Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ3YCE7)

• DOT Name: Retinal homeobox protein Rx (RAX)
• Synonyms: Retina and anterior neural fold homeobox protein
• Gene Name: RAX
• Related Disease:
  Isolated microphthalmia 3
  Microphthalmia
  Coloboma
  Melanoma
  Microphthalmia, isolated, with coloboma
  Retinoschisis
  Sclerocornea
  Isolated anophthalmia-microphthalmia syndrome
• UniProt ID: RX_HUMAN
• Pfam ID: PF00046 ; PF03826
• Sequence:
  MHLPGCAPAMADGSFSLAGHLLRSPGGSTSRLHSIEAILGFTKDDGILGTFPAERGARGA
  KERDRRLGARPACPKAPEEGSEPSPPPAPAPAPEYEAPRPYCPKEPGEARPSPGLPVGPA
  TGEAKLSEEEQPKKKHRRNRTTFTTYQLHELERAFEKSHYPDVYSREELAGKVNLPEVRV
  QVWFQNRRAKWRRQEKLEVSSMKLQDSPLLSFSRSPPSATLSPLGAGPGSGGGPAGGALP
  LESWLGPPLPGGGATALQSLPGFGPPAQSLPASYTPPPPPPPFLNSPPLGPGLQPLAPPP
  PSYPCGPGFGDKFPLDEADPRNSSIAALRLKAKEHIQAIGKPWQAL
• Function: Plays a critical role in eye formation by regulating the initial specification of retinal cells and/or their subsequent proliferation. Binds to the photoreceptor conserved element-I (PCE-1/Ret 1) in the photoreceptor cell-specific arrestin promoter.
• Tissue Specificity: Expressed in the developing eye and weakly expressed in the adult retina.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Isolated microphthalmia 3	DISXYC5W	Definitive	Autosomal recessive	[1]
Microphthalmia	DISGEBES	Definitive	Genetic Variation	[2]
Coloboma	DISP39N5	Strong	Genetic Variation	[3]
Melanoma	DIS1RRCY	Strong	Biomarker	[4]
Microphthalmia, isolated, with coloboma	DISLSEUJ	Strong	Genetic Variation	[5]
Retinoschisis	DISTTWND	Strong	Genetic Variation	[3]
Sclerocornea	DIS7HV8A	Strong	Genetic Variation	[1]
Isolated anophthalmia-microphthalmia syndrome	DISA55ZA	Supportive	Autosomal dominant	[6]

3 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 Retinal homeobox protein Rx (RAX).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Retinal homeobox protein Rx (RAX).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Retinal homeobox protein Rx (RAX).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Retinal homeobox protein Rx (RAX).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Retinal homeobox protein Rx (RAX).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Retinal homeobox protein Rx (RAX).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Retinal homeobox protein Rx (RAX).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Retinal homeobox protein Rx (RAX).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Retinal homeobox protein Rx (RAX).	[13]

References

• [1] Confirmation of RAX gene involvement in human anophthalmia. Clin Genet. 2008 Oct;74(4):392-5. doi: 10.1111/j.1399-0004.2008.01078.x. Epub 2008 Sep 9.
• [2] Mutations in the newly identified RAX regulatory sequence are not a frequent cause of micro/anophthalmia.Genet Test Mol Biomarkers. 2009 Jun;13(3):289-90. doi: 10.1089/gtmb.2008.0143.
• [3] Unraveling the genetic cause of a consanguineous family with unilateral coloboma and retinoschisis: expanding the phenotypic variability of RAX mutations.Sci Rep. 2017 Aug 22;7(1):9064. doi: 10.1038/s41598-017-09276-0.
• [4] Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas.Cancer Res. 2006 Jun 15;66(12):6080-6. doi: 10.1158/0008-5472.CAN-06-0157.
• [5] Mutations in the LHX2 gene are not a frequent cause of micro/anophthalmia.Mol Vis. 2010 Dec 18;16:2847-9.
• [6] Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia. Clin Genet. 2014 Oct;86(4):326-34. doi: 10.1111/cge.12275. Epub 2013 Oct 7.
• [7] 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.
• [8] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.