Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVS3R2X)

• DOT Name: Paired mesoderm homeobox protein 2A (PHOX2A)
• Synonyms: ARIX1 homeodomain protein; Aristaless homeobox protein homolog; Paired-like homeobox 2A
• Gene Name: PHOX2A
• Related Disease:
  Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement
  Neoplasm
  Cervical cancer
  Cervical carcinoma
  Congenital fibrosis of extraocular muscles type 1
  Epilepsy
  Fibrosis of extraocular muscles, congenital, 2
  High blood pressure
  Myopathy
  Non-insulin dependent diabetes
  Ptosis
  X-linked intellectual disability
  Congenital fibrosis of extraocular muscles
  Neuroblastoma
• UniProt ID: PHX2A_HUMAN
• Pfam ID: PF00046
• Sequence:
  MDYSYLNSYDSCVAAMEASAYGDFGACSQPGGFQYSPLRPAFPAAGPPCPALGSSNCALG
  ALRDHQPAPYSAVPYKFFPEPSGLHEKRKQRRIRTTFTSAQLKELERVFAETHYPDIYTR
  EELALKIDLTEARVQVWFQNRRAKFRKQERAASAKGAAGAAGAKKGEARCSSEDDDSKES
  TCSPTPDSTASLPPPPAPGLASPRLSPSPLPVALGSGPGPGPGPQPLKGALWAGVAGGGG
  GGPGAGAAELLKAWQPAESGPGPFSGVLSSFHRKPGPALKTNLF
• Function: May be involved in regulating the specificity of expression of the catecholamine biosynthetic genes. Acts as a transcription activator/factor. Could maintain the noradrenergic phenotype.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement	DISPG5B0	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[3]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[3]
Congenital fibrosis of extraocular muscles type 1	DISQ4HP6	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	Genetic Variation	[5]
Fibrosis of extraocular muscles, congenital, 2	DISHBITM	Strong	Autosomal recessive	[6]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[7]
Myopathy	DISOWG27	Strong	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[9]
Ptosis	DISJZNIY	Strong	Genetic Variation	[10]
X-linked intellectual disability	DISYJBY3	Strong	Genetic Variation	[5]
Congenital fibrosis of extraocular muscles	DISE84PU	Supportive	Autosomal dominant	[11]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Paired mesoderm homeobox protein 2A (PHOX2A).	[13]

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 increases the methylation of Paired mesoderm homeobox protein 2A (PHOX2A).	[14]

References

• [1] Familial unilateral Brown syndrome.Ophthalmic Genet. 2002 Sep;23(3):175-84. doi: 10.1076/opge.23.3.175.7882.
• [2] The Phox2 pathway is differentially expressed in neuroblastoma tumors, but no mutations were found in the candidate tumor suppressor gene PHOX2A.Int J Oncol. 2009 Mar;34(3):697-705. doi: 10.3892/ijo_00000196.
• [3] Genetic variability and functional implication of the long control region in HPV-16 variants in Southwest China.PLoS One. 2017 Aug 2;12(8):e0182388. doi: 10.1371/journal.pone.0182388. eCollection 2017.
• [4] Congenital fibrosis of the extraocular muscles type 2, an inherited exotropic strabismus fixus, maps to distal 11q13.Am J Hum Genet. 1998 Aug;63(2):517-25. doi: 10.1086/301980.
• [5] Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet. 2002 Apr;30(4):441-5. doi: 10.1038/ng862. Epub 2002 Mar 11.
• [6] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [7] An ancestral variant of Secretogranin II confers regulation by PHOX2 transcription factors and association with hypertension.Hum Mol Genet. 2007 Jul 15;16(14):1752-64. doi: 10.1093/hmg/ddm123. Epub 2007 Jun 21.
• [8] Neurological features of congenital fibrosis of the extraocular muscles type 2 with mutations in PHOX2A.Brain. 2006 Sep;129(Pt 9):2363-74. doi: 10.1093/brain/awl161. Epub 2006 Jun 30.
• [9] The lipid phosphatase SHIP2 controls insulin sensitivity.Nature. 2001 Jan 4;409(6816):92-7. doi: 10.1038/35051094.
• [10] Applications of molecular genetics to the understanding of congenital ocular motility disorders.Ann N Y Acad Sci. 2002 Apr;956:55-63. doi: 10.1111/j.1749-6632.2002.tb02808.x.
• [11] Congenital Fibrosis of the Extraocular Muscles Overview. 2004 Apr 27 [updated 2021 Aug 12]. 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] PHOX2A and PHOX2B are differentially regulated during retinoic acid-driven differentiation of SK-N-BE(2)C neuroblastoma cell line.Exp Cell Res. 2016 Mar 1;342(1):62-71. doi: 10.1016/j.yexcr.2016.02.014. Epub 2016 Feb 19.
• [13] 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.
• [14] 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.