Fragile X syndrome (WP4549)

Homo sapiens

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Fragile X syndrome (FXS) is a monogenetic disorder caused 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.

Authors

Megi Kass , Elisson nl , Andra Waagmeester , Egon Willighagen , Friederike Ehrhart , Eric Weitz , Martina Summer-Kutmon , Finterly Hu , Vanessa Sousa , Lars Willighagen , and Kristina Hanspers

Activity

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Organisms

Homo sapiens

Communities

Rare Diseases

Annotations

Pathway Ontology

brain disease pathway disease pathway

Disease Ontology

fragile X syndrome autism spectrum disorder

Cell Type Ontology

neuron

Participants
Query Drugst.One

Label Type Compact URI Comment
glutamate Metabolite chebi:14321
cAMP Metabolite chebi:17489
γ-aminobutyric acid Metabolite chebi:16865 γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system.
PIP2 Metabolite chebi:18348
endocannabinoids Metabolite chebi:67197
PIP3 Metabolite chebi:16618
CYFIP2 GeneProduct ensembl:ENSG00000055163
GABRD GeneProduct ensembl:ENSG00000187730
GRM5 GeneProduct ensembl:ENSG00000168959
CNR1 GeneProduct ensembl:ENSG00000118432
SRC GeneProduct ensembl:ENSG00000197122
HOMER1 GeneProduct ensembl:ENSG00000152413 The short splice variant of Homer, Homer1a, competes with Homer 1 for the binding site on mGluR. In FXS mouse model, Homer1a has been shown to associate more with mGluR than Homer1, thereby it disrupts mGluR signalling and causes constitutive, agonist-independent activity of Group I mGluR.
FYN GeneProduct ensembl:ENSG00000010810 Tyrosine-protein kinase Fyn (FYN) is a member of the Src family of tyrosine kinases which is involved in the regulation of brain function.
GRIN2A GeneProduct ensembl:ENSG00000183454
ABAT GeneProduct ensembl:ENSG00000183044 4-aminobutyrate aminotransferase (ABAT) is involved in GABA catabolism.
BDNF GeneProduct ensembl:ENSG00000176697
AP2A1 GeneProduct ensembl:ENSG00000196961
PLCB1 GeneProduct ensembl:ENSG00000182621
CLTCL1 GeneProduct ensembl:ENSG00000070371
PPP3CA GeneProduct ensembl:ENSG00000138814 Calcineurin
GRIP2 GeneProduct ensembl:ENSG00000144596 Glutamate receptor-interacting protein 2 (GRIP2) also called AMPAR binding protein (ABP) interacts with GRIP1 to regulate AMPAR trafficking
CREB1 GeneProduct ensembl:ENSG00000118260
DLG4 GeneProduct ensembl:ENSG00000132535
DLG4 GeneProduct ensembl:ENSG00000132535 postsynaptic density protein 95 (PSD-95 also known as SAP-90, encoded by the gene DLG4) is a PSD scaffolding protein, located at synapses, which is involved in the modulation of AMPAR ineternalization, stabilization of dendritic spines and synaptic strength. Translation of PSD-95 is negatively regulated by FMRP and miR-125a and positively regulated by mGluR activation. PSD-95 anchors synaptic proteins at the membrane and thus plays a cruicial role in synaptic plasticity and NMDAR-dependant LTP. In that sense, PSD-95 has a binary role, it serves as a structural scaffold which anchors AMPARs at the synapse. It also acts as a signalling scaffold required for LTD.
SLC6A1 GeneProduct ensembl:ENSG00000157103 Sodium- and chloride-dependent GABA transporter 1 (SLC6A1 or GAT-1) has a function in GABA reuptake in the cortex, cerebellum and the whole forebrain. GAT-1 ends GABA action by removing GABA from the synaptic cleft and restoring it to presynaptic terminals.
PRKCA GeneProduct ensembl:ENSG00000154229
