Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0Y3MIM)

• DOT Name: Paired box protein Pax-1 (PAX1)
• Synonyms: HuP48
• Gene Name: PAX1
• Related Disease:
  Adenocarcinoma
  Otofaciocervical syndrome 2
  Advanced cancer
  Androgen insensitivity syndrome
  Benign neoplasm
  Bone osteosarcoma
  Cervical cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Disorder of sexual differentiation
  Endometrial carcinoma
  Epithelial neoplasm
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Human papillomavirus infection
  Intrahepatic cholangiocarcinoma
  Klippel-Feil syndrome
  Klippel-Feil syndrome 1, autosomal dominant
  Neoplasm
  Neural tube defect
  Oral cancer
  Osteosarcoma
  Otofaciocervical syndrome
  Otofaciocervical syndrome 1
  Ovarian cancer
  Ovarian neoplasm
  Peters anomaly
  Severe combined immunodeficiency
  Squamous cell carcinoma
  Uterine cervix neoplasm
  Spondylocostal dysostosis
  Megalencephaly
• UniProt ID: PAX1_HUMAN
• Pfam ID: PF00292
• Sequence:
  MKFTLGLGSRAWRVSWEGAAAAAAGPGAGGSALRCRAQRVSSPRLGRRGSRLSGALPLCL
  SRGGGGAQALPDCAGPSPGHPGHPGARQLAGPLAMEQTYGEVNQLGGVFVNGRPLPNAIR
  LRIVELAQLGIRPCDISRQLRVSHGCVSKILARYNETGSILPGAIGGSKPRVTTPNVVKH
  IRDYKQGDPGIFAWEIRDRLLADGVCDKYNVPSVSSISRILRNKIGSLAQPGPYEASKQP
  PSQPTLPYNHIYQYPYPSPVSPTGAKMGSHPGVPGTAGHVSIPRSWPSAHSVSNILGIRT
  FMEQTGALAGSEGTAYSPKMEDWAGVNRTAFPATPAVNGLEKPALEADIKYTQSASTLSA
  VGGFLPACAYPASNQHGVYSAPGGGYLAPGPPWPPAQGPPLAPPGAGVAVHGGELAAAMT
  FKHPSREGSLPAPAARPRTPSVAYTDCPSRPRPPRGSSPRTRARRERQADPGAQVCAAAP
  AIGTGRIGGLAEEEASAGPRGARPASPQAQPCLWPDPPHFLYWSGFLGFSELGF
• Function: This protein is a transcriptional activator. It may play a role in the formation of segmented structures of the embryo. May play an important role in the normal development of the vertebral column.

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Biomarker	[1]
Otofaciocervical syndrome 2	DISXTTM0	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[3]
Androgen insensitivity syndrome	DISUZBBO	Strong	Biomarker	[4]
Benign neoplasm	DISDUXAD	Strong	Biomarker	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[6]
Cervical cancer	DISFSHPF	Strong	Posttranslational Modification	[7]
Cervical carcinoma	DIST4S00	Strong	Posttranslational Modification	[7]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Posttranslational Modification	[8]
Disorder of sexual differentiation	DISRMAEZ	Strong	Biomarker	[9]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[3]
Epithelial neoplasm	DIS0T594	Strong	Posttranslational Modification	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[10]
Human papillomavirus infection	DISX61LX	Strong	Posttranslational Modification	[7]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Posttranslational Modification	[7]
Klippel-Feil syndrome	DISRVCYV	Strong	Biomarker	[11]
Klippel-Feil syndrome 1, autosomal dominant	DISKGBD8	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Neural tube defect	DIS5J95E	Strong	Genetic Variation	[12]
Oral cancer	DISLD42D	Strong	Biomarker	[13]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[6]
Otofaciocervical syndrome	DISLYABR	Strong	Genetic Variation	[14]
Otofaciocervical syndrome 1	DISZJB3G	Strong	Autosomal recessive	[15]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[5]
Peters anomaly	DISERK0M	Strong	Genetic Variation	[16]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Biomarker	[15]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[17]
Uterine cervix neoplasm	DIS0BYVV	Strong	Biomarker	[18]
Spondylocostal dysostosis	DISTPWFK	moderate	Altered Expression	[19]
Megalencephaly	DISYW5SV	Limited	Biomarker	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Paired box protein Pax-1 (PAX1).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Paired box protein Pax-1 (PAX1).	[22]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Paired box protein Pax-1 (PAX1).	[24]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Paired box protein Pax-1 (PAX1).	[24]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Paired box protein Pax-1 (PAX1).	[25]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Paired box protein Pax-1 (PAX1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Paired box protein Pax-1 (PAX1).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Paired box protein Pax-1 (PAX1).	[26]

