Details of Drug Off-Target (DOT)

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

• DOT Name: Autism susceptibility gene 2 protein (AUTS2)
• Gene Name: AUTS2
• Related Disease:
  Attention deficit hyperactivity disorder
  Autism, susceptibility to, 15
  Cognitive impairment
  Syndromic intellectual disability
  T-cell acute lymphoblastic leukaemia
  Autism
  Autism spectrum disorder
  Autism spectrum disorder due to AUTS2 deficiency
  B-cell neoplasm
  Childhood acute lymphoblastic leukemia
  Epilepsy
  Hepatosplenic T-cell lymphoma
  Heroin dependence
  Major depressive disorder
  Motion sickness
  Neoplasm
  Neurodevelopmental disorder
  Schizophrenia
  T-cell leukaemia
  Acute myelogenous leukaemia
  Alcohol dependence
  Burkitt lymphoma
  Hirschsprung disease
  Acute lymphocytic leukaemia
  Alopecia
  Intellectual disability
  Isolated congenital microcephaly
  Nervous system disease
  Non-insulin dependent diabetes
  Pervasive developmental disorder
• UniProt ID: AUTS2_HUMAN
• Pfam ID: PF15336
• Sequence:
  MDGPTRGHGLRKKRRSRSQRDRERRSRGGLGAGAAGGGGAGRTRALSLASSSGSDKEDNG
  KPPSSAPSRPRPPRRKRRESTSAEEDIIDGFAMTSFVTFEALEKDVALKPQERVEKRQTP
  LTKKKREALTNGLSFHSKKSRLSHPHHYSSDRENDRNLCQHLGKRKKMPKALRQLKPGQN
  SCRDSDSESASGESKGFHRSSSRERLSDSSAPSSLGTGYFCDSDSDQEEKASDASSEKLF
  NTVIVNKDPELGVGTLPEHDSQDAGPIVPKISGLERSQEKSQDCCKEPIFEPVVLKDPCP
  QVAQPIPQPQTEPQLRAPSPDPDLVQRTEAPPQPPPLSTQPPQGPPEAQLQPAPQPQVQR
  PPRPQSPTQLLHQNLPPVQAHPSAQSLSQPLSAYNSSSLSLNSLSSSRSSTPAKTQPAPP
  HISHHPSASPFPLSLPNHSPLHSFTPTLQPPAHSHHPNMFAPPTALPPPPPLTSGSLQVA
  GHPAGSTYSEQDILRQELNTRFLASQSADRGASLGPPPYLRTEFHQHQHQHQHTHQHTHQ
  HTFTPFPHAIPPTAIMPTPAPPMFDKYPTKVDPFYRHSLFHSYPPAVSGIPPMIPPTGPF
  GSLQGAFQPKTSNPIDVAARPGTVPHTLLQKDPRLTDPFRPMLRKPGKWCAMHVHIAWQI
  YHHQQKVKKQMQSDPHKLDFGLKPEFLSRPPGPSLFGAIHHPHDLARPSTLFSAAGAAHP
  TGTPFGPPPHHSNFLNPAAHLEPFNRPSTFTGLAAVGGNAFGGLGNPSVTPNSMFGHKDG
  PSVQNFSNPHEPWNRLHRTPPSFPTPPPWLKPGELERSASAAAHDRDRDVDKRDSSVSKD
  DKERESVEKRHSSHPSPAPVLPVNALGHTRSSTEQIRAHLNTEAREKDKPKERERDHSES
  RKDLAADEHKAKEGHLPEKDGHGHEGRAAGEEAKQLARVPSPYVRTPVVESARPNSTSSR
  EAEPRKGEPAYENPKKSSEVKVKEERKEDHDLPPEAPQTHRASEPPPPNSSSSVHPGPLA
  SMPMTVGVTGIHPMNSISSLDRTRMMTPFMGISPLPGGERFPYPSFHWDPIRDPLRDPYR
  ELDIHRRDPLGRDFLLRNDPLHRLSTPRLYEADRSFRDREPHDYSHHHHHHHHPLSVDPR
  REHERGGHLDERERLHMLREDYEHTRLHSVHPASLDGHLPHPSLITPGLPSMHYPRISPT
  AGNQNGLLNKTPPTAALSAPPPLISTLGGRPVSPRRTTPLSAEIRERPPSHTLKDIEAR
• Function: Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. The PRC1-like complex that contains PCGF5, RNF2, CSNK2B, RYBP and AUTS2 has decreased histone H2A ubiquitination activity, due to the phosphorylation of RNF2 by CSNK2B. As a consequence, the complex mediates transcriptional activation. In the cytoplasm, plays a role in axon and dendrite elongation and in neuronal migration during embryonic brain development. Promotes reorganization of the actin cytoskeleton, lamellipodia formation and neurite elongation via its interaction with RAC guanine nucleotide exchange factors, which then leads to the activation of RAC1.
• Tissue Specificity: Strongly expressed in brain, skeletal muscle and kidney. Also expressed in placenta, lung and leukocytes.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway: RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Definitive	Genetic Variation	[1]
Autism, susceptibility to, 15	DISYCG6A	Definitive	Autosomal dominant	[2]
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[3]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[4]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Altered Expression	[5]
Autism	DISV4V1Z	Strong	Genetic Variation	[6]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[7]
Autism spectrum disorder due to AUTS2 deficiency	DIS3TSKQ	Strong	Autosomal dominant	[8]
B-cell neoplasm	DISVY326	Strong	Biomarker	[9]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[10]
Epilepsy	DISBB28L	Strong	Biomarker	[11]
Hepatosplenic T-cell lymphoma	DIS7KMY9	Strong	Biomarker	[12]
Heroin dependence	DISQ1H57	Strong	Genetic Variation	[13]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[14]
Motion sickness	DISZ2WZW	Strong	Genetic Variation	[15]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[9]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[16]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[17]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[18]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[19]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[20]
Burkitt lymphoma	DIS9D5XU	moderate	FusionGene	[21]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[22]
Acute lymphocytic leukaemia	DISPX75S	Limited	Altered Expression	[18]
Alopecia	DIS37HU4	Limited	Genetic Variation	[23]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[24]
Isolated congenital microcephaly	DISUXHZ6	Limited	Genetic Variation	[6]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[25]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[26]
Pervasive developmental disorder	DIS51975	Limited	Genetic Variation	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Autism susceptibility gene 2 protein (AUTS2) affects the response to substance of Topotecan.	[46]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Autism susceptibility gene 2 protein (AUTS2).	[27]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Autism susceptibility gene 2 protein (AUTS2).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Autism susceptibility gene 2 protein (AUTS2).	[40]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Autism susceptibility gene 2 protein (AUTS2).	[41]