GAD1 GeneProduct ensembl:ENSG00000128683 Glutamate decarboxylase 1 (GAD1) encoded an enzyme (glutamic acid decarboxylase) that has a role in γ-aminobutyric acid (GABA) synthesis. The enzyme catalyzes the production of GABA from L-glutamic acid.
PRKACA GeneProduct ensembl:ENSG00000072062
EIF4G1 GeneProduct ensembl:ENSG00000114867
ALDH5A1 GeneProduct ensembl:ENSG00000112294 aldehyde dehydrogenase 5 family member A1 (ALDHA1) and encodes encodes a mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenaseis that is involved in the catalysis of GABA.
SHC1 GeneProduct ensembl:ENSG00000160691
CLTC GeneProduct ensembl:ENSG00000141367
AP2B1 GeneProduct ensembl:ENSG00000006125
PRKACA GeneProduct ensembl:ENSG00000072062 Exact subunits which make up PKA in thus pathway could not be found. PKA is made up of 2 regulary subunits and 2 catalytic subunits. Because no information on the composition of subunits in this case could have been found, subunits A have been used for regulatory and catalytic parts of PKA.
GRB2 GeneProduct ensembl:ENSG00000177885
CLTB GeneProduct ensembl:ENSG00000175416
GPHN GeneProduct ensembl:ENSG00000171723 Gephyrin is involved in GABA receptor clustering in the cortex. Gephyrin is a neuronal assembly protein that anchors inhibitory neurotransmitter receptors, such as GABA receptors, to the postsynaptic cytoskeleton.
GRIP1 GeneProduct ensembl:ENSG00000155974
GRIA2 GeneProduct ensembl:ENSG00000120251
CAMK4 GeneProduct ensembl:ENSG00000152495 CAMK4 or CAMKIV
PTPN11 GeneProduct ensembl:ENSG00000179295
GRIA1 GeneProduct ensembl:ENSG00000155511
AP2S1 GeneProduct ensembl:ENSG00000042753
AGO2 GeneProduct ensembl:ENSG00000123908
AKAP5 GeneProduct ensembl:ENSG00000179841 A-kinase anchor protein 5 (AKAP5) anchors protein kinase A (PKA) at the PSD by directly interacting with PSD-95. This interaction is important for NMDAR-dependant AMPAR endocytosis and LTD.
GABRG2 GeneProduct ensembl:ENSG00000113327 GABA rceeptor subunit γ
CAMK1 GeneProduct ensembl:ENSG00000134072
ARHGAP32 GeneProduct ensembl:ENSG00000134909 Rho GTPase activating protein 32 (ARHGAP32) is a neuron-associated GAP that may regulate dendritic spine morphology and strength through modulation of Rho GTPase activity.
GAB1 GeneProduct ensembl:ENSG00000109458
GABRA1 GeneProduct ensembl:ENSG00000022355 GABA receptor subunit α
PTPN5 GeneProduct ensembl:ENSG00000110786 Tyrosine-protein phosphatase non-receptor type 5 (STEP) is involves to regulate AMPAR trafficking and negatively regulates AMPAR surface expression thereby contributing to mGluR-LTD. STEP promotes LTD by stimulating synaptic weakening by dephosphorylation of ERK1/2 and subunits of NDMA and AMPA receptors. STEP has been shown to promote NMDA internalization.
DICER1 GeneProduct ensembl:ENSG00000100697 DICER, is an endonuclease, which cleaves double stranded RNA (dsRNA) into short single stranded RNA called miRNA and tehreby faciliates the activation of RISC
AP2M1 GeneProduct ensembl:ENSG00000161203
PICK1 GeneProduct ensembl:ENSG00000100151 Protein Interacting with Kinase C 1 (PICK1)
DAG1 GeneProduct ensembl:ENSG00000173402
GRIN2B GeneProduct ensembl:ENSG00000273079 N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDAR) are ionotropic receptors activated by glutamate. NMDAR activation allows Ca2+ influx leading to NMDAR-dependant LTP and LTD. NMDA receptors contribute to dendritic structure and thus, can have impact on neuronal firing.
GABRB2 GeneProduct ensembl:ENSG00000145864 GABA receptor subunit β
NTRK2 GeneProduct ensembl:ENSG00000148053
CLTA GeneProduct ensembl:ENSG00000122705
SYNGAP1 GeneProduct ensembl:ENSG00000197283
ITPR1 GeneProduct ensembl:ENSG00000150995
