Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWTXO75)

• DOT Name: B9 domain-containing protein 1 (B9D1)
• Synonyms: MKS1-related protein 1
• Gene Name: B9D1
• Related Disease:
  Ciliopathy
  Gastrointestinal stromal tumour
  Joubert syndrome 1
  Joubert syndrome 27
  Meckel syndrome, type 9
  Schizophrenia
  Joubert syndrome
  Meckel syndrome
  Meckel syndrome, type 1
  Neoplasm
  Polydactyly
• UniProt ID: B9D1_HUMAN
• Pfam ID: PF07162
• Sequence:
  MATASPSVFLLMVNGQVESAQFPEYDDLYCKYCFVYGQDWAPTAGLEEGISQITSKSQDV
  RQALVWNFPIDVTFKSTNPYGWPQIVLSVYGPDVFGNDVVRGYGAVHVPFSPGRHKRTIP
  MFVPESTSKLQKFTSWFMGRRPEYTDPKVVAQGEGREVTRVRSQGFVTLLFNVVTKDMRK
  LGYDTGPSDTQGVLGPSPPQSFPQ
• Function: 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.
• Reactome Pathway: Anchoring of the basal body to the plasma membrane (R-HSA-5620912)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ciliopathy	DIS10G4I	Definitive	Autosomal recessive	[1]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[2]
Joubert syndrome 1	DISC9Q82	Strong	GermlineCausalMutation	[3]
Joubert syndrome 27	DIS5OYYJ	Strong	Autosomal recessive	[4]
Meckel syndrome, type 9	DIS0VU5L	Strong	Autosomal recessive	[4]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[5]
Joubert syndrome	DIS7P5CO	Supportive	Autosomal recessive	[3]
Meckel syndrome	DISXPHOY	Supportive	Autosomal recessive	[4]
Meckel syndrome, type 1	DIS4YWZU	Limited	Genetic Variation	[6]
Neoplasm	DISZKGEW	Limited	Biomarker	[7]
Polydactyly	DIS25BMZ	Limited	Biomarker	[3]

10 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 B9 domain-containing protein 1 (B9D1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of B9 domain-containing protein 1 (B9D1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of B9 domain-containing protein 1 (B9D1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of B9 domain-containing protein 1 (B9D1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of B9 domain-containing protein 1 (B9D1).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of B9 domain-containing protein 1 (B9D1).	[13]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of B9 domain-containing protein 1 (B9D1).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of B9 domain-containing protein 1 (B9D1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of B9 domain-containing protein 1 (B9D1).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of B9 domain-containing protein 1 (B9D1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of B9 domain-containing protein 1 (B9D1).	[18]

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] 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.
• [3] Mutations in B9D1 and MKS1 cause mild Joubert syndrome: expanding the genetic overlap with the lethal ciliopathy Meckel syndrome. Orphanet J Rare Dis. 2014 May 5;9:72. doi: 10.1186/1750-1172-9-72.
• [4] B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis. Hum Mol Genet. 2011 Jul 1;20(13):2524-34. doi: 10.1093/hmg/ddr151. Epub 2011 Apr 14.
• [5] Genome-wide association study of paliperidone efficacy.Pharmacogenet Genomics. 2017 Jan;27(1):7-18. doi: 10.1097/FPC.0000000000000250.
• [6] Joubert syndrome: genotyping a Northern European patient cohort.Eur J Hum Genet. 2016 Feb;24(2):214-20. doi: 10.1038/ejhg.2015.84. Epub 2015 Apr 29.
• [7] Genome-Wide CRISPR Screen Identifies Regulators of Mitogen-Activated Protein Kinase as Suppressors of Liver Tumors in Mice.Gastroenterology. 2017 Apr;152(5):1161-1173.e1. doi: 10.1053/j.gastro.2016.12.002. Epub 2016 Dec 10.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] 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.
• [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] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.