Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBGYH25)

• DOT Name: Homeobox protein ARX (ARX)
• Synonyms: Aristaless-related homeobox
• Gene Name: ARX
• Related Disease:
  Infantile spasm
  Intellectual disability
  Intellectual disability, X-linked, with or without seizures, arx-related
  Partington syndrome
  X-linked complex neurodevelopmental disorder
  Autism
  Autism spectrum disorder
  Coffin-Lowry syndrome
  Dravet syndrome
  Epithelial neoplasm
  Hydranencephaly
  Hydrocephalus
  Intellectual disability, X-linked 19
  Malabsorption syndrome
  Movement disorder
  Nervous system disease
  Neurodevelopmental disorder
  Non-insulin dependent diabetes
  Periventricular nodular heterotopia
  Rett syndrome
  Rett syndrome, congenital variant
  Schizophrenia
  SHOX-related short stature
  X-linked lissencephaly with abnormal genitalia
  Corpus callosum, agenesis of
  Subcortical band heterotopia
  Corpus callosum agenesis-abnormal genitalia syndrome
  Infantile epileptic-dyskinetic encephalopathy
  Non-syndromic X-linked intellectual disability
  West syndrome
  X-linked spasticity-intellectual disability-epilepsy syndrome
  Classic lissencephaly
  Dystonia
  Neuroendocrine neoplasm
• UniProt ID: ARX_HUMAN
• Pfam ID: PF00046 ; PF03826
• Sequence:
  MSNQYQEEGCSERPECKSKSPTLLSSYCIDSILGRRSPCKMRLLGAAQSLPAPLTSRADP
  EKAVQGSPKSSSAPFEAELHLPPKLRRLYGPGGGRLLQGAAAAAAAAAAAAAAAATATAG
  PRGEAPPPPPPTARPGERPDGAGAAAAAAAAAAAAWDTLKISQAPQVSISRSKSYRENGA
  PFVPPPPALDELGGPGGVTHPEERLGVAGGPGSAPAAGGGTGTEDDEEELLEDEEDEDEE
  EELLEDDEEELLEDDARALLKEPRRCPVAATGAVAAAAAAAVATEGGELSPKEELLLHPE
  DAEGKDGEDSVCLSAGSDSEEGLLKRKQRRYRTTFTSYQLEELERAFQKTHYPDVFTREE
  LAMRLDLTEARVQVWFQNRRAKWRKREKAGAQTHPPGLPFPGPLSATHPLSPYLDASPFP
  PHHPALDSAWTAAAAAAAAAFPSLPPPPGSASLPPSGAPLGLSTFLGAAVFRHPAFISPA
  FGRLFSTMAPLTSASTAAALLRQPTPAVEGAVASGALADPATAAADRRASSIAALRLKAK
  EHAAQLTQLNILPGTSTGKEVC
• Function: Transcription factor. Binds to specific sequence motif 5'-TAATTA-3' in regulatory elements of target genes, such as histone demethylase KDM5C. Positively modulates transcription of KDM5C. Activates expression of KDM5C synergistically with histone lysine demethylase PHF8 and perhaps in competition with transcription regulator ZNF711; synergy may be related to enrichment of histone H3K4me3 in regulatory elements. Required for normal brain development. Plays a role in neuronal proliferation, interneuronal migration and differentiation in the embryonic forebrain. May also be involved in axonal guidance in the floor plate.
• Tissue Specificity: Expressed predominantly in fetal and adult brain and skeletal muscle. Expression is specific to the telencephalon and ventral thalamus. There is an absence of expression in the cerebellum throughout development and also in adult.