PPP1CA GeneProduct ensembl:ENSG00000172531 PP1 had 4 isomforms, however, in this pathway, only one (gene PPP1CA) has been used since literature did not specify which isoform is involved in this specific case.
PLCG1 GeneProduct ensembl:ENSG00000124181
CAMK2B GeneProduct ensembl:ENSG00000058404 CAMKII catalyzes the phosphorylation of AMPAR an
SHANK1 GeneProduct ensembl:ENSG00000161681
MAP2K2 GeneProduct ensembl:ENSG00000126934
FMR1 GeneProduct ensembl:ENSG00000102081 FMR1 gene product, called fragile mental retardation protein (FMRP) is a major regulator of mGluR-dependant protein synthesis and synaptic plasticity in hippocampus and cerebellum. It functions as a translational regulator of certain target mRNAs, is involved in denrite and axon developent as well as in learning and memory.
MKNK1 GeneProduct ensembl:ENSG00000079277
RPS6KB1 GeneProduct ensembl:ENSG00000108443
MAP1B GeneProduct ensembl:ENSG00000131711 Microtubule-associated protein 1B (MAP1B) is involved in mcirotubule assembly and neurogenesis. MAP1b is involved in the regulation of the morphology of dendritic spines in glutamatergic synapses. Furthermore, MAP1b is a negative regulator of AMPAR surface expression thereby contributing to mGluR-LTD.
MAPK1 GeneProduct ensembl:ENSG00000100030
KRAS GeneProduct ensembl:ENSG00000133703
CYFIP1 GeneProduct ensembl:ENSG00000273749 CYFIP1 interacts with FMRP and with translation initiation factor eIF4E
AKT1S1 GeneProduct ensembl:ENSG00000204673
ARC GeneProduct ensembl:ENSG00000198576 Activity-regulated cytoskeleton-associated protein (ARC) is a key regulator of synaptic plasticity. It is required for protein synthesis-dependent LTP and LTD as well as for the formation of long-term memory. ARC regulates synaptic plasticity by promoting endocytosis of AMPA receptors AMPAR and thus, LTD.
MAP2K1 GeneProduct ensembl:ENSG00000169032
SOS1 GeneProduct ensembl:ENSG00000115904 SOS, a guanine-associated echange factor (GEF), activates Ras by inducing the exchange of GTDP by GTP. This positively regulates Ras signalling.
PPP2R5B GeneProduct ensembl:ENSG00000068971
EIF4EBP2 GeneProduct ensembl:ENSG00000148730
RAF1 GeneProduct ensembl:ENSG00000132155
NF1 GeneProduct ensembl:ENSG00000196712 NF1 functions as a guanine exchange factors (GEF), stimulating the conversion of GTP-bound RAS into GDP-bound RAS and tehreby negatively regulating the MEK-ERK-Mnk1 pathway.
EIF4E GeneProduct ensembl:ENSG00000151247
CAMK2A GeneProduct ensembl:ENSG00000070808 calcium/calmodulin dependent protein kinase II alpha (CAMKIIα) is expressed at synapses where its translation is negatively regulated by FMRP. CAMKIIα is a key determinant for AMPAR internalization and thus LTD. The protein kinase mediates AMPAR internalization through phosphorylation of AMPAR subunits. CAMKIIα is involved in synaptic plasticity, neurotransmitter release and LTP.
FMR1 GeneProduct ensembl:ENSG00000102081
DEPTOR GeneProduct ensembl:ENSG00000155792
TELO2 GeneProduct ensembl:ENSG00000100726
RPTOR GeneProduct ensembl:ENSG00000141564
MLST8 GeneProduct ensembl:ENSG00000167965
MTOR GeneProduct ensembl:ENSG00000198793
PIK3CB GeneProduct ensembl:ENSG00000051382
TTI1 GeneProduct ensembl:ENSG00000101407
RHEB GeneProduct ensembl:ENSG00000106615
HOMER1 GeneProduct ensembl:ENSG00000152413 Long homer variant
GRM1 GeneProduct ensembl:ENSG00000152822
PDK1 GeneProduct ensembl:ENSG00000152256
AGAP2 GeneProduct ensembl:ENSG00000135439
PTEN GeneProduct ensembl:ENSG00000171862
TSC1 GeneProduct ensembl:ENSG00000165699
AKT1 GeneProduct ensembl:ENSG00000142208
