Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPF9JIB)

• DOT Name: Bardet-Biedl syndrome 2 protein (BBS2)
• Gene Name: BBS2
• Related Disease:
  Bardet-Biedl syndrome 2
  Ciliopathy
  Retinitis pigmentosa 74
  Acrocallosal syndrome
  Bardet-Biedl syndrome 3
  Breast carcinoma
  Clear cell renal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Gastrin-producing neuroendocrine tumor
  Intellectual disability
  Kidney cancer
  McKusick-Kaufman syndrome
  Neoplasm
  Neuroblastoma
  Nijmegen breakage syndrome
  Obesity
  Polydactyly
  Prostate carcinoma
  Renal carcinoma
  Renal cell carcinoma
  Sarcoidosis
  Sleep disorder
  Trichohepatoenteric syndrome
  Hirschsprung disease
  Retinopathy
  Bardet biedl syndrome
  Retinitis pigmentosa
  Amyotrophic lateral sclerosis
  Colon adenocarcinoma
  Colon carcinoma
  Inherited retinal dystrophy
  Prostate cancer
  Stroke
• UniProt ID: BBS2_HUMAN
• Pfam ID: PF14782 ; PF14783 ; PF14781
• Sequence:
  MLLPVFTLKLRHKISPRMVAIGRYDGTHPCLAAATQTGKVFIHNPHTRNQHVSASRVFQS
  PLESDVSLLSINQAVSCLTAGVLNPELGYDALLVGTQTNLLAYDVYNNSDLFYREVADGA
  NAIVLGTLGDISSPLAIIGGNCALQGFNHEGSDLFWTVTGDNVNSLALCDFDGDGKKELL
  VGSEDFDIRVFKEDEIVAEMTETEIVTSLCPMYGSRFGYALSNGTVGVYDKTSRYWRIKS
  KNHAMSIHAFDLNSDGVNELITGWSNGKVDARSDRTGEVIFKDNFSSAIAGVVEGDYRMD
  GHIQLICCSVDGEIRGYLPGTAEMRGNLMDTSAEQDLIRELSQKKQNLLLELRNYEENAK
  AELASPLNEADGHRGIIPANTRLHTTLSVSLGNETQTAHTELRISTSNDTIIRAVLIFAE
  GIFTGESHVVHPSIHNLSSSICIPIVPPKDVPVDLHLKAFVGYRSSTQFHVFESTRQLPR
  FSMYALTSLDPASEPISYVNFTIAERAQRVVVWLGQNFLLPEDTHIQNAPFQVCFTSLRN
  GGHLHIKIKLSGEITINTDDIDLAGDIIQSMASFFAIEDLQVEADFPVYFEELRKVLVKV
  DEYHSVHQKLSADMADHSNLIRSLLVGAEDARLMRDMKTMKSRYMELYDLNRDLLNGYKI
  RCNNHTELLGNLKAVNQAIQRAGRLRVGKPKNQVITACRDAIRSNNINTLFKIMRVGTAS
  S
• 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.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: BBSome-mediated cargo-targeting to cilium (R-HSA-5620922)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bardet-Biedl syndrome 2	DIS1WLAX	Definitive	Autosomal recessive	[1]
Ciliopathy	DIS10G4I	Definitive	Autosomal recessive	[1]
Retinitis pigmentosa 74	DIS38PCE	Definitive	Autosomal recessive	[2]
Acrocallosal syndrome	DISKMCG2	Strong	Genetic Variation	[3]
Bardet-Biedl syndrome 3	DISLN372	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[6]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[7]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[7]
Gastrin-producing neuroendocrine tumor	DIS8TYKO	Strong	Biomarker	[8]
Intellectual disability	DISMBNXP	Strong	Biomarker	[9]
Kidney cancer	DISBIPKM	Strong	Biomarker	[10]
McKusick-Kaufman syndrome	DIS8JXFP	Strong	Genetic Variation	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[12]
Nijmegen breakage syndrome	DIS98HVL	Strong	Genetic Variation	[13]
Obesity	DIS47Y1K	Strong	Genetic Variation	[14]
Polydactyly	DIS25BMZ	Strong	Genetic Variation	[15]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[16]
Renal carcinoma	DISER9XT	Strong	Biomarker	[10]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[6]
Sarcoidosis	DISE5B8Z	Strong	Genetic Variation	[17]
Sleep disorder	DIS3JP1U	Strong	Biomarker	[18]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[19]
Hirschsprung disease	DISUUSM1	moderate	Genetic Variation	[20]
Retinopathy	DISB4B0F	moderate	Biomarker	[21]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[22]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[2]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[23]
Colon adenocarcinoma	DISDRE0J	Limited	Altered Expression	[24]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[24]
Inherited retinal dystrophy	DISGGL77	Limited	Genetic Variation	[25]
Prostate cancer	DISF190Y	Limited	Altered Expression	[16]
Stroke	DISX6UHX	Limited	Genetic Variation	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Bardet-Biedl syndrome 2 protein (BBS2).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Bardet-Biedl syndrome 2 protein (BBS2).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Bardet-Biedl syndrome 2 protein (BBS2).	[42]

