Details of Drug Off-Target (DOT)

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
• 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]

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]

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]

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.