNHCN1CYFIP2glutamateGABRDKCND2SRCMMP9DUSP31640ABAT76PI3K-Akt-mTOR Pathway78CAMKIV-CREB PathwayglutamateBDNFAP2A1PLCB1GAD1cAMPCLTCL1PPP3CAGRIP2CREB1DLG4DLG414, 21SLC6A111PRKCAGAD130PRKACAMEK-ERK-Mnk1 Pathway78EIF4G1ALDH5A189γ-aminobutyric acid96SHC1GRIA1CLTCAP2B1CPT1APRKACAPIP2PTPN5GRB2CLTBGPHN71GRIP1DLG4GRIA2APPmiR-125bCAMK4CREB1PTPN11GRIA1AP2S1AGO2AKAP555GABRG2CAMK1ARHGAP3232GAB1GABRA1PTPN536, 54Dynamin-1DICER185AP2M1PICK1DAG1GRIN2B37, 87GABRB2endocannabinoidsNTRK2SLC16A1CLTAGRIA2SYNGAP1ITPR1PPP1CA39PLCG1CAMK2BSHANK1DLG4DLGAP3MAP2K2FMR136MAP1BARCMKNK1RPS6KB1MAP1B36MAPK1KRASCYFIP197AKT1S1ARC83MAP2K1CAMK2ASOS149PPP2R5BEIF4EBP2RAF1NF122EIF4ECAMK2A45, 48FMR1DEPTORTELO2RPTORMLST8MTORPIK3CBTTI1GRM5RHEBHOMER1GRM1PDK1AGAP2PIP2PTENTSC1AKT1PIP3TSC2TBC1D7RHEBGTPP at Ser500KRASGDPGTPPPPPPDLGAP327, 74SHANK13GRIN2BGRIN2B53GABRA1GABRB2GABRG2GPHNSLC6A1ABATALDH5A1ALDH3A2ABCD3TECRCPT1A18, 38SLC16A138ALDH3A228, 38ABCD323TECR20PPRKAR1APRKAR1APFMR1Influx Ca2+GRIA1GRIA2AMPA ReceptorPGRIA2GRIA155GRIA1GRIA2miR-132miR-196aSH3GL1DNM2602737PP at Thr308EIF4A1TARBP2EIF4EBP250MECP234EPHA484GRIN2ACDKN2AHOXB8MAP2K2MAP2K1MAPK1MKNK1BRAFARAFPSH3GL3mGluR-LTPAMPA ReceptorAMPAR exocytosis5513907542downregulation383838NMDARLTD66PKAPRKACAPRKACAPRKAR1APRKAR1AAPP8, 4370Cerebellar cortex57Amygdala1, 5, 56Corticostriatal synapse1Neocortical layer5 neurons1Audiogenic seizures1C-fiber innervation1Suprachiasmatic nucleus135854GRIN2B87P at Y1472PAP-2AP2A1AP2B1AP2S1AP2M1ClathrinCLTCL1CLTC92CLTBCLTAGRIN2B87overactivationSomatosensoryCortexStriatumSubiculum Hippocampus CA1PTEN93PTEN93GRIN1GRIN1DUSP388NMDARLTP88NMDARintsertionEEF1A1CYFIP2GABRD70GRM5HCN1KCNC1KCND2MMP9PRKCAPPRAP1GAP41, 79PEPS8L12PSHANK13PTPN5MAP1B36, 5436PTPN5DUSP336, 5488hypofunction


Fragile X syndrome (FXS) is a monogenetic disorder cause by a mutation in the FMR1 gene and the most common form of inherited intellectual disability and autism spectrum disorder (ASD). Patients with FXS show a range of typical physical features such as macro-orchidism in males, a long and narrow face, large and protruding ears and hyperextensible joints. Common comorbidities of FXS are neuropsychiatric disorders such as hyperactivity, depression and anxiety. The mutation of FMR1 in FXS disrupts production of the FMR1 gene product, the fragile mental retardation protein (FMRP). The main function of FMRP is to locally act as a translational repressor for target mRNAs and thereby regulate de novo protein synthesis and ultimately synaptic plasticity. FMRP, together with the mTOR pathway and the ERK pathway regulates expression of target mRNAsn mediated by stimulation of Group I metabotropic glutamate receptors (mGluR) and thereby regulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalisation and thus long term depression (LTD). LTD is a form of synaptic plasticity which is involved in learning and memory. Lack of FMRP leads to exaggerated mGluR dependant LTD, which accounts for most of FXS pathogenesis.

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