Fragile X syndrome (Homo sapiens)
From WikiPathways
Description
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.
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Bibliography
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History
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External references
DataNodes
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Name | Type | Database reference | Comment |
---|---|---|---|
ABAT | Rna | ENSG00000183044 (Ensembl) | |
ABCD3 | GeneProduct | ENSG00000117528 (Ensembl) | 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. |
AGAP2 | GeneProduct | ENSG00000135439 (Ensembl) | |
AGO2 | GeneProduct | ENSG00000123908 (Ensembl) | |
AKAP5 | GeneProduct | ENSG00000179841 (Ensembl) | 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. |
AKT1 | GeneProduct | ENSG00000142208 (Ensembl) | |
AKT1S1 | GeneProduct | ENSG00000204673 (Ensembl) | |
ALDH3A2 | GeneProduct | ENSG00000072210 (Ensembl) | 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. |
ALDH5A1 | Rna | ENSG00000112294 (Ensembl) | |
AP2A1 | GeneProduct | ENSG00000196961 (Ensembl) | |
AP2B1 | GeneProduct | ENSG00000006125 (Ensembl) | |
AP2M1 | GeneProduct | ENSG00000161203 (Ensembl) | |
AP2S1 | GeneProduct | ENSG00000042753 (Ensembl) | |
APP | GeneProduct | ENSG00000142192 (Ensembl) |
|
ARAF | GeneProduct | ENSG00000078061 (Ensembl) | |
ARC | GeneProduct | ENSG00000198576 (Ensembl) | 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. |
ARHGAP32 | GeneProduct | ENSG00000134909 (Ensembl) | 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. |
BDNF-TrkB Signalling | Pathway | WP3676 (WikiPathways) | |
BDNF | GeneProduct | ENSG00000176697 (Ensembl) | |
BRAF | GeneProduct | ENSG00000157764 (Ensembl) | |
CAMK1 | GeneProduct | ENSG00000134072 (Ensembl) | |
CAMK2A | GeneProduct | ENSG00000070808 (Ensembl) | 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. |
CAMK2B | GeneProduct | ENSG00000058404 (Ensembl) | CAMKII catalyzes the phosphorylation of AMPAR an |
CAMK4 | GeneProduct | ENSG00000152495 (Ensembl) | CAMK4 or CAMKIV |
CAMKIV-CREB Pathway | Pathway | ||
CDKN2A | GeneProduct | ENSG00000147889 (Ensembl) | Cyclin-dependent kinase inhibitor 2A (CDKC2A) |
CLTA | GeneProduct | ENSG00000122705 (Ensembl) | |
CLTB | GeneProduct | ENSG00000175416 (Ensembl) | |
CLTC | GeneProduct | ENSG00000141367 (Ensembl) | Clathrin mediates the endocytosis of NMDAR by binding to AP-2 |
CLTCL1 | GeneProduct | ENSG00000070371 (Ensembl) | |
CNR1 | GeneProduct | ENSG00000118432 (Ensembl) | |
CPT1A | GeneProduct | ENSG00000110090 (Ensembl) | 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. |
CREB1 | GeneProduct | ENSG00000118260 (Ensembl) | |
CYFIP1 | GeneProduct | ENSG00000273749 (Ensembl) | CYFIP1 interacts with FMRP and with translation initiation factor eIF4E |
CYFIP2 | Rna | ENSG00000055163 (Ensembl) | |
DAG1 | GeneProduct | ENSG00000173402 (Ensembl) | |
DEPTOR | GeneProduct | ENSG00000155792 (Ensembl) | |
DICER1 | GeneProduct | ENSG00000100697 (Ensembl) | DICER, is an endonuclease, which cleaves double stranded RNA (dsRNA) into short single stranded RNA called miRNA and tehreby faciliates the activation of RISC |
DLG4 | Rna | ENSG00000132535 (Ensembl) | |
DLGAP3 | GeneProduct | ENSG00000116544 (Ensembl) | 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 |
DNM2 | GeneProduct | ENSG00000079805 (Ensembl) | Dynamin is a large GTPase modulating release of endosomes from the membrane by pinching off and fissioning the membrane. |