14 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 2 protein (BBS2).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[29]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[30]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[31]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[32]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[33]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[34]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[35]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[36]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[37]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[38]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[40]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[41]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Bardet-Biedl syndrome 2 protein (BBS2).	[43]

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] Association between missense mutations in the BBS2 gene and nonsyndromic retinitis pigmentosa. JAMA Ophthalmol. 2015 Mar;133(3):312-8. doi: 10.1001/jamaophthalmol.2014.5251.
• [3] 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.
• [4] Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3). Am J Hum Genet. 2004 Sep;75(3):475-84. doi: 10.1086/423903. Epub 2004 Jul 16.
• [5] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [6] New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey.J Med Genet. 1999 Jun;36(6):437-46.
• [7] Expression of gastrin-releasing peptide receptors in endometrial cancer.J Am Coll Surg. 2003 Jun;196(6):898-904. doi: 10.1016/S1072-7515(03)00290-4.
• [8] Mechanisms of bombesin on growth of gastrinoma (PT) in vivo.Dig Dis Sci. 1996 Nov;41(11):2180-6. doi: 10.1007/BF02071398.
• [9] Plasmolipin: genomic structure, chromosomal localization, protein expression pattern, and putative association with Bardet-Biedl syndrome.Mamm Genome. 2001 Dec;12(12):933-7. doi: 10.1007/s00335-001-3035-5.
• [10] Renal cancer and malformations in relatives of patients with Bardet-Biedl syndrome.Nephrol Dial Transplant. 2000 Dec;15(12):1977-85. doi: 10.1093/ndt/15.12.1977.
• [11] The molecular genetics of Bardet-Biedl syndrome.Curr Opin Genet Dev. 2001 Jun;11(3):317-21. doi: 10.1016/s0959-437x(00)00196-9.
• [12] Bombesin induces angiogenesis and neuroblastoma growth.Cancer Lett. 2007 Aug 18;253(2):273-81. doi: 10.1016/j.canlet.2007.02.007. Epub 2007 Mar 26.
• [13] 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.
• [14] Bardet-Biedl syndrome gene variants are associated with both childhood and adult common obesity in French Caucasians.Diabetes. 2006 Oct;55(10):2876-82. doi: 10.2337/db06-0337.
• [15] Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes.Eur J Med Genet. 2011 Mar-Apr;54(2):157-60. doi: 10.1016/j.ejmg.2010.10.004. Epub 2010 Oct 29.
• [16] Regulation of bombesin-stimulated cyclooxygenase-2 expression in prostate cancer cells.BMC Mol Biol. 2011 Jul 11;12:29. doi: 10.1186/1471-2199-12-29.
• [17] Osteoprotegerin/sRANKL Signaling System in Pulmonary Sarcoidosis: A Bronchoalveolar Lavage Study.Adv Exp Med Biol. 2017;944:1-7. doi: 10.1007/5584_2016_44.
• [18] Sleep disturbances negatively affect balance and gait function in post-stroke patients.NeuroRehabilitation. 2018;43(2):211-218. doi: 10.3233/NRE-172351.
• [19] BBS4 regulates the expression and secretion of FSTL1, a protein that participates in ciliogenesis and the differentiation of 3T3-L1.Sci Rep. 2017 Aug 29;7(1):9765. doi: 10.1038/s41598-017-10330-0.
• [20] Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease.Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13921-6. doi: 10.1073/pnas.0901219106. Epub 2009 Jul 31.
• [21] Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin.Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16588-93. doi: 10.1073/pnas.0405496101. Epub 2004 Nov 11.
• [22] 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.
• [23] Mutant SOD1 Increases APP Expression and Phosphorylation in Cellular and Animal Models of ALS.PLoS One. 2015 Nov 24;10(11):e0143420. doi: 10.1371/journal.pone.0143420. eCollection 2015.
• [24] Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells.Oncogene. 2007 Feb 15;26(7):958-69. doi: 10.1038/sj.onc.1209856. Epub 2006 Aug 14.
• [25] 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.
• [26] Group- and Individual-Level Responsiveness of the 3-Point Berg Balance Scale and 3-Point Postural Assessment Scale for Stroke Patients.Arch Phys Med Rehabil. 2018 Mar;99(3):529-533. doi: 10.1016/j.apmr.2017.08.472. Epub 2017 Sep 9.
• [27] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [28] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [29] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [30] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [31] 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.
• [32] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [33] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [34] 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.
• [35] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [36] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [37] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [38] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [39] 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.
• [40] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [41] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [42] 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.
• [43] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.