General Information of Drug Off-Target (DOT) (ID: OTAKK1SV)

DOT Name Gephyrin (GPHN)
Gene Name GPHN
Related Disease
X-linked intellectual disability ( )
Acute monocytic leukemia ( )
Adenoma ( )
Adult T-cell leukemia/lymphoma ( )
Alcohol dependence ( )
Alcohol use disorder ( )
Alzheimer disease ( )
Attention deficit hyperactivity disorder ( )
Autism ( )
Autism spectrum disorder ( )
Cocaine addiction ( )
Dravet syndrome ( )
Epilepsy, idiopathic generalized ( )
Hyperekplexia ( )
leukaemia ( )
Leukemia ( )
Lung adenocarcinoma ( )
Lung squamous cell carcinoma ( )
Major depressive disorder ( )
Molybdenum cofactor deficiency ( )
Neurodevelopmental disorder ( )
Pervasive developmental disorder ( )
Schizophrenia ( )
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C ( )
Epilepsy ( )
Hereditary hyperekplexia ( )
Advanced cancer ( )
Anxiety ( )
Anxiety disorder ( )
Breast cancer ( )
Breast carcinoma ( )
UniProt ID
GEPH_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
1JLJ
EC Number
2.10.1.1; 2.7.7.75
Pfam ID
PF00994 ; PF03454 ; PF03453
Sequence
MATEGMILTNHDHQIRVGVLTVSDSCFRNLAEDRSGINLKDLVQDPSLLGGTISAYKIVP
DEIEEIKETLIDWCDEKELNLILTTGGTGFAPRDVTPEATKEVIEREAPGMALAMLMGSL
NVTPLGMLSRPVCGIRGKTLIINLPGSKKGSQECFQFILPALPHAIDLLRDAIVKVKEVH
DELEDLPSPPPPLSPPPTTSPHKQTEDKGVQCEEEEEEKKDSGVASTEDSSSSHITAAAI
AAKIPDSIISRGVQVLPRDTASLSTTPSESPRAQATSRLSTASCPTPKVQSRCSSKENIL
RASHSAVDITKVARRHRMSPFPLTSMDKAFITVLEMTPVLGTEIINYRDGMGRVLAQDVY
AKDNLPPFPASVKDGYAVRAADGPGDRFIIGESQAGEQPTQTVMPGQVMRVTTGAPIPCG
ADAVVQVEDTELIRESDDGTEELEVRILVQARPGQDIRPIGHDIKRGECVLAKGTHMGPS
EIGLLATVGVTEVEVNKFPVVAVMSTGNELLNPEDDLLPGKIRDSNRSTLLATIQEHGYP
TINLGIVGDNPDDLLNALNEGISRADVIITSGGVSMGEKDYLKQVLDIDLHAQIHFGRVF
MKPGLPTTFATLDIDGVRKIIFALPGNPVSAVVTCNLFVVPALRKMQGILDPRPTIIKAR
LSCDVKLDPRPEYHRCILTWHHQEPLPWAQSTGNQMSSRLMSMRSANGLLMLPPKTEQYV
ELHKGEVVDVMVIGRL
Function
Microtubule-associated protein involved in membrane protein-cytoskeleton interactions. It is thought to anchor the inhibitory glycine receptor (GLYR) to subsynaptic microtubules. Acts as a major instructive molecule at inhibitory synapses, where it also clusters GABA type A receptors ; Has also a catalytic activity and catalyzes two steps in the biosynthesis of the molybdenum cofactor. In the first step, molybdopterin is adenylated. Subsequently, molybdate is inserted into adenylated molybdopterin and AMP is released.