DUSP3 | GeneProduct | ENSG00000108861 (Ensembl) | Also referred to as VHR, a ERK specific phosphatase |
Dynamin-1 | Protein | A0A0D9SFB1 (Uniprot-TrEMBL) | |
EEF1A1 | GeneProduct | ENSG00000156508 (Ensembl) | Eukarytic translation elongation factor (EF1α) |
EIF4A1 | GeneProduct | ENSG00000161960 (Ensembl) | |
EIF4EBP2 | GeneProduct | ENSG00000148730 (Ensembl) | Phosphorylated 4E-BP cannot bind to eIF4E anymore, this means that its inhibitory effect on translation is repressed |
EIF4E | GeneProduct | ENSG00000151247 (Ensembl) | |
EIF4G1 | GeneProduct | ENSG00000114867 (Ensembl) | |
EPHA4 | GeneProduct | ENSG00000116106 (Ensembl) | 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. |
EPS8L1 | GeneProduct | ENSG00000131037 (Ensembl) | 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. |
FMR1 | GeneProduct | ENSG00000102081 (Ensembl) | |
FYN | GeneProduct | ENSG00000010810 (Ensembl) | Tyrosine-protein kinase Fyn (FYN) is a member of the Src family of tyrosine kinases which is involved in the regulation of brain function. |
GAB1 | GeneProduct | ENSG00000109458 (Ensembl) | |
GABRA1 | Rna | ENSG00000022355 (Ensembl) | |
GABRB2 | Rna | ENSG00000145864 (Ensembl) | |
GABRD | Protein | ENSG00000187730 (Ensembl) | |
GABRG2 | Rna | ENSG00000113327 (Ensembl) | |
GAD1 | GeneProduct | ENSG00000128683 (Ensembl) | 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. |
GPHN | Rna | ENSG00000171723 (Ensembl) | |
GRB2 | GeneProduct | ENSG00000177885 (Ensembl) | |
GRIA1 | GeneProduct | ENSG00000155511 (Ensembl) | AMPAR subunit GuA1 |
GRIA2 | GeneProduct | ENSG00000120251 (Ensembl) | AMPAR subunit GluA2 |
GRIN1 | GeneProduct | ENSG00000176884 (Ensembl) | |
GRIN2A | GeneProduct | ENSG00000183454 (Ensembl) | NMDA receptor subunit 2 A |
GRIN2B | GeneProduct | ENSG00000273079 (Ensembl) | 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 |
GRIP1 | GeneProduct | ENSG00000155974 (Ensembl) | |
GRIP2 | GeneProduct | ENSG00000144596 (Ensembl) | Glutamate receptor-interacting protein 2 (GRIP2) also called AMPAR binding protein (ABP) interacts with GRIP1 to regulate AMPAR trafficking |
GRM1 | GeneProduct | ENSG00000152822 (Ensembl) | |
GRM5 | Rna | ENSG00000168959 (Ensembl) | |
HCN1 | GeneProduct | ENSG00000164588 (Ensembl) | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) |
HOMER1 | GeneProduct | ENSG00000152413 (Ensembl) | Long homer variant |
HOXB8 | GeneProduct | ENSG00000120068 (Ensembl) | |
ITPR1 | GeneProduct | ENSG00000150995 (Ensembl) | |
KCNC1 | GeneProduct | ENSG00000129159 (Ensembl) | |
KCND2 | GeneProduct | ENSG00000184408 (Ensembl) | |
KRAS | GeneProduct | ENSG00000133703 (Ensembl) | |
MAP1B | GeneProduct | ENSG00000131711 (Ensembl) | 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. |
MAP2K1 | GeneProduct | ENSG00000169032 (Ensembl) | |
MAP2K2 | GeneProduct | ENSG00000126934 (Ensembl) | |
MAPB1 | Protein | Q9GZQ8 (Uniprot-TrEMBL) | |
MAPK1 | GeneProduct | ENSG00000100030 (Ensembl) | |
MECP2 | GeneProduct | ENSG00000169057 (Ensembl) | 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. |
MEK-ERK-Mnk1 Pathway | Pathway | map04010 (KEGG Pathway) | Activation of ERK pathway is required for mGlur-LTD. ERK activation is thought to control the activation of specific mRNAs such as the LTD proteins. |
MKNK1 | GeneProduct | ENSG00000079277 (Ensembl) | |
MLST8 | GeneProduct | ENSG00000167965 (Ensembl) | |
MMP9 | GeneProduct | ENSG00000100985 (Ensembl) | |
MTOR | GeneProduct | ENSG00000198793 (Ensembl) | |
