Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9PYPV1)

• DOT Name: ADP-ribosylation factor-like protein 13B (ARL13B)
• Synonyms: ADP-ribosylation factor-like protein 2-like 1; ARL2-like protein 1
• Gene Name: ARL13B
• Related Disease:
  Joubert syndrome
  Joubert syndrome 8
  Alkaptonuria
  Blindness
  Carpenter syndrome
  Cystic kidney disease
  Hereditary hemochromatosis
  Joubert syndrome 1
  Medulloblastoma
  Neoplasm
  Retinopathy
  Breast cancer
  Breast carcinoma
  Obesity
  Advanced cancer
  Ciliopathy
  Intellectual disability
• UniProt ID: AR13B_HUMAN
• Pfam ID: PF00025
• Sequence:
  MFSLMASCCGWFKRWREPVRKVTLLMVGLDNAGKTATAKGIQGEYPEDVAPTVGFSKINL
  RQGKFEVTIFDLGGGIRIRGIWKNYYAESYGVIFVVDSSDEERMEETKEAMSEMLRHPRI
  SGKPILVLANKQDKEGALGEADVIECLSLEKLVNEHKCLCQIEPCSAISGYGKKIDKSIK
  KGLYWLLHVIARDFDALNERIQKETTEQRALEEQEKQERAERVRKLREERKQNEQEQAEL
  DGTSGLAELDPEPTNPFQPIASVIIENEGKLEREKKNQKMEKDSDGCHLKHKMEHEQIET
  QGQVNHNGQKNNEFGLVENYKEALTQQLKNEDETDRPSLESANGKKKTKKLRMKRNHRVE
  PLNIDDCAPESPTPPPPPPPVGWGTPKVTRLPKLEPLGETHHNDFYRKPLPPLAVPQRPN
  SDAHDVIS
• Function: Cilium-specific protein required to control the microtubule-based, ciliary axoneme structure. May act by maintaining the association between IFT subcomplexes A and B. Binds GTP but is not able to hydrolyze it; the GTPase activity remains unclear. Required to pattern the neural tube. Involved in cerebral cortex development: required for the initial formation of a polarized radial glial scaffold, the first step in the construction of the cerebral cortex, by regulating ciliary signaling. Regulates the migration and placement of postmitotic interneurons in the developing cerebral cortex. May regulate endocytic recycling traffic; however, additional evidence is required to confirm these data.
• Tissue Specificity: Expressed in the developing brain.
• Reactome Pathway:
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOJ GTPase cycle (R-HSA-9013409)
  Chaperone Mediated Autophagy (R-HSA-9613829)
  Late endosomal microautophagy (R-HSA-9615710)
  Aggrephagy (R-HSA-9646399)
  ARL13B-mediated ciliary trafficking of INPP5E (R-HSA-5624958)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Joubert syndrome	DIS7P5CO	Definitive	Autosomal recessive	[1]
Joubert syndrome 8	DIS9O1SL	Definitive	Autosomal recessive	[2]
Alkaptonuria	DISXDZWS	Strong	Altered Expression	[3]
Blindness	DISTIM10	Strong	Biomarker	[4]
Carpenter syndrome	DISU690E	Strong	Biomarker	[5]
Cystic kidney disease	DISRT1LM	Strong	Biomarker	[6]
Hereditary hemochromatosis	DISVG5MT	Strong	Biomarker	[5]
Joubert syndrome 1	DISC9Q82	Strong	GermlineCausalMutation	[7]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Retinopathy	DISB4B0F	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	moderate	Biomarker	[9]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[9]
Obesity	DIS47Y1K	moderate	Biomarker	[2]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Ciliopathy	DIS10G4I	Limited	Biomarker	[5]
Intellectual disability	DISMBNXP	Limited	Biomarker	[11]

4 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 ADP-ribosylation factor-like protein 13B (ARL13B).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of ADP-ribosylation factor-like protein 13B (ARL13B).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of ADP-ribosylation factor-like protein 13B (ARL13B).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of ADP-ribosylation factor-like protein 13B (ARL13B).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ADP-ribosylation factor-like protein 13B (ARL13B).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ADP-ribosylation factor-like protein 13B (ARL13B).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ADP-ribosylation factor-like protein 13B (ARL13B).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ADP-ribosylation factor-like protein 13B (ARL13B).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of ADP-ribosylation factor-like protein 13B (ARL13B).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of ADP-ribosylation factor-like protein 13B (ARL13B).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ADP-ribosylation factor-like protein 13B (ARL13B).	[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] Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity. Eur J Hum Genet. 2015 May;23(5):621-7. doi: 10.1038/ejhg.2014.156. Epub 2014 Aug 20.
• [3] Reduced primary cilia length and altered Arl13b expression are associated with deregulated chondrocyte Hedgehog signaling in alkaptonuria.J Cell Physiol. 2017 Sep;232(9):2407-2417. doi: 10.1002/jcp.25839. Epub 2017 Mar 31.
• [4] ARL13B, a Joubert Syndrome-Associated Protein, Is Critical for Retinogenesis and Elaboration of Mouse Photoreceptor Outer Segments.J Neurosci. 2019 Feb 20;39(8):1347-1364. doi: 10.1523/JNEUROSCI.1761-18.2018. Epub 2018 Dec 20.
• [5] Small GTPases in hedgehog signalling: emerging insights into the disease mechanisms of Rab23-mediated and Arl13b-mediated ciliopathies.Curr Opin Genet Dev. 2019 Jun;56:61-68. doi: 10.1016/j.gde.2019.07.009. Epub 2019 Aug 27.
• [6] Deletion of ADP Ribosylation Factor-Like GTPase 13B Leads to Kidney Cysts.J Am Soc Nephrol. 2016 Dec;27(12):3628-3638. doi: 10.1681/ASN.2015091004. Epub 2016 May 6.
• [7] Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. Am J Hum Genet. 2008 Aug;83(2):170-9. doi: 10.1016/j.ajhg.2008.06.023.
• [8] Disruption of the ciliary GTPase Arl13b suppresses Sonic hedgehog overactivation and inhibits medulloblastoma formation.Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):1570-1575. doi: 10.1073/pnas.1706977115. Epub 2018 Jan 29.
• [9] Arl13b Regulates Breast Cancer Cell Migration and Invasion by Controlling Integrin-Mediated Signaling.Cancers (Basel). 2019 Sep 29;11(10):1461. doi: 10.3390/cancers11101461.
• [10] Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway.Cancer Res. 2017 Aug 1;77(15):4000-4013. doi: 10.1158/0008-5472.CAN-16-2461. Epub 2017 Jun 13.
• [11] Molar tooth sign and superior vermian dysplasia: a radiological, clinical, and genetic study.Neuropediatrics. 2006 Feb;37(1):42-5. doi: 10.1055/s-2006-923838.
• [12] 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.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 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.
• [17] 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.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [20] 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.
• [21] 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.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.