17 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 Autism susceptibility gene 2 protein (AUTS2).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Autism susceptibility gene 2 protein (AUTS2).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Autism susceptibility gene 2 protein (AUTS2).	[30]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Autism susceptibility gene 2 protein (AUTS2).	[31]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Autism susceptibility gene 2 protein (AUTS2).	[32]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Autism susceptibility gene 2 protein (AUTS2).	[33]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Autism susceptibility gene 2 protein (AUTS2).	[34]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Autism susceptibility gene 2 protein (AUTS2).	[35]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Autism susceptibility gene 2 protein (AUTS2).	[36]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Autism susceptibility gene 2 protein (AUTS2).	[37]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the expression of Autism susceptibility gene 2 protein (AUTS2).	[35]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Autism susceptibility gene 2 protein (AUTS2).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Autism susceptibility gene 2 protein (AUTS2).	[42]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Autism susceptibility gene 2 protein (AUTS2).	[43]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Autism susceptibility gene 2 protein (AUTS2).	[44]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Autism susceptibility gene 2 protein (AUTS2).	[32]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Autism susceptibility gene 2 protein (AUTS2).	[45]

References

• [1] Function and regulation of AUTS2, a gene implicated in autism and human evolution.PLoS Genet. 2013;9(1):e1003221. doi: 10.1371/journal.pgen.1003221. Epub 2013 Jan 17.
• [2] Two male adults with pathogenic AUTS2 variants, including a two-base pair deletion, further delineate the AUTS2 syndrome. Eur J Hum Genet. 2015 Jun;23(6):803-7. doi: 10.1038/ejhg.2014.173. Epub 2014 Sep 10.
• [3] Cocaine-Induced Chromatin Modifications Associate With Increased Expression and Three-Dimensional Looping of Auts2.Biol Psychiatry. 2017 Dec 1;82(11):794-805. doi: 10.1016/j.biopsych.2017.04.013. Epub 2017 May 5.
• [4] 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.
• [5] NKL homeobox gene MSX1 acts like a tumor suppressor in NK-cell leukemia.Oncotarget. 2017 Jun 21;8(40):66815-66832. doi: 10.18632/oncotarget.18609. eCollection 2017 Sep 15.
• [6] AUTS2 isoforms control neuronal differentiation.Mol Psychiatry. 2021 Feb;26(2):666-681. doi: 10.1038/s41380-019-0409-1. Epub 2019 Apr 5.
• [7] Generation of an induced pluripotent stem cell line (SDQLCHi008-A) from a patient with ASD and DD carrying an 830kb de novo deletion at chr7q11.22 including the exon 1 of AUTS2 gene.Stem Cell Res. 2019 Oct;40:101557. doi: 10.1016/j.scr.2019.101557. Epub 2019 Aug 31.
• [8] Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. Am J Hum Genet. 2013 Feb 7;92(2):210-20. doi: 10.1016/j.ajhg.2012.12.011. Epub 2013 Jan 17.
• [9] Recurrent intragenic exon rearrangements of SOBP and AUTS2 in non-Hodgkin B-cell lymphoma.Int J Hematol. 2020 Jan;111(1):75-83. doi: 10.1007/s12185-019-02766-z. Epub 2019 Nov 4.
• [10] Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray.Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11921-6. doi: 10.1073/pnas.0711039105. Epub 2008 Aug 12.
• [11] Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.PLoS Genet. 2010 May 20;6(5):e1000962. doi: 10.1371/journal.pgen.1000962.
