Fragile X Syndrome (Homo sapiens)

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P7122798323827398342278232295826320797683794144922391413, 1758797679768124, 40237941235924544740599236403567679889124582333, 913623699247934780941252565, 794847502541NMDA ReceptorPoolOther targetsstalled polyribosomesFXS:loss of FMRPNMDARinternalizationNMDARsubunitsGABA A Receptor SubunitsAnterior cingulate cortexBasolateral AmygdalaDefective cAMP production2675RISC ComplexGABAergic synapse components59Dysregulated metabolic homeostasis53, 97TSC complex PKAeIF4F complexmGluR-LTD35Receptor subunitsHippocampus CA190AMPA ReceptorEnteric innervation of the ileum42upregulationTrkB ReceptorLTD proteins160ClathrinNMDA ReceptorAMPAR internalizationAMPA Receptor PoolDysregulation of GABAergic synaptic transmissiondeletionrelease of Ca2+Lipid and glucose metabolsim53AP-2Group I mGluR47mTORC170GDPKCNC1CYFIP2EPS8L1DUSP3FYNGRIN2ACNR1HCN1HOMER1SRCEEF1A1BDNF-TrkB SignallingKCND2GRIN2AGABRDGRM5glutamateMMP9449ABAT64PI3K-Akt-mTOR Pathway19CAMKIV-CREB PathwayglutamateBDNFAP2A1PLCB1GAD1cAMPCLTCL1PPP3CAGRIP2CREB1DLG4DLG42, 16SLC6A157PRKCAGAD114PRKACAMEK-ERK-Mnk1 Pathway19EIF4G1ALDH5A111γ-aminobutyric acid73SHC1GRIA1CLTCAP2B1CPT1APRKACAPIP2PTPN5GRB2CLTBGPHN77GRIP1DLG4GRIA2APPmiR-125bCAMK4CREB1PTPN11GRIA1AP2S1AGO2AKAP546GABRG2CAMK1ARHGAP3210GAB1GABRA1PTPN53, 33Dynamin-1DICER16AP2M1PICK1DAG1GRIN2B76, 82GABRB2endocannabinoidsNTRK2SLC16A1CLTAGRIA2SYNGAP1ITPR1PPP1CA51PLCG1CAMK2BSHANK1DLG4DLGAP3MAP2K2FMR13MAP1BARCMKNK1RPS6KB1MAP1B3MAPK1KRASCYFIP112AKT1S1ARC52MAP2K1CAMK2ASOS113PPP2R5BEIF4EBP2RAF1NF115EIF4ECAMK2A72, 87FMR1DEPTORTELO2RPTORMLST8MTORPIK3CBTTI1GRM5RHEBHOMER1GRM1PDK1AGAP2PIP2PTENTSC1AKT1PIP3TSC2TBC1D7RHEBGTPP at Ser500KRASGDPGTPPPPPPDLGAP329, 89SHANK162GRIN2BGRIN2B31GABRA1GABRB2GABRG2GPHNSLC6A1ABATALDH5A1ALDH3A2ABCD3TECRCPT1A53, 67SLC16A153ALDH3A253, 55ABCD366TECR96PPRKAR1APRKAR1APFMR1Influx Ca2+GRIA1GRIA2AMPA ReceptorPGRIA2GRIA146GRIA1GRIA2miR-132miR-196aSH3GL1DNM217260360PP at Thr308EIF4A1TARBP2EIF4EBP254MECP274EPHA41GRIN2ACDKN2AHOXB8MAP2K2MAP2K1MAPK1MKNK1BRAFARAFPSH3GL3mGluR-LTPAMPA ReceptorAMPAR exocytosis46730385downregulation535353NMDARLTD61PKAPRKACAPRKACAPRKAR1APRKAR1AAPP21, 4534Cerebellar cortex43Amygdala23, 42, 94Corticostriatal synapse42Neocortical layer5 neurons42Audiogenic seizures42C-fiber innervation42Suprachiasmatic nucleus42372133GRIN2B76P at Y1472PAP-2AP2A1AP2B1AP2S1AP2M1ClathrinCLTCL1CLTCCLTB22CLTAGRIN2B76overactivationSomatosensoryCortexStriatumSubiculum Hippocampus CA1PTENPTEN6868GRIN1GRIN1DUSP38686NMDARLTPNMDARintsertionEEF1A1CYFIP2GABRDGRM534HCN1KCNC1KCND2MMP9PRKCAPPRAP1GAP18, 84PEPS8L185PSHANK1PTPN562MAP1B3, 333PTPN5DUSP33, 3386hypofunction


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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