NF1 | GeneProduct | ENSG00000196712 (Ensembl) | 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. |
NTRK2 | GeneProduct | ENSG00000148053 (Ensembl) | |
PDK1 | GeneProduct | ENSG00000152256 (Ensembl) | |
PI3K-Akt-mTOR
Pathway | Pathway | WP4172 (WikiPathways) | Activation of mTOR pathway is required for mGlur-LTD. mTOR activation is believed to sustain the increase in overall rate of mRNA translation at the synapse. |
PICK1 | GeneProduct | ENSG00000100151 (Ensembl) | Protein Interacting with Kinase C 1 (PICK1) |
PIK3CB | GeneProduct | ENSG00000051382 (Ensembl) | |
PIP2 | Metabolite | CHEBI:18348 (ChEBI) | |
PIP3 | Metabolite | CHEBI:16618 (ChEBI) | |
PLCB1 | GeneProduct | ENSG00000182621 (Ensembl) | |
PLCG1 | GeneProduct | ENSG00000124181 (Ensembl) | |
PPP1CA | GeneProduct | ENSG00000172531 (Ensembl) | 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. |
PPP2R5B | GeneProduct | ENSG00000068971 (Ensembl) | |
PPP3CA | GeneProduct | ENSG00000138814 (Ensembl) | Calcineurin |
PRKACA | GeneProduct | ENSG00000072062 (Ensembl) | |
PRKAR1A | GeneProduct | ENSG00000108946 (Ensembl) | |
PRKCA | GeneProduct | ENSG00000154229 (Ensembl) |
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PTEN | Rna | ENSG00000171862 (Ensembl) | 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 |
PTPN11 | GeneProduct | ENSG00000179295 (Ensembl) | |
PTPN5 | GeneProduct | ENSG00000110786 (Ensembl) | 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. |
RAF1 | GeneProduct | ENSG00000132155 (Ensembl) | |
RAP1GAP | GeneProduct | ENSG00000076864 (Ensembl) | 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 |
RHEB | GeneProduct | ENSG00000106615 (Ensembl) | |
RPS6KB1 | GeneProduct | ENSG00000108443 (Ensembl) | |
RPTOR | GeneProduct | ENSG00000141564 (Ensembl) | |
SH3GL1 | GeneProduct | ENSG00000141985 (Ensembl) | Endophoilin 2 |
SH3GL3 | GeneProduct | ENSG00000140600 (Ensembl) | Endopilin 3 |
SHANK1 | GeneProduct | ENSG00000161681 (Ensembl) | Shank, an adapter protein in the PSD of excitatory synapses, is necessary for the structural and functional integrity of dendritic spines and synaptic junction. |
SHC1 | GeneProduct | ENSG00000160691 (Ensembl) | |
SLC16A1 | GeneProduct | ENSG00000155380 (Ensembl) | 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. |
SLC6A1 | Rna | ENSG00000157103 (Ensembl) | |
SOS1 | GeneProduct | ENSG00000115904 (Ensembl) | SOS, a guanine-associated echange factor (GEF), activates Ras by inducing the exchange of GTDP by GTP. This positively regulates Ras signalling. |
SRC | GeneProduct | ENSG00000197122 (Ensembl) | |
SYNGAP1 | GeneProduct | ENSG00000197283 (Ensembl) | |
TARBP2 | GeneProduct | ENSG00000139546 (Ensembl) | |
TBC1D7 | GeneProduct | ENSG00000145979 (Ensembl) | |
TECR | GeneProduct | ENSG00000099797 (Ensembl) | 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. |
TELO2 | GeneProduct | ENSG00000100726 (Ensembl) | |
TSC1 | GeneProduct | ENSG00000165699 (Ensembl) | |
TSC2 | GeneProduct | ENSG00000103197 (Ensembl) | |
TTI1 | GeneProduct | ENSG00000101407 (Ensembl) | |
cAMP | Metabolite | CHEBI:17489 (ChEBI) | |
endocannabinoids | Metabolite | CHEBI:67197 (ChEBI) | |
glutamate | Metabolite | CHEBI:14321 (ChEBI) | |
miR-125b | Rna | MIMAT0042091 (miRBase mature sequence) | |
miR-132 | Rna | MIMAT0004594 (miRBase mature sequence) | |
miR-196a | Rna | MIMAT0000226 (miRBase mature sequence) | |
γ-aminobutyric acid | Metabolite | CHEBI:16865 (ChEBI) | γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. |
Annotated Interactions
No annotated interactions