Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQEVL7L)

• DOT Name: Transmembrane protein 237 (TMEM237)
• Synonyms: Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 4 protein
• Gene Name: TMEM237
• Related Disease:
  Joubert syndrome 14
  Ciliopathy
  Joubert syndrome 1
  Head-neck squamous cell carcinoma
  Joubert syndrome
  Joubert syndrome with oculorenal defect
  Joubert syndrome with renal defect
  Meckel syndrome
  Lung carcinoma
• UniProt ID: TM237_HUMAN
• Pfam ID: PF15383
• Sequence:
  MRTDSGARLEEGHLRPPRALPPVPSQDDIPLSRPKKKKPRTKNTPASASLEGLAQTAGRR
  PSEGNEPSTKELKEHPEAPVQRRQKKTRLPLELETSSTQKKSSSSSLLRNENGIDAEPAE
  EAVIQKPRRKTKKTQPAELQYANELGVEDEDIITDEQTTVEQQSVFTAPTGISQPVGKVF
  VEKSRRFQAADRSELIKTTENIDVSMDVKPSWTTRDVALTVHRAFRMIGLFSHGFLAGCA
  VWNIVVIYVLAGDQLSNLSNLLQQYKTLAYPFQSLLYLLLALSTISAFDRIDFAKISVAI
  RNFLALDPTALASFLYFTALILSLSQQMTSDRIHLYTPSSVNGSLWEAGIEEQILQPWIV
  VNLVVALLVGLSWLFLSYRPGMDLSEELMFSSEVEEYPDKEKEIKASS
• Function: Component of the transition zone in primary cilia. Required for ciliogenesis.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Joubert syndrome 14	DISAHGV4	Definitive	Autosomal recessive	[1]
Ciliopathy	DIS10G4I	Strong	Biomarker	[2]
Joubert syndrome 1	DISC9Q82	Strong	GermlineCausalMutation	[3]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[4]
Joubert syndrome	DIS7P5CO	Supportive	Autosomal recessive	[3]
Joubert syndrome with oculorenal defect	DISU0IPO	Supportive	Autosomal recessive	[5]
Joubert syndrome with renal defect	DIS52E3N	Supportive	Autosomal recessive	[5]
Meckel syndrome	DISXPHOY	Supportive	Autosomal recessive	[6]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transmembrane protein 237 (TMEM237).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transmembrane protein 237 (TMEM237).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane protein 237 (TMEM237).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transmembrane protein 237 (TMEM237).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transmembrane protein 237 (TMEM237).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Transmembrane protein 237 (TMEM237).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Transmembrane protein 237 (TMEM237).	[14]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Transmembrane protein 237 (TMEM237).	[15]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Transmembrane protein 237 (TMEM237).	[16]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Transmembrane protein 237 (TMEM237).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transmembrane protein 237 (TMEM237).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transmembrane protein 237 (TMEM237).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Transmembrane protein 237 (TMEM237).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Transmembrane protein 237 (TMEM237).	[20]

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] TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. Am J Hum Genet. 2011 Dec 9;89(6):713-30. doi: 10.1016/j.ajhg.2011.11.005.
• [3] Molecular characterization of Joubert syndrome in Saudi Arabia. Hum Mutat. 2012 Oct;33(10):1423-8. doi: 10.1002/humu.22134. Epub 2012 Jul 11.
• [4] Integration of high-risk human papillomavirus into cellular cancer-related genes in head and neck cancer cell lines.Head Neck. 2017 May;39(5):840-852. doi: 10.1002/hed.24729. Epub 2017 Feb 25.
• [5] Joubert Syndrome. 2003 Jul 9 [updated 2017 Jun 29]. 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.
• [6] Enhanced diagnostic yield in Meckel-Gruber and Joubert syndrome through exome sequencing supplemented with split-read mapping. BMC Med Genet. 2016 Jan 4;17:1. doi: 10.1186/s12881-015-0265-z.
• [7] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [16] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [17] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.