Details of Drug Off-Target (DOT)

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

• DOT Name: Trafficking protein particle complex subunit 6B (TRAPPC6B)
• Synonyms: TRAPP complex subunit 6B
• Gene Name: TRAPPC6B
• Related Disease:
  Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy
  Restless legs syndrome
• UniProt ID: TPC6B_HUMAN
• PDB ID: 2BJN; 2CFH; 3KXC
• Pfam ID: PF04051
• Sequence:
  MADEALFLLLHNEMVSGVYKSAEQGEVENGRCITKLENMGFRVGQGLIERFTKDTARFKD
  ELDIMKFICKDFWTTVFKKQIDNLRTNHQGIYVLQDNKFRLLTQMSAGKQYLEHASKYLA
  FTCGLIRGGLSNLGIKSIVTAEVSSMPACKFQVMIQKL
• Function: Component of a transport protein particle (TRAPP) complex that may function in specific stages of inter-organelle traffic. Specifically involved in the early development of neural circuitry, likely by controlling the frequency and amplitude of intracellular calcium transients implicated in the regulation of neuron differentiation and survival (Probable).
• Tissue Specificity: Both isoforms are expressed ubiquitously (at transcript level), isoform 1 being the most predominant . Expressed in the fetal brain and different regions of the adult brain and spinal cord .
• Reactome Pathway:
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy	DISL9R2R	Strong	Autosomal recessive	[1]
Restless legs syndrome	DISNWY00	Strong	Genetic Variation	[2]

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 Trafficking protein particle complex subunit 6B (TRAPPC6B).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Trafficking protein particle complex subunit 6B (TRAPPC6B).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Trafficking protein particle complex subunit 6B (TRAPPC6B).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Trafficking protein particle complex subunit 6B (TRAPPC6B).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Trafficking protein particle complex subunit 6B (TRAPPC6B).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Trafficking protein particle complex subunit 6B (TRAPPC6B).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Trafficking protein particle complex subunit 6B (TRAPPC6B).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Trafficking protein particle complex subunit 6B (TRAPPC6B).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Trafficking protein particle complex subunit 6B (TRAPPC6B).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Trafficking protein particle complex subunit 6B (TRAPPC6B).	[12]

References

• [1] A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features. J Med Genet. 2018 Jan;55(1):48-54. doi: 10.1136/jmedgenet-2017-104627. Epub 2017 Jun 16.
• [2] A TRAPPC6B splicing variant associates to restless legs syndrome.Parkinsonism Relat Disord. 2016 Oct;31:135-138. doi: 10.1016/j.parkreldis.2016.08.016. Epub 2016 Aug 18.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] 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.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [11] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.