References

• [1] High methylation rate of LMX1A, NKX6-1, PAX1, PTPRR, SOX1, and ZNF582 genes in cervical adenocarcinoma.Int J Gynecol Cancer. 2014 Feb;24(2):201-9. doi: 10.1097/IGC.0000000000000054.
• [2] 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.
• [3] The promising role of PAX1 (aliases: HUP48, OFC2) gene methylation in cancer screening.Mol Genet Genomic Med. 2019 Mar;7(3):e506. doi: 10.1002/mgg3.506. Epub 2019 Jan 12.
• [4] Genetic polymorphisms of PAX1 are functionally associated with different PUMC types of adolescent idiopathic scoliosis in a northern Chinese Han population.Gene. 2019 Mar 10;688:215-220. doi: 10.1016/j.gene.2018.12.013. Epub 2018 Dec 17.
• [5] An epigenetic marker panel for screening and prognostic prediction of ovarian cancer.Int J Cancer. 2009 Jan 15;124(2):387-93. doi: 10.1002/ijc.23957.
• [6] Altered regulation of platelet-derived growth factor receptor-alpha gene-transcription in vitro by spina bifida-associated mutant Pax1 proteins.Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14459-63. doi: 10.1073/pnas.95.24.14459.
• [7] Association between dense PAX1 promoter methylation and HPV16 infection in cervical squamous epithelial neoplasms of Xin Jiang Uyghur and Han women.Gene. 2020 Jan 10;723:144142. doi: 10.1016/j.gene.2019.144142. Epub 2019 Oct 4.
• [8] PAX1 Methylation as a Potential Biomarker to Predict the Progression of Cervical Intraepithelial Neoplasia: A Meta-analysis of Related Studies.Int J Gynecol Cancer. 2017 Sep;27(7):1480-1488. doi: 10.1097/IGC.0000000000001011.
• [9] Diaphanospondylodysostosis: six new cases and exclusion of the candidate genes, PAX1 and MEOX1.Am J Med Genet A. 2007 Oct 1;143A(19):2292-302. doi: 10.1002/ajmg.a.31934.
• [10] Aberrant DNA methylation of PAX1, SOX1 and ZNF582 genes as potential biomarkers for esophageal squamous cell carcinoma.Biomed Pharmacother. 2019 Dec;120:109488. doi: 10.1016/j.biopha.2019.109488. Epub 2019 Oct 16.
• [11] Mutations in PAX1 may be associated with Klippel-Feil syndrome. Eur J Hum Genet. 2003 Jun;11(6):468-74. doi: 10.1038/sj.ejhg.5200987.
• [12] Pax1/E2a double-mutant mice develop non-lethal neural tube defects that resemble human malformations.Transgenic Res. 2005 Dec;14(6):983-7. doi: 10.1007/s11248-005-2540-9.
• [13] Hypermethylated ZNF582 and PAX1 genes in mouth rinse samples as biomarkers for oral dysplasia and oral cancer detection.Head Neck. 2018 Feb;40(2):355-368. doi: 10.1002/hed.24958. Epub 2017 Sep 27.
• [14] Autosomal recessive otofaciocervical syndrome type 2 with novel homozygous small insertion in PAX1 gene.Am J Med Genet A. 2018 May;176(5):1200-1206. doi: 10.1002/ajmg.a.38659.
• [15] A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency. Clin Genet. 2017 Dec;92(6):664-668. doi: 10.1111/cge.13085. Epub 2017 Oct 24.
• [16] Reciprocal effect of Waardenburg syndrome mutations on DNA binding by the Pax-3 paired domain and homeodomain.Hum Mol Genet. 1997 Oct;6(11):1781-90. doi: 10.1093/hmg/6.11.1781.
• [17] Concordance analysis of methylation biomarkers detection in self-collected and physician-collected samples in cervical neoplasm.BMC Cancer. 2015 May 19;15:418. doi: 10.1186/s12885-015-1411-x.
• [18] Testing for methylated PCDH10 or WT1 is superior to the HPV test in detecting severe neoplasms (CIN3 or greater) in the triage of ASC-US smear results.Am J Obstet Gynecol. 2011 Jan;204(1):21.e1-7. doi: 10.1016/j.ajog.2010.07.036. Epub 2010 Sep 15.
• [19] Aberrant Pax1 and Pax9 expression in Jarcho-Levin syndrome: report of two Caucasian siblings and literature review.Am J Med Genet A. 2003 Jul 15;120A(2):241-6. doi: 10.1002/ajmg.a.20192.
• [20] Macrocephaly, epilepsy, autism, dysmorphic features, and mental retardation in two sisters: a new autosomal recessive syndrome?.J Med Genet. 1997 Oct;34(10):849-51. doi: 10.1136/jmg.34.10.849.
• [21] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [22] 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.
• [23] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [24] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [25] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [26] 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.
• [27] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.