Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3SFR2O)

• DOT Name: Paired mesoderm homeobox protein 2B (PHOX2B)
• Synonyms: Neuroblastoma Phox; NBPhox; PHOX2B homeodomain protein; Paired-like homeobox 2B
• Gene Name: PHOX2B
• Related Disease:
  Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease
  Haddad syndrome
  Neuroblastoma, susceptibility to, 2
  Advanced cancer
  Alpha thalassemia-X-linked intellectual disability syndrome
  Arteriosclerosis
  Atherosclerosis
  Autonomic nervous system disorder
  Autosomal dominant prognathism
  Congenital fiber-type disproportion myopathy
  Crohn disease
  Epilepsy
  Ganglioneuroblastoma
  Hereditary Wilms tumor
  Inflammatory bowel disease
  Medulloblastoma
  Mowat-Wilson syndrome
  Obstructive sleep apnea
  Paraganglioma
  Parkinson disease
  Pineoblastoma
  Respiratory disease
  Wilms tumor
  Neurodevelopmental disorder
  Rhabdomyosarcoma
  Obsolete congenital central hypoventilation syndrome
  Childhood kidney Wilms tumor
  Constipation
  Diverticulitis
  Dysautonomia
  Generalized anxiety disorder
• UniProt ID: PHX2B_HUMAN
• PDB ID: 7MJA; 8EK5
• Pfam ID: PF00046
• Sequence:
  MYKMEYSYLNSSAYESCMAGMDTSSLASAYADFSSCSQASGFQYNPIRTTFGATSGCPSL
  TPGSCSLGTLRDHQSSPYAAVPYKLFTDHGGLNEKRKQRRIRTTFTSAQLKELERVFAET
  HYPDIYTREELALKIDLTEARVQVWFQNRRAKFRKQERAAAAAAAAAKNGSSGKKSDSSR
  DDESKEAKSTDPDSTGGPGPNPNPTPSCGANGGGGGGPSPAGAPGAAGPGGPGGEPGKGG
  AAAAAAAAAAAAAAAAAAAAGGLAAAGGPGQGWAPGPGPITSIPDSLGGPFASVLSSLQR
  PNGAKAALVKSSMF
• Function: Involved in the development of several major noradrenergic neuron populations, including the locus coeruleus. Transcription factor which could determine a neurotransmitter phenotype in vertebrates. Enhances second-messenger-mediated activation of the dopamine beta-hydrolase and c-fos promoters, and of several enhancers including cAMP-response element and serum-response element.
• Tissue Specificity: Expressed in neuroblastoma, brain and adrenal gland.

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease	DISODX61	Definitive	Autosomal dominant	[1]
Haddad syndrome	DISF128S	Definitive	Autosomal dominant	[1]
Neuroblastoma, susceptibility to, 2	DISPD991	Definitive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Alpha thalassemia-X-linked intellectual disability syndrome	DISV7OEV	Strong	Genetic Variation	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Autonomic nervous system disorder	DIS6JLTA	Strong	Biomarker	[6]
Autosomal dominant prognathism	DIS2G3FF	Strong	Genetic Variation	[7]
Congenital fiber-type disproportion myopathy	DISU9T2M	Strong	Genetic Variation	[8]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[9]
Epilepsy	DISBB28L	Strong	Biomarker	[10]
Ganglioneuroblastoma	DIS6FPB6	Strong	Biomarker	[11]
Hereditary Wilms tumor	DISYBXFF	Strong	Biomarker	[12]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[13]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[14]
Mowat-Wilson syndrome	DISD1AW7	Strong	Genetic Variation	[15]
Obstructive sleep apnea	DIS0SVD1	Strong	Biomarker	[7]
Paraganglioma	DIS2XXH5	Strong	Altered Expression	[16]
Parkinson disease	DISQVHKL	Strong	Biomarker	[17]
Pineoblastoma	DISQK8F3	Strong	Altered Expression	[14]
Respiratory disease	DISGGAGJ	Strong	Biomarker	[18]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[19]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[20]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[21]
Obsolete congenital central hypoventilation syndrome	DIS26RCJ	Supportive	Autosomal dominant	[22]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Genetic Variation	[19]
Constipation	DISRQXWI	Limited	Genetic Variation	[23]
Diverticulitis	DIS1AK7Q	Limited	Altered Expression	[24]
Dysautonomia	DISF4MT6	Limited	Genetic Variation	[25]
Generalized anxiety disorder	DISPSQCW	Limited	Biomarker	[26]

2 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 Paired mesoderm homeobox protein 2B (PHOX2B).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Paired mesoderm homeobox protein 2B (PHOX2B).	[35]

8 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 Paired mesoderm homeobox protein 2B (PHOX2B).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Paired mesoderm homeobox protein 2B (PHOX2B).	[29]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Paired mesoderm homeobox protein 2B (PHOX2B).	[30]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Paired mesoderm homeobox protein 2B (PHOX2B).	[31]
Dexamethasone	DMMWZET	Approved	Dexamethasone affects the expression of Paired mesoderm homeobox protein 2B (PHOX2B).	[32]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Paired mesoderm homeobox protein 2B (PHOX2B).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Paired mesoderm homeobox protein 2B (PHOX2B).	[33]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Paired mesoderm homeobox protein 2B (PHOX2B).	[34]

