Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAUDKC1)

• DOT Name: Forkhead box protein E3 (FOXE3)
• Synonyms: Forkhead-related protein FKHL12; Forkhead-related transcription factor 8; FREAC-8
• Gene Name: FOXE3
• Related Disease:
  Anterior segment dysgenesis 1
  Congenital primary aphakia
  Glaucoma/ocular hypertension
  Aniridia
  Aortic aneurysm, familial thoracic 11, susceptibility to
  Aortic disorder
  Atrial septal defect
  Autism spectrum disorder
  Cataract
  Childhood acute lymphoblastic leukemia
  Sclerocornea
  T-cell leukaemia
  Triple negative breast cancer
  Coloboma
  Familial thoracic aortic aneurysm and aortic dissection
  Anterior segment dysgenesis
  Peters anomaly
• UniProt ID: FOXE3_HUMAN
• Pfam ID: PF00250
• Sequence:
  MAGRSDMDPPAAFSGFPALPAVAPSGPPPSPLAGAEPGREPEEAAAGRGEAAPTPAPGPG
  RRRRRPLQRGKPPYSYIALIAMALAHAPGRRLTLAAIYRFITERFAFYRDSPRKWQNSIR
  HNLTLNDCFVKVPREPGNPGKGNYWTLDPAAADMFDNGSFLRRRKRFKRAELPAHAAAAP
  GPPLPFPYAPYAPAPGPALLVPPPSAGPGPSPPARLFSVDSLVNLQPELAGLGAPEPPCC
  AAPDAAAAAFPPCAAAASPPLYSQVPDRLVLPATRPGPGPLPAEPLLALAGPAAALGPLS
  PGEAYLRQPGFASGLERYL
• Function: Transcription factor that controls lens epithelial cell growth through regulation of proliferation, apoptosis and cell cycle. During lens development, controls the ratio of the lens fiber cells to the cells of the anterior lens epithelium by regulating the rate of proliferation and differentiation. Controls lens vesicle closure and subsequent separation of the lens vesicle from ectoderm. Controls the expression of DNAJB1 in a pathway that is crucial for the development of the anterior segment of the eye.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anterior segment dysgenesis 1	DIS4K5KH	Definitive	Autosomal dominant	[1]
Congenital primary aphakia	DISG5AY9	Definitive	Autosomal recessive	[2]
Glaucoma/ocular hypertension	DISLBXBY	Definitive	Genetic Variation	[3]
Aniridia	DIS1P333	Strong	Genetic Variation	[4]
Aortic aneurysm, familial thoracic 11, susceptibility to	DIS8OWUJ	Strong	Autosomal dominant	[5]
Aortic disorder	DISKXISV	Strong	Genetic Variation	[6]
Atrial septal defect	DISJT76B	Strong	Genetic Variation	[7]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[7]
Cataract	DISUD7SL	Strong	Genetic Variation	[8]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Posttranslational Modification	[9]
Sclerocornea	DIS7HV8A	Strong	Genetic Variation	[10]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[9]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[11]
Coloboma	DISP39N5	moderate	Genetic Variation	[12]
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Moderate	Autosomal dominant	[13]
Anterior segment dysgenesis	DIS12OKO	Supportive	Autosomal dominant	[7]
Peters anomaly	DISERK0M	Supportive	Autosomal dominant	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Forkhead box protein E3 (FOXE3).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Forkhead box protein E3 (FOXE3).	[16]

References

• [1] FOXE3 mutations: genotype-phenotype correlations. Clin Genet. 2018 Apr;93(4):837-845. doi: 10.1111/cge.13177.
• [2] Targeted 'next-generation' sequencing in anophthalmia and microphthalmia patients confirms SOX2, OTX2 and FOXE3 mutations. BMC Med Genet. 2011 Dec 28;12:172. doi: 10.1186/1471-2350-12-172.
• [3] Functional analysis of FOXE3 mutations causing dominant and recessive ocular anterior segment disease.Hum Mutat. 2015 Mar;36(3):296-300. doi: 10.1002/humu.22741.
• [4] Identification of dominant FOXE3 and PAX6 mutations in patients with congenital cataract and aniridia.Mol Vis. 2010 Aug 22;16:1705-11.
• [5] [Liver cirrhosis or malignant tumor of the pancreas head?]. MMW Munch Med Wochenschr. 1979 Apr 20;121(16):suppl: 39.
• [6] FOXE3 mutations predispose to thoracic aortic aneurysms and dissections. J Clin Invest. 2016 Mar 1;126(3):948-61. doi: 10.1172/JCI83778. Epub 2016 Feb 8.
• [7] A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly. Eur J Hum Genet. 2011 Mar;19(3):293-9. doi: 10.1038/ejhg.2010.210. Epub 2010 Dec 8.
• [8] A zebrafish model of foxe3 deficiency demonstrates lens and eye defects with dysregulation of key genes involved in cataract formation in humans.Hum Genet. 2018 Apr;137(4):315-328. doi: 10.1007/s00439-018-1884-1. Epub 2018 Apr 30.
• [9] Validation of DNA methylation biomarkers for diagnosis of acute lymphoblastic leukemia.Clin Chem. 2014 Jul;60(7):995-1003. doi: 10.1373/clinchem.2013.219956. Epub 2014 May 14.
• [10] Sclerocornea-Microphthalmia-Aphakia Complex: Description of Two Additional Cases Associated With Novel FOXE3 Mutations and Review of the Literature.Cornea. 2018 Sep;37(9):1178-1181. doi: 10.1097/ICO.0000000000001655.
• [11] Identification of FOXE3 transcription factor as a potent oncogenic factor in triple-negative breast cancer.Biochem Biophys Res Commun. 2020 Feb 26;523(1):78-85. doi: 10.1016/j.bbrc.2019.12.034. Epub 2019 Dec 9.
• [12] The genetic architecture of microphthalmia, anophthalmia and coloboma. Eur J Med Genet. 2014 Aug;57(8):369-80. doi: 10.1016/j.ejmg.2014.05.002. Epub 2014 May 22.
• [13] 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.
• [14] FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. Nat Commun. 2016 Apr 6;7:10953. doi: 10.1038/ncomms10953.
• [15] 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.
• [16] 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.