Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR5NU7K)

• DOT Name: Protein broad-minded (TBC1D32)
• Synonyms: TBC1 domain family member 32
• Gene Name: TBC1D32
• Related Disease:
  Ciliopathy
  Osteofibrous dysplasia
  Orofaciodigital syndrome
  Orofaciodigital syndrome IX
• UniProt ID: BROMI_HUMAN
• Pfam ID: PF14961
• Sequence:
  MAHFSSEDQAMLQAMLRRLFQSVKEKITGAPSLECAEEILLHLEETDENFHNYEFVKYLR
  QHIGNTLGSMIEEEMEKCTSDRNQGEECGYDTVVQQVTKRTQESKEYKEMMHYLKNIMIA
  VVESMINKFEEDETRNQERQKKIQKEKSHSYRTDNCSDSDSSLNQSYKFCQGKLQLILDQ
  LDPGQPKEVRYEALQTLCSAPPSDVLNCENWTTLCEKLTVSLSDPDPVFSDRILKFCAQT
  FLLSPLHMTKEIYTSLAKYLESYFLSRENHIPTLSAGVDITNPNMTRLLKKVRLLNEYQK
  EAPSFWIRHPEKYMEEIVESTLSLLTVKHNQSHVVSQKILDPIYFFALVDTKAVWFKKWM
  HAHYSRTTVLRLLETKYKSLVTTAIQQCVQYFEMCKTRKADETLGHSKHCRNKQKTFYYL
  GQELQYIYFIHSLCLLGRLLIYKQGRKLFPIKLKNKKGLVSLIDLLVLFTQLIYYSPSCP
  KMTSAAHSENYSPASMVTEVLWILSDQKECAVECLYNNIVIETLLQPIHNLMKGNEASPN
  CSETALIHIAGILARIASVEEGLILLLYGANMNSSEESPTGAHIIAQFSKKLLDEDISIF
  SGSEMLPVVKGAFISVCRHIYSTCEGLQVLITYNLHESIAKAWKKTSLLSERIPTPVEGS
  DSVSSVSQESQNIMAWEDNLLDDLLHFAATPKGLLLLQRTGAINECVTFIFNRYAKKLQV
  SRHKKFGYGVLVTRVASTAAGGIALKKSGFINELITELWSNLEYGRDDVRVTHPRTTPVD
  PIDRSCQKSFLALVNLLSYPAIYELVRNQDLPNKTEYSLREVPTCVIDIIDRLIILNSEA
  KIRSLFNYEQSHIFGLRDFIIDGLSVERNHVLVRINLVGGPLERILPPRLLEKSDNPYPW
  PMFSSYPLPNCYLSDITRNAGIKQDNDLDKLLLCLKISDKQTEWIENCQRQFCKMMKAKP
  DIISGEALIELLEKFVLHLTESPSECYFPSVEYTATDANVKNESLSSVQQLGIKMTVRYG
  KFLSLLKDGAENDLTWVLKHCERFLKQQQTSIKSSLLCLQGNYAGHDWFVSSLFMIMLGD
  KEKTFQFLHQFSRLLTSAFLWLPRLHISSYLPNDTVESGIHPVYFCSTHYIEMLLKAELP
  LVFSAFHMSGFAPSQICLQWITQCFWNYLDWIEICHYIATCVFLGPDYQVYICIAVFKHL
  QQDILQHTQTQDLQVFLKEEALHGFRVSDYFEYMEILEQNYRTVLLRDMRNIRLQST
• Function: Required for high-level Shh responses in the developing neural tube. Together with CDK20, controls the structure of the primary cilium by coordinating assembly of the ciliary membrane and axoneme, allowing GLI2 to be properly activated in response to Shh signaling.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ciliopathy	DIS10G4I	Definitive	Autosomal recessive	[1]
Osteofibrous dysplasia	DISU5HAO	Strong	Biomarker	[1]
Orofaciodigital syndrome	DISSB296	Moderate	Autosomal recessive	[2]
Orofaciodigital syndrome IX	DISMM3HW	Limited	Unknown	[3]

5 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 Protein broad-minded (TBC1D32).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein broad-minded (TBC1D32).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein broad-minded (TBC1D32).	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein broad-minded (TBC1D32).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein broad-minded (TBC1D32).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein broad-minded (TBC1D32).	[7]

References

• [1] Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX. Hum Mutat. 2014 Jan;35(1):36-40. doi: 10.1002/humu.22477. Epub 2013 Nov 25.
• [2] Confirming TBC1D32-related ciliopathy in humans. Am J Med Genet A. 2020 Aug;182(8):1985-1987. doi: 10.1002/ajmg.a.61717. Epub 2020 Jun 23.
• [3] Using genomewide mutagenesis screens to identify the genes required for neural tube closure in the mouse. Birth Defects Res A Clin Mol Teratol. 2005 Sep;73(9):583-90. doi: 10.1002/bdra.20164.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [8] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.