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile spasm	DISZSKDG	Definitive	X-linked	[1]
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[2]
Intellectual disability, X-linked, with or without seizures, arx-related	DISC7ATK	Definitive	X-linked	[3]
Partington syndrome	DIS3H205	Definitive	X-linked recessive	[4]
X-linked complex neurodevelopmental disorder	DISI3QE9	Definitive	X-linked	[1]
Autism	DISV4V1Z	Strong	Altered Expression	[5]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[6]
Coffin-Lowry syndrome	DISMTBDA	Strong	Genetic Variation	[7]
Dravet syndrome	DISJF7LY	Strong	Biomarker	[8]
Epithelial neoplasm	DIS0T594	Strong	Biomarker	[9]
Hydranencephaly	DISE02PO	Strong	Genetic Variation	[10]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[11]
Intellectual disability, X-linked 19	DIS240KZ	Strong	Genetic Variation	[7]
Malabsorption syndrome	DISGMUVS	Strong	Biomarker	[12]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[13]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[14]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[15]
Periventricular nodular heterotopia	DISU3ZRI	Strong	Genetic Variation	[16]
Rett syndrome	DISGG5UV	Strong	Genetic Variation	[17]
Rett syndrome, congenital variant	DISQTBQI	Strong	Biomarker	[18]
Schizophrenia	DISSRV2N	Strong	Biomarker	[19]
SHOX-related short stature	DIS4A87B	Strong	Genetic Variation	[20]
X-linked lissencephaly with abnormal genitalia	DIS2120P	Strong	X-linked	[21]
Corpus callosum, agenesis of	DISO9P40	moderate	Genetic Variation	[22]
Subcortical band heterotopia	DISHN7JS	moderate	Biomarker	[23]
Corpus callosum agenesis-abnormal genitalia syndrome	DISQ50MY	Supportive	X-linked	[24]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Supportive	X-linked	[25]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[26]
West syndrome	DISLIAU9	Supportive	Autosomal dominant	[27]
X-linked spasticity-intellectual disability-epilepsy syndrome	DISOL6BE	Supportive	X-linked	[28]
Classic lissencephaly	DISR8S3S	Limited	Biomarker	[29]
Dystonia	DISJLFGW	Limited	Biomarker	[30]
Neuroendocrine neoplasm	DISNPLOO	Limited	Biomarker	[31]

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 Homeobox protein ARX (ARX).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Homeobox protein ARX (ARX).	[35]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Homeobox protein ARX (ARX).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Homeobox protein ARX (ARX).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Homeobox protein ARX (ARX).	[33]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Homeobox protein ARX (ARX).	[34]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Homeobox protein ARX (ARX).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Homeobox protein ARX (ARX).	[38]

