Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0D3JC0)

• DOT Name: Bardet-Biedl syndrome 4 protein (BBS4)
• Gene Name: BBS4
• Related Disease:
  Bardet-Biedl syndrome 4
  Ciliopathy
  Retinitis pigmentosa
  Acrocallosal syndrome
  Epilepsy
  Myopia
  Nijmegen breakage syndrome
  Obesity
  Polydactyly
  Schizophrenia
  Retinopathy
  Bardet biedl syndrome
  Meckel syndrome, type 1
• UniProt ID: BBS4_HUMAN
• PDB ID: 6XT9
• Pfam ID: PF13414 ; PF13432 ; PF13181
• Sequence:
  MAEERVATRTQFPVSTESQKPRQKKAPEFPILEKQNWLIHLHYIRKDYEACKAVIKEQLQ
  ETQGLCEYAIYVQALIFRLEGNIQESLELFQTCAVLSPQSADNLKQVARSLFLLGKHKAA
  IEVYNEAAKLNQKDWEISHNLGVCYIYLKQFNKAQDQLHNALNLNRHDLTYIMLGKIHLL
  EGDLDKAIEVYKKAVEFSPENTELLTTLGLLYLQLGIYQKAFEHLGNALTYDPTNYKAIL
  AAGSMMQTHGDFDVALTKYRVVACAVPESPPLWNNIGMCFFGKKKYVAAISCLKRANYLA
  PFDWKILYNLGLVHLTMQQYASAFHFLSAAINFQPKMGELYMLLAVALTNLEDIENAKRA
  YAEAVHLDKCNPLVNLNYAVLLYNQGEKKNALAQYQEMEKKVSLLKDNSSLEFDSEMVEM
  AQKLGAALQVGEALVWTKPVKDPKSKHQTTSTSKPASFQQPLGSNQALGQAMSSAAAYRT
  LPSGAGGTSQFTKPPSLPLEPEPAVESSPTETSEQIREK
• Function: The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia. The BBSome complex is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Firstly the BBSome associates with the ciliary membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and promotes docking and fusion of carrier vesicles to the base of the ciliary membrane. The BBSome complex, together with the LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. Required for proper BBSome complex assembly and its ciliary localization. Required for microtubule anchoring at the centrosome but not for microtubule nucleation. May be required for the dynein-mediated transport of pericentriolar proteins to the centrosome.
• Tissue Specificity: Ubiquitously expressed. The highest level of expression is found in the kidney.
• Reactome Pathway: BBSome-mediated cargo-targeting to cilium (R-HSA-5620922)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bardet-Biedl syndrome 4	DISTSZC7	Definitive	Autosomal recessive	[1]
Ciliopathy	DIS10G4I	Definitive	Autosomal recessive	[2]
Retinitis pigmentosa	DISCGPY8	Definitive	Genetic Variation	[3]
Acrocallosal syndrome	DISKMCG2	Strong	Genetic Variation	[4]
Epilepsy	DISBB28L	Strong	Genetic Variation	[5]
Myopia	DISK5S60	Strong	Biomarker	[3]
Nijmegen breakage syndrome	DIS98HVL	Strong	Genetic Variation	[6]
Obesity	DIS47Y1K	Strong	Biomarker	[7]
Polydactyly	DIS25BMZ	Strong	Genetic Variation	[8]
Schizophrenia	DISSRV2N	Strong	Biomarker	[9]
Retinopathy	DISB4B0F	moderate	Biomarker	[10]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[11]
Meckel syndrome, type 1	DIS4YWZU	Limited	Biomarker	[12]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Bardet-Biedl syndrome 4 protein (BBS4) affects the response to substance of Doxorubicin.	[24]

11 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 Bardet-Biedl syndrome 4 protein (BBS4).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Bardet-Biedl syndrome 4 protein (BBS4).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Bardet-Biedl syndrome 4 protein (BBS4).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Bardet-Biedl syndrome 4 protein (BBS4).	[16]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Bardet-Biedl syndrome 4 protein (BBS4).	[17]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Bardet-Biedl syndrome 4 protein (BBS4).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Bardet-Biedl syndrome 4 protein (BBS4).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Bardet-Biedl syndrome 4 protein (BBS4).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Bardet-Biedl syndrome 4 protein (BBS4).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Bardet-Biedl syndrome 4 protein (BBS4).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Bardet-Biedl syndrome 4 protein (BBS4).	[23]

References

• [1] Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat Genet. 2001 Jun;28(2):188-91. doi: 10.1038/88925.
• [2] 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.
• [3] Ocular phenotypes of three genetic variants of Bardet-Biedl syndrome.Am J Med Genet A. 2005 Jan 30;132A(3):283-7. doi: 10.1002/ajmg.a.30466.
• [4] Acrocallosal syndrome: identification of a novel KIF7 mutation and evidence for oligogenic inheritance.Eur J Med Genet. 2013 Jan;56(1):39-42. doi: 10.1016/j.ejmg.2012.10.004. Epub 2012 Nov 7.
• [5] 15q24.1 BP4-BP1 microdeletion unmasking paternally inherited functional polymorphisms combined with distal 15q24.2q24.3 duplication in a patient with epilepsy, psychomotor delay, overweight, ventricular arrhythmia.Eur J Med Genet. 2018 Aug;61(8):459-464. doi: 10.1016/j.ejmg.2018.03.005. Epub 2018 Mar 14.
• [6] Genetic heterogeneity of Bardet-Biedl syndrome in a distinct Canadian population: evidence for a fifth locus.Genomics. 1999 Jan 1;55(1):2-9. doi: 10.1006/geno.1998.5626.
• [7] Bardet-Biedl syndrome obesity: BBS4 regulates cellular ER stress in early adipogenesis.Mol Genet Metab. 2019 Apr;126(4):495-503. doi: 10.1016/j.ymgme.2019.03.006. Epub 2019 Mar 15.
• [8] Canadian Bardet-Biedl syndrome family reduces the critical region of BBS3 (3p) and presents with a variable phenotype.Am J Med Genet. 1998 Aug 6;78(5):461-7. doi: 10.1002/(sici)1096-8628(19980806)78:5<461::aid-ajmg12>3.0.co;2-d.
• [9] Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: a candidate for psychiatric illnesses.Arch Gen Psychiatry. 2008 Sep;65(9):996-1006. doi: 10.1001/archpsyc.65.9.996.
• [10] Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly.Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8664-9. doi: 10.1073/pnas.0402354101. Epub 2004 Jun 1.
• [11] Bardet-Biedl Syndrome Overview. 2003 Jul 14 [updated 2023 Mar 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [12] The Meckel syndrome- associated protein MKS1 functionally interacts with components of the BBSome and IFT complexes to mediate ciliary trafficking and hedgehog signaling.PLoS One. 2017 Mar 14;12(3):e0173399. doi: 10.1371/journal.pone.0173399. eCollection 2017.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] 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.
• [18] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [19] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [20] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [21] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.