KEGG Pathway
Folate biosynthesis (hsa00790 )
Metabolic pathways (hsa01100 )
Biosynthesis of cofactors (hsa01240 )
GABAergic sy.pse (hsa04727 )
Reactome Pathway
Molybdenum cofactor biosynthesis (R-HSA-947581 )
BioCyc Pathway
MetaCyc:ENSG00000171723-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
X-linked intellectual disability DISYJBY3 Definitive Genetic Variation [1]
Acute monocytic leukemia DIS28NEL Strong Genetic Variation [2]
Adenoma DIS78ZEV Strong Altered Expression [3]
Adult T-cell leukemia/lymphoma DIS882XU Strong Genetic Variation [4]
Alcohol dependence DIS4ZSCO Strong Biomarker [5]
Alcohol use disorder DISMB65Y Strong Biomarker [5]
Alzheimer disease DISF8S70 Strong Genetic Variation [6]
Attention deficit hyperactivity disorder DISL8MX9 Strong Genetic Variation [7]
Autism DISV4V1Z Strong Biomarker [8]
Autism spectrum disorder DISXK8NV Strong Genetic Variation [6]
Cocaine addiction DISHTRXG Strong Biomarker [5]
Dravet syndrome DISJF7LY Strong Genetic Variation [9]
Epilepsy, idiopathic generalized DISODZC9 Strong Genetic Variation [10]
Hyperekplexia DISY3CG8 Strong Biomarker [11]
leukaemia DISS7D1V Strong Biomarker [12]
Leukemia DISNAKFL Strong Biomarker [12]
Lung adenocarcinoma DISD51WR Strong Biomarker [13]
Lung squamous cell carcinoma DISXPIBD Strong Altered Expression [13]
Major depressive disorder DIS4CL3X Strong Genetic Variation [14]
Molybdenum cofactor deficiency DISKS8QN Strong Genetic Variation [15]
Neurodevelopmental disorder DIS372XH Strong Genetic Variation [16]
Pervasive developmental disorder DIS51975 Strong Genetic Variation [10]
Schizophrenia DISSRV2N Strong Genetic Variation [6]
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C DISFZ9C9 Strong Autosomal recessive [17]
Epilepsy DISBB28L moderate Genetic Variation [18]
Hereditary hyperekplexia DIS9YXFE Supportive Autosomal dominant [19]
Advanced cancer DISAT1Z9 Limited Biomarker [16]
Anxiety DISIJDBA Limited Biomarker [20]
Anxiety disorder DISBI2BT Limited Biomarker [20]
Breast cancer DIS7DPX1 Limited Biomarker [21]
Breast carcinoma DIS2UE88 Limited Biomarker [21]
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⏷ Show the Full List of 31 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
13 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of Gephyrin (GPHN). [22]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Gephyrin (GPHN). [23]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Gephyrin (GPHN). [24]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Gephyrin (GPHN). [25]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Gephyrin (GPHN). [26]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Gephyrin (GPHN). [27]
Testosterone DM7HUNW Approved Testosterone decreases the expression of Gephyrin (GPHN). [28]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Gephyrin (GPHN). [29]
Bortezomib DMNO38U Approved Bortezomib decreases the expression of Gephyrin (GPHN). [31]
Fenofibrate DMFKXDY Approved Fenofibrate increases the expression of Gephyrin (GPHN). [32]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Gephyrin (GPHN). [33]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Gephyrin (GPHN). [23]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Gephyrin (GPHN). [34]
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⏷ Show the Full List of 13 Drug(s)
3 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Fulvestrant DM0YZC6 Approved Fulvestrant increases the methylation of Gephyrin (GPHN). [30]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of Gephyrin (GPHN). [35]
Coumarin DM0N8ZM Investigative Coumarin affects the phosphorylation of Gephyrin (GPHN). [35]
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References

1 Collybistin splice variants differentially interact with gephyrin and Cdc42 to regulate gephyrin clustering at GABAergic synapses.J Cell Sci. 2011 Aug 15;124(Pt 16):2786-96. doi: 10.1242/jcs.086199.
2 t(11;14)(q23;q24) generates an MLL-human gephyrin fusion gene along with a de facto truncated MLL in acute monoblastic leukemia.Cancer Res. 2001 Mar 15;61(6):2665-9.
