Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW2E47S)

• DOT Name: Visual system homeobox 2
• Synonyms: Ceh-10 homeodomain-containing homolog; Homeobox protein CHX10
• Gene Name: VSX2
• Related Disease:
  Isolated microphthalmia 2
  Microphthalmia, isolated, with coloboma 3
  Microphthalmia
  Isolated anophthalmia-microphthalmia syndrome
  Microphthalmia, isolated, with coloboma
• UniProt ID: VSX2_HUMAN
• Pfam ID: PF00046 ; PF03826
• Sequence:
  MTGKAGEALSKPKSETVAKSTSGGAPARCTGFGIQEILGLNKEPPSSHPRAALDGLAPGH
  LLAARSVLSPAGVGGMGLLGPGGLPGFYTQPTFLEVLSDPQSVHLQPLGRASGPLDTSQT
  ASSDSEDVSSSDRKMSKSALNQTKKRKKRRHRTIFTSYQLEELEKAFNEAHYPDVYAREM
  LAMKTELPEDRIQVWFQNRRAKWRKREKCWGRSSVMAEYGLYGAMVRHSIPLPESILKSA
  KDGIMDSCAPWLLGMHKKSLEAAAESGRKPEGERQALPKLDKMEQDERGPDAQAAISQEE
  LRENSIAVLRAKAQEHSTKVLGTVSGPDSLARSTEKPEEEEAMDEDRPAERLSPPQLEDM
  A
• Function: Acts as a transcriptional regulator through binding to DNA at the consensus sequence 5'-[TC]TAATT[AG][AG]-3' upstream of gene promoters. Plays a significant role in the specification and morphogenesis of the sensory retina. May play a role in specification of V2a interneurons during spinal cord development. Mediates differentiation of V2a interneurons by repression of motor neuron gene transcription, via competitively binding to response elements that are activated by the ISL1-LHX3 complex, such as VSX1. Acts as a positive transcriptional regulator of NXNL1; regulation is significantly increased in synergy with VSX1. Acts as a negative transcriptional regulator of MITF. Represses SAG transcription by competitive inhibition of ISL1-LHX3 response elements. Binds to the photoreceptor conserved element-1 (PCE-1) in the promoter of rod photoreceptor arrestin SAG and acts as a transcriptional repressor. Involved in the development of retinal ganglion cells (RGCs) which leads to release of SHH by RGCs, promoting Hedgehog signaling and subsequent proliferation of retinal progenitor cells. Participates in the development of the cells of the inner nuclear layer, by promoting postnatal differentiation of bipolar cells with a comparable inhibition of rod cell differentiation. May play a role in the maintenance of neural retina identity during development by regulation of canonical Wnt genes and CTNNB1 localization, suggesting a role in the regulation of canonical Wnt signaling.
• Tissue Specificity: Abundantly expressed in retinal neuroblasts during eye development and in the inner nuclear layer of the adult retina. Within this layer, expression is stronger in the outer margin where bipolar cells predominate.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Isolated microphthalmia 2	DISKMF8U	Definitive	Autosomal recessive	[1]
Microphthalmia, isolated, with coloboma 3	DISTBOXP	Definitive	Autosomal recessive	[1]
Microphthalmia	DISGEBES	Strong	Autosomal recessive	[2]
Isolated anophthalmia-microphthalmia syndrome	DISA55ZA	Supportive	Autosomal dominant	[3]
Microphthalmia, isolated, with coloboma	DISLSEUJ	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Visual system homeobox 2.	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Visual system homeobox 2.	[6]

References

• [1] 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.
• [2] 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.
• [3] Human microphthalmia associated with mutations in the retinal homeobox gene CHX10. Nat Genet. 2000 Aug;25(4):397-401. doi: 10.1038/78071.
• [4] CHX10 mutations cause non-syndromic microphthalmia/ anophthalmia in Arab and Jewish kindreds. Hum Genet. 2004 Sep;115(4):302-9. doi: 10.1007/s00439-004-1154-2.
• [5] 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.
• [6] Development of human retinal organoid models for bisphenol toxicity assessment. Ecotoxicol Environ Saf. 2022 Oct 15;245:114094. doi: 10.1016/j.ecoenv.2022.114094. Epub 2022 Sep 18.