Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF4UYIE)

• DOT Name: Transmembrane protein 231 (TMEM231)
• Gene Name: TMEM231
• Related Disease:
  Ciliopathy
  Joubert syndrome 20
  Acute coronary syndrome
  Gastrointestinal stromal tumour
  Meckel syndrome, type 1
  Orofaciodigital syndrome
  Orofaciodigital syndrome type 6
  Cystic kidney disease
  Joubert syndrome with oculorenal defect
  Meckel syndrome
  Orofaciodigital syndrome III
  Joubert syndrome
  Joubert syndrome 14
• UniProt ID: TM231_HUMAN
• Pfam ID: PF10149
• Sequence:
  MALYELFSHPVERSYRAGLCSKAALFLLLAAALTYIPPLLVAFRSHGFWLKRSSYEEQPT
  VRFQHQVLLVALLGPESDGFLAWSTFPAFNRLQGDRLRVPLVSTREEDRNQDGKTDMLHF
  KLELPLQSTEHVLGVQLILTFSYRLHRMATLVMQSMAFLQSSFPVPGSQLYVNGDLRLQQ
  KQPLSCGGLDARYNISVINGTSPFAYDYDLTHIVAAYQERNVTTVLNDPNPIWLVGRAAD
  APFVINAIIRYPVEVISYQPGFWEMVKFAWVQYVSILLIFLWVFERIKIFVFQNQVVTTI
  PVTVTPRGDLCKEHLS
• Function: Transmembrane component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Required for ciliogenesis and sonic hedgehog/SHH signaling.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ciliopathy	DIS10G4I	Definitive	Autosomal recessive	[1]
Joubert syndrome 20	DISXS29L	Definitive	Autosomal recessive	[2]
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[3]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[4]
Meckel syndrome, type 1	DIS4YWZU	Strong	Genetic Variation	[5]
Orofaciodigital syndrome	DISSB296	Strong	Genetic Variation	[6]
Orofaciodigital syndrome type 6	DISQY7K4	Strong	Genetic Variation	[7]
Cystic kidney disease	DISRT1LM	moderate	Biomarker	[6]
Joubert syndrome with oculorenal defect	DISU0IPO	Supportive	Autosomal recessive	[8]
Meckel syndrome	DISXPHOY	Supportive	Autosomal recessive	[9]
Orofaciodigital syndrome III	DISLYV75	Supportive	Autosomal recessive	[6]
Joubert syndrome	DIS7P5CO	Limited	Genetic Variation	[10]
Joubert syndrome 14	DISAHGV4	Limited	Biomarker	[11]

10 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 Transmembrane protein 231 (TMEM231).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transmembrane protein 231 (TMEM231).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transmembrane protein 231 (TMEM231).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transmembrane protein 231 (TMEM231).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane protein 231 (TMEM231).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transmembrane protein 231 (TMEM231).	[17]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Transmembrane protein 231 (TMEM231).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transmembrane protein 231 (TMEM231).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Transmembrane protein 231 (TMEM231).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transmembrane protein 231 (TMEM231).	[21]

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] Mutations in TMEM231 cause Joubert syndrome in French Canadians. J Med Genet. 2012 Oct;49(10):636-41. doi: 10.1136/jmedgenet-2012-101132. Epub 2012 Sep 25.
• [3] Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib.PLoS One. 2017 Jul 28;12(7):e0182115. doi: 10.1371/journal.pone.0182115. eCollection 2017.
• [4] Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
• [5] Long-read nanopore sequencing resolves a TMEM231 gene conversion event causing Meckel-Gruber syndrome.Hum Mutat. 2020 Feb;41(2):525-531. doi: 10.1002/humu.23940. Epub 2019 Nov 11.
• [6] TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone. J Cell Biol. 2015 Apr 13;209(1):129-42. doi: 10.1083/jcb.201411087.
• [7] MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone.PLoS Biol. 2016 Mar 16;14(3):e1002416. doi: 10.1371/journal.pbio.1002416. eCollection 2016 Mar.
• [8] 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.
• [9] Mutations in TMEM231 cause Meckel-Gruber syndrome. J Med Genet. 2013 Mar;50(3):160-2. doi: 10.1136/jmedgenet-2012-101431. Epub 2013 Jan 24.
• [10] Tectocerebellar dysraphia with occipital encephalocele: a phenotypic variant of the TMEM231 gene mutation induced Joubert syndrome.Childs Nerv Syst. 2019 Jul;35(7):1257-1261. doi: 10.1007/s00381-019-04048-9. Epub 2019 Jan 7.
• [11] TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubertsyndrome.Nat Cell Biol. 2016 Jan;18(1):122-31. doi: 10.1038/ncb3273. Epub 2015 Nov 23.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] 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.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.