Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2UFOE2)

• DOT Name: Forkhead box protein I1 (FOXI1)
• Synonyms: Forkhead-related protein FKHL10; Forkhead-related transcription factor 6; FREAC-6; Hepatocyte nuclear factor 3 forkhead homolog 3; HFH-3; HNF-3/fork-head homolog 3
• Gene Name: FOXI1
• Related Disease:
  Autosomal recessive nonsyndromic hearing loss 4
  Clear cell renal carcinoma
  Cystic fibrosis
  Distal renal tubular acidosis
  Hereditary haemolytic anemia
  Renal cell carcinoma
  Acute myelogenous leukaemia
  Gastric cancer
  Hearing loss, autosomal recessive
  Neoplasm
  Renal tubular acidosis
  Stomach cancer
  Autosomal recessive distal renal tubular acidosis
  Pendred syndrome
  Enlarged vestibular aqueduct syndrome
  Deafness
• UniProt ID: FOXI1_HUMAN
• Pfam ID: PF00250
• Sequence:
  MSSFDLPAPSPPRCSPQFPSIGQEPPEMNLYYENFFHPQGVPSPQRPSFEGGGEYGATPN
  PYLWFNGPTMTPPPYLPGPNASPFLPQAYGVQRPLLPSVSGLGGSDLGWLPIPSQEELMK
  LVRPPYSYSALIAMAIHGAPDKRLTLSQIYQYVADNFPFYNKSKAGWQNSIRHNLSLNDC
  FKKVPRDEDDPGKGNYWTLDPNCEKMFDNGNFRRKRKRKSDVSSSTASLALEKTESSLPV
  DSPKTTEPQDILDGASPGGTTSSPEKRPSPPPSGAPCLNSFLSSMTAYVSGGSPTSHPLV
  TPGLSPEPSDKTGQNSLTFNSFSPLTNLSNHSGGGDWANPMPTNMLSYGGSVLSQFSPHF
  YNSVNTSGVLYPREGTEV
• Function: Transcriptional activator required for the development of normal hearing, sense of balance and kidney function. Required for the expression of SLC26A4/PDS, JAG1 and COCH in a subset of epithelial cells and the development of the endolymphatic system in the inner ear. Also required for the expression of SLC4A1/AE1, SLC4A9/AE4, ATP6V1B1 and the differentiation of intercalated cells in the epithelium of distal renal tubules.
• Tissue Specificity: Expressed in kidney.

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive nonsyndromic hearing loss 4	DISCJIDF	Strong	Autosomal recessive	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[2]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[3]
Distal renal tubular acidosis	DISP6CYE	Strong	Genetic Variation	[4]
Hereditary haemolytic anemia	DIS487SI	Strong	Biomarker	[5]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[6]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[7]
Hearing loss, autosomal recessive	DIS8G9R9	moderate	Biomarker	[8]
Neoplasm	DISZKGEW	moderate	Biomarker	[7]
Renal tubular acidosis	DISE1NDR	moderate	Biomarker	[1]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[7]
Autosomal recessive distal renal tubular acidosis	DISCJR4O	Supportive	Autosomal recessive	[1]
Pendred syndrome	DISZ1MU8	Supportive	Autosomal recessive	[9]
Enlarged vestibular aqueduct syndrome	DISLGBBO	Disputed	Autosomal recessive	[10]
Deafness	DISKCLH4	Limited	Autosomal recessive	[10]

3 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 Forkhead box protein I1 (FOXI1).	[11]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Forkhead box protein I1 (FOXI1).	[12]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Forkhead box protein I1 (FOXI1).	[14]

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 Forkhead box protein I1 (FOXI1).	[13]

References

• [1] Acidosis and Deafness in Patients with Recessive Mutations in FOXI1. J Am Soc Nephrol. 2018 Mar;29(3):1041-1048. doi: 10.1681/ASN.2017080840. Epub 2017 Dec 14.
• [2] Cell-Type-Specific Gene Programs of the Normal Human Nephron Define Kidney Cancer Subtypes.Cell Rep. 2017 Aug 8;20(6):1476-1489. doi: 10.1016/j.celrep.2017.07.043.
• [3] A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte.Nature. 2018 Aug;560(7718):377-381. doi: 10.1038/s41586-018-0394-6. Epub 2018 Aug 1.
• [4] Molecular Pathophysiology of Acid-Base Disorders.Semin Nephrol. 2019 Jul;39(4):340-352. doi: 10.1016/j.semnephrol.2019.04.004.
• [5] Silencing of Odorant-Binding Protein Gene OBP3 Using RNA Interference Reduced Virus Transmission of Tomato Chlorosis Virus.Int J Mol Sci. 2019 Oct 9;20(20):4969. doi: 10.3390/ijms20204969.
• [6] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [7] miR-491-5p, mediated by Foxi1, functions as a tumor suppressor by targeting Wnt3a/-catenin signaling in the development of gastric cancer.Cell Death Dis. 2017 Mar 30;8(3):e2714. doi: 10.1038/cddis.2017.134.
• [8] A unique case of de novo 5q33.3-q34 triplication with uniparental isodisomy of 5q34-qter.Am J Med Genet A. 2013 Aug;161A(8):1904-9. doi: 10.1002/ajmg.a.36026. Epub 2013 Jul 4.
• [9] Pendred Syndrome?/ Nonsyndromic Enlarged Vestibular Aqueduct. 1998 Sep 28 [updated 2020 Jun 18]. 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.
• [10] 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.
• [11] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [12] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [13] 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.
• [14] Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways. Environ Int. 2020 Feb;135:105414. doi: 10.1016/j.envint.2019.105414. Epub 2019 Dec 23.