• [12] Deregulated expression of NKL homeobox genes in T-cell lymphomas.Oncotarget. 2019 May 14;10(35):3227-3247. doi: 10.18632/oncotarget.26929. eCollection 2019 May 14.
• [13] The evidence for the contribution of the autism susceptibility candidate 2 (AUTS2) gene in heroin dependence susceptibility.J Mol Neurosci. 2014 Dec;54(4):811-9. doi: 10.1007/s12031-014-0421-5. Epub 2014 Nov 15.
• [14] A genome-wide association study of antidepressant response in Koreans.Transl Psychiatry. 2015 Sep 8;5(9):e633. doi: 10.1038/tp.2015.127.
• [15] Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis.Hum Mol Genet. 2015 May 1;24(9):2700-8. doi: 10.1093/hmg/ddv028. Epub 2015 Jan 26.
• [16] De novo exon 1 deletion of AUTS2 gene in a patient with autism spectrum disorder and developmental delay: a case report and a brief literature review.Am J Med Genet A. 2015 Jun;167(6):1381-5. doi: 10.1002/ajmg.a.37050. Epub 2015 Apr 6.
• [17] Association study identifying a new susceptibility gene (AUTS2) for schizophrenia.Int J Mol Sci. 2014 Oct 24;15(11):19406-16. doi: 10.3390/ijms151119406.
• [18] Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia.Oncotarget. 2016 Jul 19;7(29):45398-45413. doi: 10.18632/oncotarget.9982.
• [19] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [20] Association between AUTS2 haplotypes and alcohol dependence in a Japanese population.Acta Neuropsychiatr. 2016 Aug;28(4):214-20. doi: 10.1017/neu.2015.70. Epub 2016 Jan 14.
• [21] PAX5-AUTS2: a recurrent fusion gene in childhood B-cell precursor acute lymphoblastic leukemia.Leuk Res. 2012 Aug;36(8):e178-81. doi: 10.1016/j.leukres.2012.04.015. Epub 2012 May 12.
• [22] Association of NRG1 and AUTS2 genetic polymorphisms with Hirschsprung disease in a South Chinese population.J Cell Mol Med. 2018 Apr;22(4):2190-2199. doi: 10.1111/jcmm.13498. Epub 2018 Jan 29.
• [23] Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
• [24] A detailed clinical analysis of 13 patients with AUTS2 syndrome further delineates the phenotypic spectrum and underscores the behavioural phenotype.J Med Genet. 2016 Aug;53(8):523-32. doi: 10.1136/jmedgenet-2015-103601. Epub 2016 Apr 13.
• [25] No Association between the Polymorphism rs6943555 in the AUTS2 Gene and Personality Traits in Japanese University Students.Psychiatry Investig. 2017 Sep;14(5):681-686. doi: 10.4306/pi.2017.14.5.681. Epub 2017 Sep 11.
• [26] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [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] 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.
• [29] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [30] 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.
• [31] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [32] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [33] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [34] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [35] Synergistic effects of arsenic trioxide combined with ascorbic acid in human osteosarcoma MG-63 cells: a systems biology analysis. Eur Rev Med Pharmacol Sci. 2014;18(24):3877-88.
• [36] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [37] 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.
• [38] 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.
• [39] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [40] 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.
• [41] 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.
• [42] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [43] 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.
• [44] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [45] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [46] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.