Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDL1T6E)

• DOT Name: TBC1 domain family member 20 (TBC1D20)
• Gene Name: TBC1D20
• Related Disease:
  Acrocephalopolysyndactyly
  Apert syndrome
  Craniofacial microsomia
  Fraser syndrome
  Freeman-Sheldon syndrome
  Hepatitis C virus infection
  Intellectual disability
  Isolated Pierre-Robin syndrome
  Male infertility
  Mobius syndrome
  Orofaciodigital syndrome
  Warburg micro syndrome 1
  Warburg micro syndrome 4
  Warburg micro syndrome
  Cataract
• UniProt ID: TBC20_HUMAN
• PDB ID: 4HL4; 4HLQ
• Pfam ID: PF00566
• Sequence:
  MALRSAQGDGPTSGHWDGGAEKADFNAKRKKKVAEIHQALNSDPTDVAALRRMAISEGGL
  LTDEIRRKVWPKLLNVNANDPPPISGKNLRQMSKDYQQVLLDVRRSLRRFPPGMPEEQRE
  GLQEELIDIILLILERNPQLHYYQGYHDIVVTFLLVVGERLATSLVEKLSTHHLRDFMDP
  TMDNTKHILNYLMPIIDQVNPELHDFMQSAEVGTIFALSWLITWFGHVLSDFRHVVRLYD
  FFLACHPLMPIYFAAVIVLYREQEVLDCDCDMASVHHLLSQIPQDLPYETLISRAGDLFV
  QFPPSELAREAAAQQQAERTAASTFKDFELASAQQRPDMVLRQRFRGLLRPEDRTKDVLT
  KPRTNRFVKLAVMGLTVALGAAALAVVKSALEWAPKFQLQLFP
• Function: GTPase-activating protein specific for Rab1 and Rab2 small GTPase families for which it can accelerate the intrinsic GTP hydrolysis rate by more than five orders of magnitude. Involved in maintaining endoplasmic reticulum structure.
• Reactome Pathway:
  TBC/RABGAPs (R-HSA-8854214)
  COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acrocephalopolysyndactyly	DISKE9JR	Strong	Biomarker	[1]
Apert syndrome	DISGIYXQ	Strong	Biomarker	[1]
Craniofacial microsomia	DISYHJ2P	Strong	Biomarker	[1]
Fraser syndrome	DISCLC2B	Strong	Biomarker	[1]
Freeman-Sheldon syndrome	DIS7V9PS	Strong	Biomarker	[1]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[2]
Intellectual disability	DISMBNXP	Strong	Biomarker	[3]
Isolated Pierre-Robin syndrome	DISVEHG7	Strong	Biomarker	[1]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[1]
Mobius syndrome	DIS9YXP5	Strong	Biomarker	[1]
Orofaciodigital syndrome	DISSB296	Strong	Biomarker	[1]
Warburg micro syndrome 1	DIS90EI2	Strong	Genetic Variation	[3]
Warburg micro syndrome 4	DISNSIB1	Strong	Autosomal recessive	[1]
Warburg micro syndrome	DISSEZ2V	Supportive	Autosomal recessive	[1]
Cataract	DISUD7SL	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of TBC1 domain family member 20 (TBC1D20).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of TBC1 domain family member 20 (TBC1D20).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of TBC1 domain family member 20 (TBC1D20).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of TBC1 domain family member 20 (TBC1D20).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of TBC1 domain family member 20 (TBC1D20).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of TBC1 domain family member 20 (TBC1D20).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of TBC1 domain family member 20 (TBC1D20).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of TBC1 domain family member 20 (TBC1D20).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of TBC1 domain family member 20 (TBC1D20).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of TBC1 domain family member 20 (TBC1D20).	[12]

References

• [1] Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet. 2013 Dec 5;93(6):1001-14. doi: 10.1016/j.ajhg.2013.10.011. Epub 2013 Nov 14.
• [2] Role for TBC1D20 and Rab1 in hepatitis C virus replication via interaction with lipid droplet-bound nonstructural protein 5A.J Virol. 2012 Jun;86(12):6491-502. doi: 10.1128/JVI.00496-12. Epub 2012 Apr 4.
• [3] Warburg Micro syndrome is caused by RAB18 deficiency or dysregulation.Open Biol. 2015 Jun;5(6):150047. doi: 10.1098/rsob.150047.
• [4] Targeted disruption of Tbc1d20 with zinc-finger nucleases causes cataracts and testicular abnormalities in mice.BMC Genet. 2014 Dec 5;15:135. doi: 10.1186/s12863-014-0135-2.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] 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.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [9] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] 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.
• [12] 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.
• [13] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.