Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDB24YV)

• DOT Name: Tetratricopeptide repeat protein 12 (TTC12)
• Synonyms: TPR repeat protein 12
• Gene Name: TTC12
• Related Disease:
  Drug dependence
  Alcohol dependence
  Attention deficit hyperactivity disorder
  Ciliary dyskinesia, primary, 45
  Major depressive disorder
  Melanoma
  Mood disorder
  Neoplasm
  Nicotine dependence
  Schizophrenia
  Primary ciliary dyskinesia
  Substance dependence
• UniProt ID: TTC12_HUMAN
• Pfam ID: PF00515 ; PF13181
• Sequence:
  MDADKEKDLQKFLKNVDEISNLIQEMNSDDPVVQQKAVLETEKRLLLMEEDQEEDECRTT
  LNKTMISPPQTAMKSAEEINSEAFLASVEKDAKERAKRRRENKVLADALKEKGNEAFAEG
  NYETAILRYSEGLEKLKDMKVLYTNRAQAYMKLEDYEKALVDCEWALKCDEKCTKAYFHM
  GKANLALKNYSVSRECYKKILEINPKLQTQVKGYLNQVDLQEKADLQEKEAHELLDSGKN
  TAVTTKNLLETLSKPDQIPLFYAGGIEILTEMINECTEQTLFRMHNGFSIISDNEVIRRC
  FSTAGNDAVEEMVCVSVLKLWQAVCSRNEENQRVLVIHHDRARLLAALLSSKVLAIRQQS
  FALLLHLAQTESGRSLIINHLDLTRLLEALVSFLDFSDKEANTAMGLFTDLALEERFQVW
  FQANLPGVLPALTGVLKTDPKVSSSSALCQCIAIMGNLSAEPTTRRHMAACEEFGDGCLS
  LLARCEEDVDLFREVIYTLLGLMMNLCLQAPFVSEVWAVEVSRRCLSLLNSQDGGILTRA
  AGVLSRTLSSSLKIVEEALRAGVVKKMMKFLKTGGETASRYAIKILAICTNSYHEAREEV
  IRLDKKLSVMMKLLSSEDEVLVGNAALCLGNCMEVPNVASSLLKTDLLQVLLKLAGSDTQ
  KTAVQVNAGIALGKLCTAEPRFAAQLRKLHGLEILNSTMKYISDS
• Function: Cytoplasmic protein that plays a role in the proper assembly of dynein arm complexes in motile cilia in both respiratory cells and sperm flagella.
• Tissue Specificity: Expressed in testis and in epithelial cells of trachea and bronchial tube.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Drug dependence	DIS9IXRC	Definitive	Genetic Variation	[1]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[3]
Ciliary dyskinesia, primary, 45	DISEPPON	Strong	Autosomal recessive	[4]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[6]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Nicotine dependence	DISZD9W7	Strong	Genetic Variation	[7]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[8]
Primary ciliary dyskinesia	DISOBC7V	Supportive	Autosomal dominant	[9]
Substance dependence	DISDRAAR	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Tetratricopeptide repeat protein 12 (TTC12).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tetratricopeptide repeat protein 12 (TTC12).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tetratricopeptide repeat protein 12 (TTC12).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Tetratricopeptide repeat protein 12 (TTC12).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tetratricopeptide repeat protein 12 (TTC12).	[16]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Tetratricopeptide repeat protein 12 (TTC12).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tetratricopeptide repeat protein 12 (TTC12).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Tetratricopeptide repeat protein 12 (TTC12).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tetratricopeptide repeat protein 12 (TTC12).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Tetratricopeptide repeat protein 12 (TTC12).	[18]

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 Tetratricopeptide repeat protein 12 (TTC12).	[15]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Tetratricopeptide repeat protein 12 (TTC12).	[17]

References

• [1] Haplotypic variants in DRD2, ANKK1, TTC12, and NCAM1 are associated with comorbid alcohol and drug dependence.Alcohol Clin Exp Res. 2008 Dec;32(12):2117-27. doi: 10.1111/j.1530-0277.2008.00800.x. Epub 2008 Sep 30.
• [2] Influence of DRD2 and ANKK1 genotypes on apomorphine-induced growth hormone (GH) response in alcohol-dependent patients.Prog Neuropsychopharmacol Biol Psychiatry. 2010 Feb 1;34(1):45-9. doi: 10.1016/j.pnpbp.2009.08.024. Epub 2009 Sep 29.
• [3] Further replication of the synergistic interaction between LPHN3 and the NTAD gene cluster on ADHD and its clinical course throughout adulthood.Prog Neuropsychopharmacol Biol Psychiatry. 2017 Oct 3;79(Pt B):120-127. doi: 10.1016/j.pnpbp.2017.06.011. Epub 2017 Jun 15.
• [4] TTC12 Loss-of-Function Mutations Cause Primary Ciliary Dyskinesia and Unveil Distinct Dynein Assembly Mechanisms in Motile Cilia Versus Flagella. Am J Hum Genet. 2020 Feb 6;106(2):153-169. doi: 10.1016/j.ajhg.2019.12.010. Epub 2020 Jan 23.
• [5] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [6] Identification and characterization of TPARM gene in silico.Int J Oncol. 2003 Oct;23(4):1213-7.
• [7] NCAM1-TTC12-ANKK1-DRD2 variants and smoking motives as intermediate phenotypes for nicotine dependence.Psychopharmacology (Berl). 2015 Apr;232(7):1177-86. doi: 10.1007/s00213-014-3748-2. Epub 2014 Oct 3.
• [8] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [9] Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases. Acta Neuropathol. 2020 Mar;139(3):415-442. doi: 10.1007/s00401-019-02109-6. Epub 2019 Dec 9.
• [10] Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations.Hum Mol Genet. 2006 Dec 15;15(24):3498-507. doi: 10.1093/hmg/ddl426. Epub 2006 Nov 3.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [15] 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.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] 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.
• [18] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [19] 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.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] 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.