Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW82NET)

• DOT Name: Protein RFT1 homolog (RFT1)
• Gene Name: RFT1
• Related Disease:
  Congenital disorder of glycosylation
  Developmental and epileptic encephalopathy, 36
  RFT1-congenital disorder of glycosylation
  Schizophrenia
  Type-1/2 diabetes
  Crohn disease
• UniProt ID: RFT1_HUMAN
• Pfam ID: PF04506
• Sequence:
  MGSQEVLGHAARLASSGLLLQVLFRLITFVLNAFILRFLSKEIVGVVNVRLTLLYSTTLF
  LAREAFRRACLSGGTQRDWSQTLNLLWLTVPLGVFWSLFLGWIWLQLLEVPDPNVVPHYA
  TGVVLFGLSAVVELLGEPFWVLAQAHMFVKLKVIAESLSVILKSVLTAFLVLWLPHWGLY
  IFSLAQLFYTTVLVLCYVIYFTKLLGSPESTKLQTLPVSRITDLLPNITRNGAFINWKEA
  KLTWSFFKQSFLKQILTEGERYVMTFLNVLNFGDQGVYDIVNNLGSLVARLIFQPIEESF
  YIFFAKVLERGKDATLQKQEDVAVAAAVLESLLKLALLAGLTITVFGFAYSQLALDIYGG
  TMLSSGSGPVLLRSYCLYVLLLAINGVTECFTFAAMSKEEVDRYNFVMLALSSSFLVLSY
  LLTRWCGSVGFILANCFNMGIRITQSLCFIHRYYRRSPHRPLAGLHLSPVLLGTFALSGG
  VTAVSEVFLCCEQGWPARLAHIAVGAFCLGATLGTAFLTETKLIHFLRTQLGVPRRTDKM
  T
• Function: May be involved in N-linked oligosaccharide assembly. May participate in the translocation of oligosaccharide from the cytoplasmic side to the lumenal side of the endoplasmic reticulum membrane.
• Reactome Pathway:
  Defective RFT1 causes CDG-1n (R-HSA-4570571)
  Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein (R-HSA-446193)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital disorder of glycosylation	DIS400QP	Strong	Biomarker	[1]
Developmental and epileptic encephalopathy, 36	DISG4MY5	Strong	Biomarker	[2]
RFT1-congenital disorder of glycosylation	DISA78DX	Strong	Autosomal recessive	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[5]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[6]

1 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 Protein RFT1 homolog (RFT1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein RFT1 homolog (RFT1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein RFT1 homolog (RFT1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein RFT1 homolog (RFT1).	[10]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Protein RFT1 homolog (RFT1).	[11]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Protein RFT1 homolog (RFT1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein RFT1 homolog (RFT1).	[13]

References

• [1] RFT1-CDG: deafness as a novel feature of congenital disorders of glycosylation.J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S335-8. doi: 10.1007/s10545-009-1297-3. Epub 2009 Oct 24.
• [2] A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation.Eur J Med Genet. 2019 Apr;62(4):248-253. doi: 10.1016/j.ejmg.2018.07.023. Epub 2018 Jul 31.
• [3] Human RFT1 deficiency leads to a disorder of N-linked glycosylation. Am J Hum Genet. 2008 Mar;82(3):600-6. doi: 10.1016/j.ajhg.2007.12.021. Epub 2008 Feb 28.
• [4] Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.Mol Autism. 2017 May 22;8:21. doi: 10.1186/s13229-017-0137-9. eCollection 2017.
• [5] Downregulation of reduced-folate transporter by glucose in cultured RPE cells and in RPE of diabetic mice.Invest Ophthalmol Vis Sci. 2002 Feb;43(2):556-63.
• [6] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [7] 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.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.