Details of Drug Off-Target (DOT)

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

• DOT Name: Oligophrenin-1 (OPHN1)
• Gene Name: OPHN1
• Related Disease: X-linked intellectual disability-cerebellar hypoplasia syndrome
• UniProt ID: OPHN1_HUMAN
• Pfam ID: PF16746 ; PF00169 ; PF00620
• Sequence:
  MGHPPLEFSDCYLDSPDFRERLKCYEQELERTNKFIKDVIKDGNALISAMRNYSSAVQKF
  SQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLNEVENERMMMVHNASDLLIKPLENFR
  KEQIGFTKERKKKFEKDGERFYSLLDRHLHLSSKKKESQLQEADLQVDKERHNFFESSLD
  YVYQIQEVQESKKFNIVEPVLAFLHSLFISNSLTVELTQDFLPYKQQLQLSLQNTRNHFS
  STREEMEELKKRMKEAPQTCKLPGQPTIEGYLYTQEKWALGISWVKYYCQYEKETKTLTM
  TPMEQKPGAKQGPLDLTLKYCVRRKTESIDKRFCFDIETNERPGTITLQALSEANRRLWM
  EAMDGKEPIYHSPITKQQEMELNEVGFKFVRKCINIIETKGIKTEGLYRTVGSNIQVQKL
  LNAFFDPKCPGDVDFHNSDWDIKTITSSLKFYLRNLSEPVMTYRLHKELVSAAKSDNLDY
  RLGAIHSLVYKLPEKNREMLELLIRHLVNVCEHSKENLMTPSNMGVIFGPTLMRAQEDTV
  AAMMNIKFQNIVVEILIEHFGKIYLGPPEESAAPPVPPPRVTARRHKPITISKRLLRERT
  VFYTSSLDESEDEIQHQTPNGTITSSIEPPKPPQHPKLPIQRSGETDPGRKSPSRPILDG
  KLEPCPEVDVGKLVSRLQDGGTKITPKATNGPMPGSGPTKTPSFHIKRPAPRPLAHHKEG
  DADSFSKVRPPGEKPTIIRPPVRPPDPPCRAATPQKPEPKPDIVAGNAGEITSSVVASRT
  RFFETASRKTGSSQGRLPGDES
• Function: Stimulates GTP hydrolysis of members of the Rho family. Its action on RHOA activity and signaling is implicated in growth and stabilization of dendritic spines, and therefore in synaptic function. Critical for the stabilization of AMPA receptors at postsynaptic sites. Critical for the regulation of synaptic vesicle endocytosis at presynaptic terminals. Required for the localization of NR1D1 to dendrites, can suppress its repressor activity and protect it from proteasomal degradation.
• Tissue Specificity: Expressed in brain.
• Reactome Pathway:
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOG GTPase cycle (R-HSA-9013408)
  RHOJ GTPase cycle (R-HSA-9013409)
  RAC3 GTPase cycle (R-HSA-9013423)
  RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked intellectual disability-cerebellar hypoplasia syndrome	DISVOJFH	Definitive	X-linked	[1]

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Oligophrenin-1 (OPHN1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Oligophrenin-1 (OPHN1).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Oligophrenin-1 (OPHN1).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Oligophrenin-1 (OPHN1).	[5]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Oligophrenin-1 (OPHN1).	[5]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Oligophrenin-1 (OPHN1).	[6]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Oligophrenin-1 (OPHN1).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Oligophrenin-1 (OPHN1).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Oligophrenin-1 (OPHN1).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Oligophrenin-1 (OPHN1).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Oligophrenin-1 (OPHN1).	[12]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Oligophrenin-1 (OPHN1).	[9]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [3] 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.
• [4] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [5] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [6] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [7] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [8] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.