Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLV3SBS)

• DOT Name: ADP-ribosylation factor-like protein 6 (ARL6)
• Synonyms: Bardet-Biedl syndrome 3 protein
• Gene Name: ARL6
• Related Disease:
  Bardet-Biedl syndrome 1
  Bardet-Biedl syndrome 3
  Disorder of orbital region
  Retinitis pigmentosa 55
  Hereditary hemochromatosis
  Inherited retinal dystrophy
  Myopia
  Nijmegen breakage syndrome
  Polydactyly
  Retinopathy
  Bardet biedl syndrome
  Retinitis pigmentosa
• UniProt ID: ARL6_HUMAN
• PDB ID: 2H57
• Pfam ID: PF00025
• Sequence:
  MGLLDRLSVLLGLKKKEVHVLCLGLDNSGKTTIINKLKPSNAQSQNILPTIGFSIEKFKS
  SSLSFTVFDMSGQGRYRNLWEHYYKEGQAIIFVIDSSDRLRMVVAKEELDTLLNHPDIKH
  RRIPILFFANKMDLRDAVTSVKVSQLLCLENIKDKPWHICASDAIKGEGLQEGVDWLQDQ
  IQTVKT
• Function: Involved in membrane protein trafficking at the base of the ciliary organelle. Mediates recruitment onto plasma membrane of the BBSome complex which would constitute a coat complex required for sorting of specific membrane proteins to the primary cilia. Together with BBS1, is necessary for correct trafficking of PKD1 to primary cilia. Together with the BBSome complex and LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. May regulate cilia assembly and disassembly and subsequent ciliary signaling events such as the Wnt signaling cascade. Isoform 2 may be required for proper retinal function and organization.
• Reactome Pathway: BBSome-mediated cargo-targeting to cilium (R-HSA-5620922)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bardet-Biedl syndrome 1	DISRLPZE	Definitive	Biomarker	[1]
Bardet-Biedl syndrome 3	DISLN372	Definitive	Autosomal recessive	[2]
Disorder of orbital region	DISH0ECJ	Definitive	Biomarker	[1]
Retinitis pigmentosa 55	DIS9REPG	Definitive	Autosomal recessive	[3]
Hereditary hemochromatosis	DISVG5MT	Strong	Genetic Variation	[4]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[5]
Myopia	DISK5S60	Strong	Biomarker	[6]
Nijmegen breakage syndrome	DIS98HVL	Strong	Genetic Variation	[7]
Polydactyly	DIS25BMZ	Strong	Biomarker	[8]
Retinopathy	DISB4B0F	moderate	Biomarker	[9]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[10]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of ADP-ribosylation factor-like protein 6 (ARL6).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ADP-ribosylation factor-like protein 6 (ARL6).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ADP-ribosylation factor-like protein 6 (ARL6).	[14]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of ADP-ribosylation factor-like protein 6 (ARL6).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ADP-ribosylation factor-like protein 6 (ARL6).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ADP-ribosylation factor-like protein 6 (ARL6).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ADP-ribosylation factor-like protein 6 (ARL6).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of ADP-ribosylation factor-like protein 6 (ARL6).	[12]

References

• [1] The embryonic expression patterns and the knockdown phenotypes of zebrafish ADP-ribosylation factor-like 6 interacting protein gene.Dev Dyn. 2009 Jan;238(1):232-40. doi: 10.1002/dvdy.21832.
• [2] 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.
• [3] Molecular characterization of retinitis pigmentosa in Saudi Arabia. Mol Vis. 2009 Nov 24;15:2464-9.
• [4] 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.
• [5] Extensive genic and allelic heterogeneity underlying inherited retinal dystrophies in Mexican patients molecularly analyzed by next-generation sequencing.Mol Genet Genomic Med. 2020 Jan;8(1):10.1002/mgg3.1044. doi: 10.1002/mgg3.1044. Epub 2019 Nov 17.
• [6] 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.
• [7] 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.
• [8] Clinical and molecular characterisation of Bardet-Biedl syndrome in consanguineous populations: the power of homozygosity mapping.J Med Genet. 2010 Apr;47(4):236-41. doi: 10.1136/jmg.2009.070755. Epub 2009 Oct 26.
• [9] Pathological but not physiological retinal neovascularization is altered in TNF-Rp55-receptor-deficient mice.Invest Ophthalmol Vis Sci. 2006 Nov;47(11):5057-65. doi: 10.1167/iovs.06-0407.
• [10] 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.
• [11] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. 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] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [13] 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.
• [14] 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.
• [15] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [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] 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.
• [18] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.