TSC2 GeneProduct ensembl:ENSG00000103197
TBC1D7 GeneProduct ensembl:ENSG00000145979
DLGAP3 GeneProduct ensembl:ENSG00000116544 SAP90/PSD-95-associated protein 3 (SAPAP3) plays a role in the organization of synapses and neuronal cell signaling and is negatively regulated by FMRP. SAPAP3 is a postsynaptic scaffolding protein which is associated with PSD-95 and localized in dendrites. SAPAP3 plays an improtant role in maturation of synapses
SHANK1 GeneProduct ensembl:ENSG00000161681 Shank, an adapter protein in the PSD of excitatory synapses, is necessary for the structural and functional integrity of dendritic spines and synaptic junction.
GRIN2B GeneProduct ensembl:ENSG00000273079
GRIN2B GeneProduct ensembl:ENSG00000273079 Glutamate receptor ionotropic, NMDA 2B (GluN2B) is a subunit of the NMDAR receptor which is negatively regulated by FMRP.
CPT1A GeneProduct ensembl:ENSG00000110090 CPT1A encodes the hepatic enzyme carnitine palmitoyltransferase 1A. The enzyme is responsible for fatty acid oxidation within the mitochondria, it connects carnitine to long-chain fatty acids thereby enabling the crossing of the fatty acid into the inner membrane of mitochondria. FMRP negatively regulates CPT1A and thus lipid metabolism.
SLC16A1 GeneProduct ensembl:ENSG00000155380 Monocarboxylate transporter 1 (MCT1) is a proton coupled monocarboxylate transporter which function is to catalyse the rapid transport of many monocarboxylates across the plasma membrane.
ALDH3A2 GeneProduct ensembl:ENSG00000072210 Fatty aldehyde dehydrogenase (ALDH3A2) catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acids. ALDH3A2 has shown to be essential for the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation.
ABCD3 GeneProduct ensembl:ENSG00000117528 ABCD3, a peroxisomal membrane protein, is involved in the transport of branched chain acyl-CoA into peroxisomes. ABCD3 is a fatty acid (FA) transporter protein.
TECR GeneProduct ensembl:ENSG00000099797 Very-long-chain enoyl-CoA reductase (TECR) is responsible to catalyze the last of the four reactions of the long-chain fatty acids elongation cycle.
PRKAR1A GeneProduct ensembl:ENSG00000108946
GRIA1 GeneProduct ensembl:ENSG00000155511 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) are ionotropic glutamate transmembrane receptors that mediate the majority of fast excitatory transmission in the central nervous system (CNS).
GRIA1 GeneProduct ensembl:ENSG00000155511 AMPAR subunit GuA1
GRIA2 GeneProduct ensembl:ENSG00000120251 AMPAR subunit GluA2
SH3GL1 GeneProduct ensembl:ENSG00000141985 Endophoilin 2
DNM2 GeneProduct ensembl:ENSG00000079805 Dynamin is a large GTPase modulating release of endosomes from the membrane by pinching off and fissioning the membrane.
EIF4A1 GeneProduct ensembl:ENSG00000161960
TARBP2 GeneProduct ensembl:ENSG00000139546
EIF4EBP2 GeneProduct ensembl:ENSG00000148730 Phosphorylated 4E-BP cannot bind to eIF4E anymore, this means that its inhibitory effect on translation is repressed
MECP2 GeneProduct ensembl:ENSG00000169057 Methyl-CpG-binding protein 2 (MECP2) is a nuclear protein that is capable of binding to methylated DNA. It is essential for nerve cell functionality.
EPHA4 GeneProduct ensembl:ENSG00000116106 Ephrin type-A receptor 4 (EPHA4) is a receptor tyrosine kinase binding tp ephrin ligands. EPHA4 is has a function in the development of the nervous system.
GRIN2A GeneProduct ensembl:ENSG00000183454 NMDA receptor subunit 2 A
CDKN2A GeneProduct ensembl:ENSG00000147889 Cyclin-dependent kinase inhibitor 2A (CDKC2A)
HOXB8 GeneProduct ensembl:ENSG00000120068
