Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT23V9YF)

• DOT Name: Protein PTHB1 (BBS9)
• Synonyms: Bardet-Biedl syndrome 9 protein; Parathyroid hormone-responsive B1 gene protein
• Gene Name: BBS9
• Related Disease:
  Bardet-Biedl syndrome 9
  Ciliopathy
  Craniosynostosis 4
  Narcolepsy
  Trigonocephaly
  TWIST1-related craniosynostosis
  Age-related macular degeneration
  Craniosynostosis
  Hydrocephalus
  Hydrocephalus, nonsyndromic, autosomal recessive 1
  Obesity
  Wilms tumor
  Female hypogonadism
  Retinitis pigmentosa
  Bardet biedl syndrome
  Leprosy
  Meningeal tuberculosis
• UniProt ID: PTHB1_HUMAN
• PDB ID: 4YD8; 6XT9
• Pfam ID: PF14728 ; PF14727
• Sequence:
  MSLFKARDWWSTILGDKEEFDQGCLCLANVDNSGNGQDKIIVGSFMGYLRIFSPHPAKTG
  DGAQAEDLLLEVDLRDPVLQVEVGKFVSGTEMLHLAVLHSRKLCVYSVSGTLGNVEHGNQ
  CQMKLMYEHNLQRTACNMTYGSFGGVKGRDLICIQSMDGMLMVFEQESYAFGRFLPGFLL
  PGPLAYSSRTDSFLTVSSCQQVESYKYQVLAFATDADKRQETEQQKLGSGKRLVVDWTLN
  IGEQALDICIVSFNQSASSVFVLGERNFFCLKDNGQIRFMKKLDWSPSCFLPYCSVSEGT
  INTLIGNHNNMLHIYQDVTLKWATQLPHIPVAVRVGCLHDLKGVIVTLSDDGHLQCSYLG
  TDPSLFQAPNVQSRELNYDELDVEMKELQKIIKDVNKSQGVWPMTEREDDLNVSVVVSPN
  FDSVSQATDVEVGTDLVPSVTVKVTLQNRVILQKAKLSVYVQPPLELTCDQFTFEFMTPD
  LTRTVSFSVYLKRSYTPSELEGNAVVSYSRPTDRNPDGIPRVIQCKFRLPLKLICLPGQP
  SKTASHKITIDTNKSPVSLLSLFPGFASQSDDDQVNVMGFHFLGGARITVLASKTSQRYR
  IQSEQFEDLWLITNELILRLQEYFEKQGVKDFACSFSGSIPLQEYFELIDHHFELRINGE
  KLEELLSERAVQFRAIQRRLLARFKDKTPAPLQHLDTLLDGTYKQVIALADAVEENQGNL
  FQSFTRLKSATHLVILLIALWQKLSADQVAILEAAFLPLQEDTQELGWEETVDAAISHLL
  KTCLSKSSKEQALNLNSQLNIPKDTSQLKKHITLLCDRLSKGGRLCLSTDAAAPQTMVMP
  GGCTTIPESDLEERSVEQDSTELFTNHRHLTAETPRPEVSPLQGVSE
• 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. Required for proper BBSome complex assembly and its ciliary localization.
• Tissue Specificity: Widely expressed. Expressed in adult heart, skeletal muscle, lung, liver, kidney, placenta and brain, and in fetal kidney, lung, liver and brain.
• Reactome Pathway: BBSome-mediated cargo-targeting to cilium (R-HSA-5620922)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bardet-Biedl syndrome 9	DISK5CXN	Definitive	Autosomal recessive	[1]
Ciliopathy	DIS10G4I	Definitive	Autosomal recessive	[2]
Craniosynostosis 4	DISZX1GK	Definitive	Biomarker	[3]
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[4]
Trigonocephaly	DISHV6BA	Definitive	Biomarker	[3]
TWIST1-related craniosynostosis	DISGRP2G	Definitive	Biomarker	[3]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[5]
Craniosynostosis	DIS6J405	Strong	Biomarker	[6]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[7]
Hydrocephalus, nonsyndromic, autosomal recessive 1	DISCYZI4	Strong	Biomarker	[7]
Obesity	DIS47Y1K	Strong	Genetic Variation	[8]
Wilms tumor	DISB6T16	Strong	Biomarker	[9]
Female hypogonadism	DISWASB4	moderate	Biomarker	[10]
Retinitis pigmentosa	DISCGPY8	moderate	Genetic Variation	[1]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[11]
Leprosy	DISAA4UI	Limited	Genetic Variation	[12]
Meningeal tuberculosis	DIS8KHDE	Limited	Genetic Variation	[13]

13 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 Protein PTHB1 (BBS9).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein PTHB1 (BBS9).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein PTHB1 (BBS9).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein PTHB1 (BBS9).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein PTHB1 (BBS9).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protein PTHB1 (BBS9).	[20]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Protein PTHB1 (BBS9).	[21]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Protein PTHB1 (BBS9).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein PTHB1 (BBS9).	[23]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Protein PTHB1 (BBS9).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein PTHB1 (BBS9).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Protein PTHB1 (BBS9).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein PTHB1 (BBS9).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein PTHB1 (BBS9).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein PTHB1 (BBS9).	[25]

References

• [1] In search of triallelism in Bardet-Biedl syndrome. Eur J Hum Genet. 2012 Apr;20(4):420-7. doi: 10.1038/ejhg.2011.205. Epub 2012 Feb 22.
• [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] A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9.Nat Genet. 2012 Dec;44(12):1360-4. doi: 10.1038/ng.2463. Epub 2012 Nov 18.
• [4] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [5] Genome-wide analysis of disease progression in age-related macular degeneration.Hum Mol Genet. 2018 Mar 1;27(5):929-940. doi: 10.1093/hmg/ddy002.
• [6] Nonsyndromic craniosynostosis: novel coding variants.Pediatr Res. 2019 Mar;85(4):463-468. doi: 10.1038/s41390-019-0274-2. Epub 2019 Jan 14.
• [7] Knockdown of Bardet-Biedl syndrome gene BBS9/PTHB1 leads to cilia defects.PLoS One. 2012;7(3):e34389. doi: 10.1371/journal.pone.0034389. Epub 2012 Mar 29.
• [8] Screening of 31 genes involved in monogenic forms of obesity in 23 Pakistani probands with early-onset childhood obesity: a case report.BMC Med Genet. 2019 Sep 5;20(1):152. doi: 10.1186/s12881-019-0886-8.
• [9] The parathyroid hormone-responsive B1 gene is interrupted by a t(1;7)(q42;p15) breakpoint associated with Wilms' tumour.Oncogene. 2003 Mar 6;22(9):1371-80. doi: 10.1038/sj.onc.1206332.
• [10] Parathyroid hormone-responsive B1 gene is associated with premature ovarian failure.Hum Reprod. 2008 Jun;23(6):1457-65. doi: 10.1093/humrep/den086. Epub 2008 Mar 18.
• [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] A large-scale genome-wide association and meta-analysis identified four novel susceptibility loci for leprosy.Nat Commun. 2016 Dec 15;7:13760. doi: 10.1038/ncomms13760.
• [13] Cerebral tryptophan metabolism and outcome of tuberculous meningitis: an observational cohort study.Lancet Infect Dis. 2018 May;18(5):526-535. doi: 10.1016/S1473-3099(18)30053-7. Epub 2018 Feb 3.
• [14] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [24] 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.
• [25] 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.
• [26] 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.