Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF9I3CX)

• DOT Name: Tetraspanin-12 (TSPAN12)
• Synonyms: Tspan-12; Tetraspan NET-2; Transmembrane 4 superfamily member 12
• Gene Name: TSPAN12
• Related Disease:
  TSPAN12-related vitreoretinopathy
  Advanced cancer
  Autism spectrum disorder
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Cystic fibrosis
  Epithelial ovarian cancer
  Exudative vitreoretinopathy 5
  Neoplasm
  Non-small-cell lung cancer
  Osteoporosis-pseudoglioma syndrome
  Ovarian cancer
  Ovarian neoplasm
  Persistent hyperplastic primary vitreous
  Pervasive developmental disorder
  Retinopathy
  Exudative vitreoretinopathy 1
  Meningioma
  Small-cell lung cancer
  Exudative vitreoretinopathy
• UniProt ID: TSN12_HUMAN
• Pfam ID: PF00335
• Sequence:
  MAREDSVKCLRCLLYALNLLFWLMSISVLAVSAWMRDYLNNVLTLTAETRVEEAVILTYF
  PVVHPVMIAVCCFLIIVGMLGYCGTVKRNLLLLAWYFGSLLVIFCVELACGVWTYEQELM
  VPVQWSDMVTLKARMTNYGLPRYRWLTHAWNFFQREFKCCGVVYFTDWLEMTEMDWPPDS
  CCVREFPGCSKQAHQEDLSDLYQEGCGKKMYSFLRGTKQLQVLRFLGISIGVTQILAMIL
  TITLLWALYYDRREPGTDQMMSLKNDNSQHLSCPSVELLKPSLSRIFEHTSMANSFNTHF
  EMEEL
• Function: Regulator of cell surface receptor signal transduction. Plays a central role in retinal vascularization by regulating norrin (NDP) signal transduction. Acts in concert with norrin (NDP) to promote FZD4 multimerization and subsequent activation of FZD4, leading to promote accumulation of beta-catenin (CTNNB1) and stimulate LEF/TCF-mediated transcriptional programs. Suprisingly, it only activates the norrin (NDP)-dependent activation of FZD4, while it does not activate the Wnt-dependent activation of FZD4, suggesting the existence of a Wnt-independent signaling that also promote accumulation the beta-catenin (CTNNB1). Acts as a regulator of membrane proteinases such as ADAM10 and MMP14/MT1-MMP. Activates ADAM10-dependent cleavage activity of amyloid precursor protein (APP). Activates MMP14/MT1-MMP-dependent cleavage activity.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
TSPAN12-related vitreoretinopathy	DISIS7NH	Definitive	Semidominant	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Exudative vitreoretinopathy 5	DISCHKOU	Strong	Autosomal dominant	[6]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Osteoporosis-pseudoglioma syndrome	DISIXWT1	Strong	Genetic Variation	[9]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Persistent hyperplastic primary vitreous	DISABPH6	Strong	Biomarker	[3]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[3]
Retinopathy	DISB4B0F	Strong	Biomarker	[10]
Exudative vitreoretinopathy 1	DISRC9YA	moderate	Genetic Variation	[11]
Meningioma	DISPT4TG	moderate	Biomarker	[12]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[13]
Exudative vitreoretinopathy	DISWN0TG	Supportive	Autosomal dominant	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Tetraspanin-12 (TSPAN12).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tetraspanin-12 (TSPAN12).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tetraspanin-12 (TSPAN12).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tetraspanin-12 (TSPAN12).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Tetraspanin-12 (TSPAN12).	[19]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Tetraspanin-12 (TSPAN12).	[21]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Tetraspanin-12 (TSPAN12).	[18]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Tetraspanin-12 (TSPAN12).	[18]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Tetraspanin-12 (TSPAN12).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Tetraspanin-12 (TSPAN12).	[22]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Tetraspanin-12 (TSPAN12).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Tetraspanin-12 (TSPAN12).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Tetraspanin-12 (TSPAN12).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tetraspanin-12 (TSPAN12).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Tetraspanin-12 (TSPAN12).	[24]

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] TSPAN12 Precedes Tumor Proliferation by Cell Cycle Control in Ovarian Cancer.Mol Cells. 2019 Jul 31;42(7):557-567. doi: 10.14348/molcells.2019.0015.
• [3] Submicroscopic deletion in 7q31 encompassing CADPS2 and TSPAN12 in a child with autism spectrum disorder and PHPV.Am J Med Genet A. 2011 Jul;155A(7):1568-73. doi: 10.1002/ajmg.a.34028. Epub 2011 May 27.
• [4] Upregulation of TSPAN12 is associated with the colorectal cancer growth and metastasis.Am J Transl Res. 2017 Feb 15;9(2):812-822. eCollection 2017.
• [5] Familial exudative vitreoretinopathy caused by a homozygous mutation in TSPAN12 in a cystic fibrosis infant.Ophthalmic Genet. 2014 Sep;35(3):184-6. doi: 10.3109/13816810.2013.811270. Epub 2013 Jul 8.
• [6] 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.
• [7] Machine learning for semi-automated classification of glioblastoma, brain metastasis and central nervous system lymphoma using magnetic resonance advanced imaging.Ann Transl Med. 2019 Jun;7(11):232. doi: 10.21037/atm.2018.08.05.
• [8] TSPAN12 is overexpressed in NSCLC via p53 inhibition and promotes NSCLC cell growth in vitro and in vivo.Onco Targets Ther. 2018 Mar 1;11:1095-1103. doi: 10.2147/OTT.S155620. eCollection 2018.
• [9] Simultaneous Novel Mutations of LRP5 and TSPAN12 in a Case of Familial Exudative Vitreoretinopathy.J Pediatr Ophthalmol Strabismus. 2016 Feb 4;53 Online:e1-5. doi: 10.3928/01913913-20151215-01.
• [10] Correction: Antibody targeting TSPAN12/-catenin signaling in vasoproliferative retinopathy.Oncotarget. 2018 Sep 4;9(69):33244. doi: 10.18632/oncotarget.26102. eCollection 2018 Sep 4.
• [11] Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy. Am J Hum Genet. 2010 Feb 12;86(2):248-53. doi: 10.1016/j.ajhg.2010.01.012.
• [12] A comparison of the prevalence and risk factors of complications in intracranial tumor embolization between the Japanese Registry of NeuroEndovascular Therapy 2 (JR-NET2) and JR-NET3.Acta Neurochir (Wien). 2019 Aug;161(8):1675-1682. doi: 10.1007/s00701-019-03970-w. Epub 2019 Jun 7.
• [13] TSPAN12 promotes chemoresistance and proliferation of SCLC under the regulation of miR-495.Biochem Biophys Res Commun. 2017 Apr 29;486(2):349-356. doi: 10.1016/j.bbrc.2017.03.044. Epub 2017 Mar 14.
• [14] Familial Exudative Vitreoretinopathy, Autosomal Dominant C RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2005 Mar 21 [updated 2011 Sep 22]. 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.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [20] 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.
• [21] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [24] 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.
• [25] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.