Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0K44H1)

• DOT Name: mRNA export factor GLE1 (GLE1)
• Synonyms: hGLE1; GLE1 RNA export mediator; GLE1-like protein; Nucleoporin GLE1
• Gene Name: GLE1
• Related Disease:
  Arthrogryposis
  Lethal arthrogryposis-anterior horn cell disease syndrome
  Lethal congenital contracture syndrome 1
  Motor neurone disease
  Respiratory failure
  Amyotrophic lateral sclerosis
  Fetal akinesia deformation sequence 1
• UniProt ID: GLE1_HUMAN
• PDB ID: 6B4F; 6B4I; 6B4J
• Pfam ID: PF07817
• Sequence:
  MPSEGRCWETLKALRSSDKGRLCYYRDWLLRREDVLEECMSLPKLSSYSGWVVEHVLPHM
  QENQPLSETSPSSTSASALDQPSFVPKSPDASSAFSPASPATPNGTKGKDESQHTESMVL
  QSSRGIKVEGCVRMYELVHRMKGTEGLRLWQEEQERKVQALSEMASEQLKRFDEWKELKQ
  HKEFQDLREVMEKSSREALGHQEKLKAEHRHRAKILNLKLREAEQQRVKQAEQERLRKEE
  GQIRLRALYALQEEMLQLSQQLDASEQHKALLKVDLAAFQTRGNQLCSLISGIIRASSES
  SYPTAESQAEAERALREMRDLLMNLGQEITRACEDKRRQDEEEAQVKLQEAQMQQGPEAH
  KEPPAPSQGPGGKQNEDLQVKVQDITMQWYQQLQDASMQCVLTFEGLTNSKDSQAKKIKM
  DLQKAATIPVSQISTIAGSKLKEIFDKIHSLLSGKPVQSGGRSVSVTLNPQGLDFVQYKL
  AEKFVKQGEEEVASHHEAAFPIAVVASGIWELHPRVGDLILAHLHKKCPYSVPFYPTFKE
  GMALEDYQRMLGYQVKDSKVEQQDNFLKRMSGMIRLYAAIIQLRWPYGNRQEIHPHGLNH
  GWRWLAQILNMEPLSDVTATLLFDFLEVCGNALMKQYQVQFWKMLILIKEDYFPRIEAIT
  SSGQMGSFIRLKQFLEKCLQHKDIPVPKGFLTSSFWRS
• Function: Required for the export of mRNAs containing poly(A) tails from the nucleus into the cytoplasm. May be involved in the terminal step of the mRNA transport through the nuclear pore complex (NPC).
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  mR. surveillance pathway (hsa03015)
  Amyotrophic lateral sclerosis (hsa05014)
• Reactome Pathway: Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthrogryposis	DISC81CM	Definitive	Genetic Variation	[1]
Lethal arthrogryposis-anterior horn cell disease syndrome	DIS7W18S	Definitive	Autosomal recessive	[2]
Lethal congenital contracture syndrome 1	DIS7MT3R	Strong	Autosomal recessive	[2]
Motor neurone disease	DISUHWUI	Strong	Genetic Variation	[1]
Respiratory failure	DISVMYJO	moderate	Genetic Variation	[3]
Amyotrophic lateral sclerosis	DISF7HVM	Supportive	Autosomal dominant	[4]
Fetal akinesia deformation sequence 1	DISKDI9L	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of mRNA export factor GLE1 (GLE1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of mRNA export factor GLE1 (GLE1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of mRNA export factor GLE1 (GLE1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of mRNA export factor GLE1 (GLE1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of mRNA export factor GLE1 (GLE1).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of mRNA export factor GLE1 (GLE1).	[13]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of mRNA export factor GLE1 (GLE1).	[10]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of mRNA export factor GLE1 (GLE1).	[14]

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 mRNA export factor GLE1 (GLE1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of mRNA export factor GLE1 (GLE1).	[12]

References

• [1] A homozygous I684T in GLE1 as a novel cause of arthrogryposis and motor neuron loss.Clin Genet. 2018 Jan;93(1):173-177. doi: 10.1111/cge.13086. Epub 2017 Nov 24.
• [2] Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat Genet. 2008 Feb;40(2):155-7. doi: 10.1038/ng.2007.65. Epub 2008 Jan 20.
• [3] Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1.Am J Med Genet A. 2017 Nov;173(11):3098-3103. doi: 10.1002/ajmg.a.38406. Epub 2017 Sep 8.
• [4] Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Hum Mol Genet. 2015 Mar 1;24(5):1363-73. doi: 10.1093/hmg/ddu545. Epub 2014 Oct 24.
• [5] Next generation sequencing in recurrent pregnancy loss-approaches and outcomes.Eur J Med Genet. 2020 Feb;63(2):103644. doi: 10.1016/j.ejmg.2019.04.001. Epub 2019 Apr 13.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] 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.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.