Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQNB4KI)

• DOT Name: CSC1-like protein 2 (TMEM63B)
• Synonyms: Transmembrane protein 63B
• Gene Name: TMEM63B
• Related Disease:
  Diabetic retinopathy
  Advanced cancer
  Complex neurodevelopmental disorder
• UniProt ID: CSCL2_HUMAN
• PDB ID: 8EHX
• Pfam ID: PF14703 ; PF02714 ; PF13967
• Sequence:
  MLPFLLATLGTTALNNSNPKDYCYSARIRSTVLQGLPFGGVPTVLALDFMCFLALLFLFS
  ILRKVAWDYGRLALVTDADRLRRQERDRVEQEYVASAMHGDSHDRYERLTSVSSSVDFDQ
  RDNGFCSWLTAIFRIKDDEIRDKCGGDAVHYLSFQRHIIGLLVVVGVLSVGIVLPVNFSG
  DLLENNAYSFGRTTIANLKSGNNLLWLHTSFAFLYLLLTVYSMRRHTSKMRYKEDDLVKR
  TLFINGISKYAESEKIKKHFEEAYPNCTVLEARPCYNVARLMFLDAERKKAERGKLYFTN
  LQSKENVPTMINPKPCGHLCCCVVRGCEQVEAIEYYTKLEQKLKEDYKREKEKVNEKPLG
  MAFVTFHNETITAIILKDFNVCKCQGCTCRGEPRPSSCSESLHISNWTVSYAPDPQNIYW
  EHLSIRGFIWWLRCLVINVVLFILLFFLTTPAIIITTMDKFNVTKPVEYLNNPIITQFFP
  TLLLWCFSALLPTIVYYSAFFEAHWTRSGENRTTMHKCYTFLIFMVLLLPSLGLSSLDLF
  FRWLFDKKFLAEAAIRFECVFLPDNGAFFVNYVIASAFIGNAMDLLRIPGLLMYMIRLCL
  ARSAAERRNVKRHQAYEFQFGAAYAWMMCVFTVVMTYSITCPIIVPFGLMYMLLKHLVDR
  YNLYYAYLPAKLDKKIHSGAVNQVVAAPILCLFWLLFFSTMRTGFLAPTSMFTFVVLVIT
  IVICLCHVCFGHFKYLSAHNYKIEHTETDTVDPRSNGRPPTAAAVPKSAKYIAQVLQDSE
  VDGDGDGAPGSSGDEPPSSSSQDEELLMPPDALTDTDFQSCEDSLIENEIHQ
• Function: Acts as an osmosensitive calcium-permeable cation channel. Mechanosensitive ion channel that converts mechanical stimuli into a flow of ion. Acts as an inner ear osmosensor, essential for normal hearing and survival of inner ear outer hair cells (OHCs). Mediates calcium-dependent regulatory volume decrease in OHCs which is necessary for their survival. Required for the maintenance of the morphological integrity of OHCs under hypotonic conditions. Mediates hypo-osmolarity-induced calcium influx, leading to activation of calcium-dependent potassium channels required for the maintenance of OHC morphology.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic retinopathy	DISHGUJM	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Complex neurodevelopmental disorder	DISB9AFI	Strong	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of CSC1-like protein 2 (TMEM63B).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of CSC1-like protein 2 (TMEM63B).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of CSC1-like protein 2 (TMEM63B).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of CSC1-like protein 2 (TMEM63B).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of CSC1-like protein 2 (TMEM63B).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of CSC1-like protein 2 (TMEM63B).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of CSC1-like protein 2 (TMEM63B).	[7]

References

• [1] Association of genes on chromosome 6, GRIK2 , TMEM217 and TMEM63B (linked to MRPL14 ) with diabetic retinopathy.Ophthalmologica. 2013;229(1):54-60. doi: 10.1159/000342616. Epub 2012 Sep 28.
• [2] Overexpression of Osmosensitive Ca(2+)-Permeable Channel TMEM63B Promotes Migration in HEK293T Cells.Biochemistry. 2019 Jul 2;58(26):2861-2866. doi: 10.1021/acs.biochem.9b00224. Epub 2019 Jun 20.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [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] 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.