BRAF GeneProduct ensembl:ENSG00000157764
ARAF GeneProduct ensembl:ENSG00000078061
SH3GL3 GeneProduct ensembl:ENSG00000140600 Endopilin 3
PRKACA GeneProduct ensembl:ENSG00000072062 Exact subunits which make up PKA in thus pathway could not be found. PKA is made up of 2 regulary subunits and 2 catalytic subunits. Because no information on the composition of subunits in this case could have been found, subunits A have been used for regulatory and catalytic parts of PKA.
APP GeneProduct ensembl:ENSG00000142192 Amyloid-beta precursor protein (APP), large membrane-spanning glycoprotein, is implicated in neurogenesis and synapse formation. It is mainly expressed in synapses. APP is suspected to contribute to altered mGluR-LTD.
GRIN2B GeneProduct ensembl:ENSG00000273079 N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDAR) are ionotropic receptors activated by glutamate. NMDAR activation allows Ca2+ influx leading to NMDAR-dependant LTP and LTD
CLTC GeneProduct ensembl:ENSG00000141367 Clathrin mediates the endocytosis of NMDAR by binding to AP-2
PTEN GeneProduct ensembl:ENSG00000171862 PTEN is enhanced by FMRP and negatively regulates GABA A receptor subunits, this way PTEN has a protective role in reducing GABA A deficiency-indiced incidence of seizures
GRIN1 GeneProduct ensembl:ENSG00000176884
DUSP3 GeneProduct ensembl:ENSG00000108861 Also referred to as VHR, a ERK specific phosphatase
EEF1A1 GeneProduct ensembl:ENSG00000156508 Eukarytic translation elongation factor (EF1α)
HCN1 GeneProduct ensembl:ENSG00000164588 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1)
KCNC1 GeneProduct ensembl:ENSG00000129159
KCND2 GeneProduct ensembl:ENSG00000184408
MMP9 GeneProduct ensembl:ENSG00000100985
PRKCA GeneProduct ensembl:ENSG00000154229 Protein Kinase C
mGluR activation leads to activation of the PLC pathway which induces release of Ca2+ and PKC. PKC will phohsphorylate and activate RAF1 and tehereby activate RAF1 and thus the ERK pathway
RAP1GAP GeneProduct ensembl:ENSG00000076864 RAP1 is phsohprylated and activated by PKA and in turn stimulates the activation of B-Raf, thus leading to the activation of the ERK pathway
EPS8L1 GeneProduct ensembl:ENSG00000131037 Epidermal growth factor receptor pathway substrate 8-related protein 1 (EPS8L1) is an FMRP target and important for teh remodelling of actin in response to EGF stimulation. EPS8L1 gene product EPS8 is needed for normal spine morphology, synaptic plasticity, and memory formation. EPS8 has been shown to be downregulated in autism, since it's a binding partner of FMRP, it is likely that it is also downregulated in FXS.
PTPN5 GeneProduct ensembl:ENSG00000110786 Tyrosine-protein phosphatase non-receptor type 5 (STEP) is involves to regulate AMPAR trafficking and negatively regulates AMPAR surface expression thereby contributing to mGluR-LTD. STEP promotes LTD by stimulating synaptic weakening by dephosphorylation of ERK1/2 and subunits of NDMA and AMPA receptors. STEP has been shown to promote NMDA internalization.
MAP1B GeneProduct ensembl:ENSG00000131711 Microtubule-associated protein 1B (MAP1B) is involved in mcirotubule assembly and neurogenesis. MAP1b is involved in the regulation of the morphology of dendritic spines in glutamatergic synapses. Furthermore, MAP1b is a negative regulator of AMPAR surface expression thereby contributing to mGluR-LTD.
MAPB1 Protein uniprot:Q9GZQ8
Dynamin-1 Protein uniprot:A0A0D9SFB1
GABRD Protein ensembl:ENSG00000187730

References

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