Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXSXB1K)

• DOT Name: Bardet-Biedl syndrome 1 protein (BBS1)
• Synonyms: BBS2-like protein 2
• Gene Name: BBS1
• Related Disease:
  Bardet-Biedl syndrome 1
  Ciliopathy
  Inherited retinal dystrophy
  Retinal degeneration
  Cardiovascular disease
  Klinefelter syndrome
  Nijmegen breakage syndrome
  Obesity
  Polydactyly
  Retinitis pigmentosa
  Retinopathy
  Spinocerebellar ataxia type 5
  Cohen syndrome
  Bardet biedl syndrome
  Congenital stationary night blindness
  Malignant pleural mesothelioma
  Neoplasm
  Severe early-childhood-onset retinal dystrophy
  Usher syndrome
• UniProt ID: BBS1_HUMAN
• PDB ID: 6XT9
• Pfam ID: PF14779
• Sequence:
  MAAASSSDSDACGAESNEANSKWLDAHYDPMANIHTFSACLALADLHGDGEYKLVVGDLG
  PGGQQPRLKVLKGPLVMTESPLPALPAAAATFLMEQHEPRTPALALASGPCVYVYKNLRP
  YFKFSLPQLPPNPLEQDLWNQAKEDRIDPLTLKEMLESIRETAEEPLSIQSLRFLQLELS
  EMEAFVNQHKSNSIKRQTVITTMTTLKKNLADEDAVSCLVLGTENKELLVLDPEAFTILA
  KMSLPSVPVFLEVSGQFDVEFRLAAACRNGNIYILRRDSKHPKYCIELSAQPVGLIRVHK
  VLVVGSTQDSLHGFTHKGKKLWTVQMPAAILTMNLLEQHSRGLQAVMAGLANGEVRIYRD
  KALLNVIHTPDAVTSLCFGRYGREDNTLIMTTRGGGLIIKILKRTAVFVEGGSEVGPPPA
  QAMKLNVPRKTRLYVDQTLREREAGTAMHRAFQTDLYLLRLRAARAYLQALESSLSPLST
  TAREPLKLHAVVQGLGPTFKLTLHLQNTSTTRPVLGLLVCFLYNEALYSLPRAFFKVPLL
  VPGLNYPLETFVESLSNKGISDIIKVLVLREGQSAPLLSAHVNMPGSEGLAAA
• 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. Plays a role in olfactory cilium biogenesis/maintenance and trafficking.
• Tissue Specificity: Highly expressed in the kidney. Also found in fetal tissue, testis, retina, adipose tissue, heart, skeletal muscle and pancreas.
• Reactome Pathway: BBSome-mediated cargo-targeting to cilium (R-HSA-5620922)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bardet-Biedl syndrome 1	DISRLPZE	Definitive	Autosomal recessive	[1]
Ciliopathy	DIS10G4I	Definitive	Autosomal recessive	[1]
Inherited retinal dystrophy	DISGGL77	Definitive	CausalMutation	[2]
Retinal degeneration	DISM1JHQ	Definitive	Biomarker	[3]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[4]
Klinefelter syndrome	DISOUI7W	Strong	Biomarker	[5]
Nijmegen breakage syndrome	DIS98HVL	Strong	Biomarker	[6]
Obesity	DIS47Y1K	Strong	Genetic Variation	[7]
Polydactyly	DIS25BMZ	Strong	Biomarker	[8]
Retinitis pigmentosa	DISCGPY8	Strong	CausalMutation	[9]
Retinopathy	DISB4B0F	Strong	Genetic Variation	[10]
Spinocerebellar ataxia type 5	DISPYXJ0	Strong	Biomarker	[11]
Cohen syndrome	DISOOFEZ	moderate	Biomarker	[12]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[13]
Congenital stationary night blindness	DISX0CWK	Limited	Biomarker	[14]
Malignant pleural mesothelioma	DIST2R60	Limited	Altered Expression	[15]
Neoplasm	DISZKGEW	Limited	Biomarker	[16]
Severe early-childhood-onset retinal dystrophy	DISFDRFO	Limited	Genetic Variation	[14]
Usher syndrome	DIS9YIS7	Limited	CausalMutation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Bardet-Biedl syndrome 1 protein (BBS1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Bardet-Biedl syndrome 1 protein (BBS1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bardet-Biedl syndrome 1 protein (BBS1).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Bardet-Biedl syndrome 1 protein (BBS1).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Bardet-Biedl syndrome 1 protein (BBS1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Bardet-Biedl syndrome 1 protein (BBS1).	[23]