3 Follicle stimulating hormone-beta subunit gene is expressed in parallel with a transcription factor Ad4BP/SF-1 in human pituitary adenomas.Clin Endocrinol (Oxf). 1996 Aug;45(2):187-93. doi: 10.1046/j.1365-2265.1996.d01-1555.x.
4 Rapid isolation of viral integration site reveals frequent integration of HTLV-1 into expressed loci.J Hum Genet. 2004;49(3):154-165. doi: 10.1007/s10038-004-0126-7. Epub 2004 Feb 26.
5 GABAergic gene expression in postmortem hippocampus from alcoholics and cocaine addicts; corresponding findings in alcohol-nave P and NP rats.PLoS One. 2012;7(1):e29369. doi: 10.1371/journal.pone.0029369. Epub 2012 Jan 13.
6 Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions.Neuroscience. 2020 Jul 15;439:125-136. doi: 10.1016/j.neuroscience.2019.07.036. Epub 2019 Jul 26.
7 A novel maternally inherited 8q24.3 and a rare paternally inherited 14q23.3 CNVs in a family with neurodevelopmental disorders.Am J Med Genet A. 2015 Aug;167A(8):1921-6. doi: 10.1002/ajmg.a.37110. Epub 2015 Apr 10.
8 Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses.Elife. 2016 Nov 2;5:e19236. doi: 10.7554/eLife.19236.
9 Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy.EMBO Mol Med. 2015 Dec;7(12):1580-94. doi: 10.15252/emmm.201505323.
10 Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy.Neurobiol Dis. 2014 Jul;67:88-96. doi: 10.1016/j.nbd.2014.02.001. Epub 2014 Feb 19.
11 Molybdenum cofactor deficiency presenting as neonatal hyperekplexia: a clinical, biochemical and genetic study.Neuropediatrics. 2005 Dec;36(6):389-94. doi: 10.1055/s-2005-872877.
12 The small oligomerization domain of gephyrin converts MLL to an oncogene.Blood. 2004 May 15;103(10):3876-82. doi: 10.1182/blood-2003-11-3817. Epub 2004 Jan 29.
13 Gephyrin suppresses lung squamous cell carcinoma development by reducing mTOR pathway activation.Cancer Manag Res. 2019 Jun 7;11:5333-5341. doi: 10.2147/CMAR.S204358. eCollection 2019.
14 GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores.Am J Psychiatry. 2019 Aug 1;176(8):651-660. doi: 10.1176/appi.ajp.2019.18080957. Epub 2019 Jun 5.
15 Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures.Hum Mol Genet. 2013 May 15;22(10):2055-66. doi: 10.1093/hmg/ddt056. Epub 2013 Feb 7.
16 The FRA14B common fragile site maps to a region prone to somatic and germline rearrangements within the large GPHN gene.Genes Chromosomes Cancer. 2019 May;58(5):284-294. doi: 10.1002/gcc.22706. Epub 2018 Dec 20.
17 A mutation in the gene for the neurotransmitter receptor-clustering protein gephyrin causes a novel form of molybdenum cofactor deficiency. Am J Hum Genet. 2001 Jan;68(1):208-13. doi: 10.1086/316941. Epub 2000 Nov 28.
18 ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation.Neurogenetics. 2018 Jan;19(1):9-16. doi: 10.1007/s10048-017-0528-2. Epub 2017 Nov 13.
19 Hereditary Hyperekplexia Overview. 2007 Jul 31 [updated 2019 Dec 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
20 A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation.Hum Mutat. 2009 Jan;30(1):61-8. doi: 10.1002/humu.20814.
21 Her2-Functionalized Gold-Nanoshelled Magnetic Hybrid Nanoparticles: a Theranostic Agent for Dual-Modal Imaging and Photothermal Therapy of Breast Cancer.Nanoscale Res Lett. 2019 Aug 26;14(1):235. doi: 10.1186/s11671-019-3053-4.
22 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
23 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
24 Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
25 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
26 The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
27 Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
28 The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
29 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
30 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
31 The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
32 Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
33 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
34 Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
35 Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.