References

• [1] 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.
• [2] Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13. Cancer Res. 2002 Nov 15;62(22):6651-8.
• [3] Retrospective evaluation of a decision-support algorithm (MIPOGG) for genetic referrals for children with neuroblastic tumors.Pediatr Blood Cancer. 2018 Dec;65(12):e27390. doi: 10.1002/pbc.27390. Epub 2018 Aug 16.
• [4] New insights into the genetics of neuroblastoma.Mol Diagn Ther. 2013 Apr;17(2):63-9. doi: 10.1007/s40291-013-0019-6.
• [5] SCARB1 Gene Variants Are Associated With the Phenotype of Combined High High-Density Lipoprotein Cholesterol and High Lipoprotein (a).Circ Cardiovasc Genet. 2016 Oct;9(5):408-418. doi: 10.1161/CIRCGENETICS.116.001402. Epub 2016 Sep 20.
• [6] Rare occurrence of PHOX2b mutations in sporadic neuroblastomas.J Pediatr Hematol Oncol. 2008 Oct;30(10):728-32. doi: 10.1097/MPH.0b013e3181772141.
• [7] Obstructive sleep apnea syndrome (OSAS) in children with Class III malocclusion: involvement of the PHOX2B gene.Sleep Breath. 2013 Dec;17(4):1275-80. doi: 10.1007/s11325-013-0833-4. Epub 2013 Mar 28.
• [8] Congenital muscle fiber-type disproportion in a patient with congenital central hypoventilation syndrome due to PHOX2B mutations.J Child Neurol. 2008 Jul;23(7):829-31. doi: 10.1177/0883073808314895.
• [9] IL23R, NOD2/CARD15, ATG16L1 and PHOX2B polymorphisms in a group of patients with Crohn's disease and correlation with sub-phenotypes.Int J Mol Med. 2011 Mar;27(3):469-77. doi: 10.3892/ijmm.2010.591. Epub 2010 Dec 27.
• [10] Genetic analysis of PHOX2B in sudden unexpected death in epilepsy cases.Neurology. 2014 Sep 9;83(11):1018-21. doi: 10.1212/WNL.0000000000000781. Epub 2014 Aug 1.
• [11] PHOX2B mutations and genetic predisposition to neuroblastoma.Oncogene. 2005 Apr 21;24(18):3050-3. doi: 10.1038/sj.onc.1208532.
• [12] A new familial cancer syndrome including predisposition to Wilms tumor and neuroblastoma.Fam Cancer. 2010 Sep;9(3):425-30. doi: 10.1007/s10689-009-9319-8.
• [13] Confirmation of association of IRGM and NCF4 with ileal Crohn's disease in a population-based cohort.Genes Immun. 2008 Sep;9(6):561-5. doi: 10.1038/gene.2008.49. Epub 2008 Jun 26.
• [14] PHOX2B is a reliable immunomarker in distinguishing peripheral neuroblastic tumours from CNS embryonal tumours.Histopathology. 2018 Sep;73(3):483-491. doi: 10.1111/his.13648. Epub 2018 Jul 4.
• [15] Mutations of the RET gene in isolated and syndromic Hirschsprung's disease in human disclose major and modifier alleles at a single locus.J Med Genet. 2006 May;43(5):419-23. doi: 10.1136/jmg.2005.040113. Epub 2006 Jan 27.
• [16] Examination of PHOX2B in adult neuroendocrine neoplasms reveals relatively frequent expression in phaeochromocytomas and paragangliomas.Histopathology. 2017 Oct;71(4):503-510. doi: 10.1111/his.13243. Epub 2017 Jul 13.
• [17] Respiratory disturbances in a mouse model of Parkinson's disease.Exp Physiol. 2019 May;104(5):729-739. doi: 10.1113/EP087507. Epub 2019 Mar 7.
• [18] Phox2b, congenital central hypoventilation syndrome and the control of respiration.Semin Cell Dev Biol. 2010 Oct;21(8):814-22. doi: 10.1016/j.semcdb.2010.07.006. Epub 2010 Aug 4.
• [19] Association between PHOX2B gene rs28647582 T>C polymorphism and Wilms tumor susceptibility.Biosci Rep. 2019 Oct 30;39(10):BSR20192529. doi: 10.1042/BSR20192529.
• [20] Alanine Expansions Associated with Congenital Central Hypoventilation Syndrome Impair PHOX2B Homeodomain-mediated Dimerization and Nuclear Import.J Biol Chem. 2016 Jun 17;291(25):13375-93. doi: 10.1074/jbc.M115.679027. Epub 2016 Apr 27.
• [21] Utility of Phox2b immunohistochemical stain in neural crest tumours and non-neural crest tumours in paediatric patients.Histopathology. 2018 Mar;72(4):685-696. doi: 10.1111/his.13412. Epub 2017 Dec 21.
• [22] Congenital Central Hypoventilation Syndrome. 2004 Jan 28 [updated 2021 Jan 28]. 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.
• [23] An official ATS clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis, and management.Am J Respir Crit Care Med. 2010 Mar 15;181(6):626-44. doi: 10.1164/rccm.200807-1069ST.
• [24] Altered enteric expression of the homeobox transcription factor Phox2b in patients with diverticular disease.United European Gastroenterol J. 2019 Apr;7(3):349-357. doi: 10.1177/2050640618824913. Epub 2019 Jan 16.
• [25] Atypical presentations associated with non-polyalanine repeat PHOX2B mutations.Am J Med Genet A. 2018 Jul;176(7):1627-1631. doi: 10.1002/ajmg.a.38720. Epub 2018 Apr 28.
• [26] Descriptive Epidemiology of Generalized Anxiety Disorder in Canada.Can J Psychiatry. 2017 Jan;62(1):24-29. doi: 10.1177/0706743716645304. Epub 2016 Jul 10.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [29] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [30] 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.
• [31] The synergistic effect of 5-aza-2'-deoxycytidine and 5-fluorouracil on drug-resistant tumors. Oncology. 2006;71(5-6):437-45. doi: 10.1159/000107110. Epub 2007 Aug 9.
• [32] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [33] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [34] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [35] 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.