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 Bardet-Biedl syndrome 1 protein (BBS1).	[22]

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] Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease.Ophthalmology. 2016 May;123(5):1143-50. doi: 10.1016/j.ophtha.2016.01.009. Epub 2016 Feb 9.
• [3] Retinal disease expression in Bardet-Biedl syndrome-1 (BBS1) is a spectrum from maculopathy to retina-wide degeneration.Invest Ophthalmol Vis Sci. 2006 Nov;47(11):5004-10. doi: 10.1167/iovs.06-0517.
• [4] Genetic predictors of cardiovascular morbidity in Bardet-Biedl syndrome.Clin Genet. 2015 Apr;87(4):343-9. doi: 10.1111/cge.12373. Epub 2014 Apr 8.
• [5] Definable somatic disorders in overweight children and adolescents.J Pediatr. 2007 Jun;150(6):618-22, 622.e1-5. doi: 10.1016/j.jpeds.2007.01.042.
• [6] Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome.Am J Hum Genet. 2003 May;72(5):1187-99. doi: 10.1086/375178. Epub 2003 Apr 3.
• [7] Next-generation sequence analysis of genes associated with obesity and nonalcoholic fatty liver disease-related cirrhosis in extreme obesity.Hum Hered. 2013;75(2-4):144-51. doi: 10.1159/000351719. Epub 2013 Sep 27.
• [8] Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder.Science. 2001 Sep 21;293(5538):2256-9. doi: 10.1126/science.1063525.
• [9] Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.Sci Rep. 2019 Feb 4;9(1):1219. doi: 10.1038/s41598-018-38007-2.
• [10] Phenotypic expression of Bardet-Biedl syndrome in patients homozygous for the common M390R mutation in the BBS1 gene.Vision Res. 2012 Dec 15;75:77-87. doi: 10.1016/j.visres.2012.08.005. Epub 2012 Aug 24.
• [11] A 3-Mb sequence-ready contig map encompassing the multiple disease gene cluster on chromosome 11q13.1-q13.3.DNA Res. 1997 Aug 31;4(4):281-9. doi: 10.1093/dnares/4.4.281.
• [12] MORM syndrome (mental retardation, truncal obesity, retinal dystrophy and micropenis), a new autosomal recessive disorder, links to 9q34.Eur J Hum Genet. 2006 May;14(5):543-8. doi: 10.1038/sj.ejhg.5201577.
• [13] 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.
• [14] Genetic Mutation Profiles in Korean Patients with Inherited Retinal Diseases.J Korean Med Sci. 2019 Jun 2;34(21):e161. doi: 10.3346/jkms.2019.34.e161.
• [15] Computational genomic analysis of PARK7 interactome reveals high BBS1 gene expression as a prognostic factor favoring survival in malignant pleural mesothelioma.Am J Physiol Lung Cell Mol Physiol. 2015 Oct 1;309(7):L677-86. doi: 10.1152/ajplung.00051.2015. Epub 2015 Aug 7.
• [16] A novel gene expression signature for bone metastasis in breast carcinomas.Breast Cancer Res Treat. 2016 Apr;156(2):249-59. doi: 10.1007/s10549-016-3741-z. Epub 2016 Mar 10.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [22] 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.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.