References

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• [2] Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders.Hum Mol Genet. 2019 Dec 15;28(24):4089-4102. doi: 10.1093/hmg/ddz254.
• [3] A novel de novo 27 bp duplication of the ARX gene, resulting from postzygotic mosaicism and leading to three severely affected males in two generations. Am J Med Genet A. 2009 Aug;149A(8):1655-60. doi: 10.1002/ajmg.a.32842.
• [4] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [5] Embryonic forebrain transcriptome of mice with polyalanine expansion mutations in the ARX homeobox gene.Hum Mol Genet. 2016 Dec 15;25(24):5433-5443. doi: 10.1093/hmg/ddw360.
• [6] Mutation screening of the ARX gene in patients with autism.Am J Med Genet B Neuropsychiatr Genet. 2007 Mar 5;144B(2):228-30. doi: 10.1002/ajmg.b.30440.
• [7] Regional localization of an X-linked mental retardation gene to Xp21.1-Xp22.13 (MRX38).Am J Med Genet. 1996 Jul 12;64(1):89-96. doi: 10.1002/(SICI)1096-8628(19960712)64:1<89::AID-AJMG16>3.0.CO;2-O.
• [8] CDKL5 and ARX mutations are not responsible for early onset severe myoclonic epilepsy in infancy.Epilepsy Res. 2009 Nov;87(1):25-30. doi: 10.1016/j.eplepsyres.2009.07.004. Epub 2009 Sep 5.
• [9] Detection of Aristaless-related homeobox protein in ovarian sex cord-stromal tumors.Exp Mol Pathol. 2018 Feb;104(1):38-44. doi: 10.1016/j.yexmp.2017.12.005. Epub 2017 Dec 21.
• [10] Frameshift mutations of the ARX gene in familial Ohtahara syndrome.Epilepsia. 2010 Sep;51(9):1679-84. doi: 10.1111/j.1528-1167.2010.02559.x.
• [11] [ARX--one gene--many phenotypes].Neurol Neurochir Pol. 2008 Jul-Aug;42(4):338-44.
• [12] Lipid malabsorption from altered hormonal signaling changes early gut microbial responses.Am J Physiol Gastrointest Liver Physiol. 2018 Oct 1;315(4):G580-G591. doi: 10.1152/ajpgi.00135.2018. Epub 2018 Jun 28.
• [13] A novel ARX phenotype: rapid neurodegeneration with Ohtahara syndrome and a dyskinetic movement disorder.Dev Med Child Neurol. 2010 Mar;52(3):305-7. doi: 10.1111/j.1469-8749.2009.03470.x. Epub 2010 Feb 4.
• [14] Arx polyalanine expansion in mice leads to reduced pancreatic -cell specification and increased -cell death.PLoS One. 2013 Nov 13;8(11):e78741. doi: 10.1371/journal.pone.0078741. eCollection 2013.
• [15] Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis.Am J Physiol Endocrinol Metab. 2006 Nov;291(5):E982-94. doi: 10.1152/ajpendo.00067.2006. Epub 2006 Jun 13.
• [16] Asymmetric polymicrogyria and periventricular nodular heterotopia due to mutation in ARX.Am J Med Genet A. 2012 Jun;158A(6):1472-6. doi: 10.1002/ajmg.a.35365. Epub 2012 May 14.
• [17] X-linked mental deficiency.Handb Clin Neurol. 2013;111:297-306. doi: 10.1016/B978-0-444-52891-9.00035-X.
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• [19] The maternal immune activation model uncovers a role for the Arx gene in GABAergic dysfunction in schizophrenia.Brain Behav Immun. 2019 Oct;81:161-171. doi: 10.1016/j.bbi.2019.06.009. Epub 2019 Jun 5.
• [20] Two new familial severe infantile spasm syndromes in males.Epilepsy Behav. 2009 Apr;14(4):696-700. doi: 10.1016/j.yebeh.2009.02.011. Epub 2009 Feb 20.
• [21] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [22] An Emerging Female Phenotype with Loss-of-Function Mutations in the Aristaless-Related Homeodomain Transcription Factor ARX.Hum Mutat. 2017 May;38(5):548-555. doi: 10.1002/humu.23190. Epub 2017 Feb 15.
• [23] Identification of DCX gene mutation in lissencephaly spectrum with subcortical band heterotopia using whole exome sequencing.Pediatr Neurol. 2013 May;48(5):411-4. doi: 10.1016/j.pediatrneurol.2012.12.033.
• [24] Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat. 2004 Feb;23(2):147-159. doi: 10.1002/humu.10310.
• [25] Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus. Neurology. 2007 Jul 31;69(5):427-33. doi: 10.1212/01.wnl.0000266594.16202.c1.
• [26] XLMR in MRX families 29, 32, 33 and 38 results from the dup24 mutation in the ARX (Aristaless related homeobox) gene. BMC Med Genet. 2005 Apr 25;6:16. doi: 10.1186/1471-2350-6-16.
• [27] ARX spectrum disorders: making inroads into the molecular pathology. Hum Mutat. 2010 Aug;31(8):889-900. doi: 10.1002/humu.21288.
• [28] X-linked myoclonic epilepsy with spasticity and intellectual disability: mutation in the homeobox gene ARX. Neurology. 2002 Aug 13;59(3):348-56. doi: 10.1212/wnl.59.3.348.
• [29] Genotypically defined lissencephalies show distinct pathologies.J Neuropathol Exp Neurol. 2005 Oct;64(10):847-57. doi: 10.1097/01.jnen.0000182978.56612.41.
• [30] Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach.Mol Genet Genomic Med. 2015 May;3(3):203-14. doi: 10.1002/mgg3.133. Epub 2015 Feb 25.
• [31] Assessment of ARX expression, a novel biomarker for metastatic risk in pancreatic neuroendocrine tumors, in endoscopic ultrasound fine-needle aspiration.Diagn Cytopathol. 2020 Apr;48(4):308-315. doi: 10.1002/dc.24368. Epub 2019 Dec 17.
• [32] 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.
• [33] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [34] 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.
• [35] 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.
• [36] 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.
• [37] 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.
• [38] 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.