Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP5GZ9V)

• DOT Name: Elongator complex protein 4 (ELP4)
• Synonyms: hELP4; PAX6 neighbor gene protein
• Gene Name: ELP4
• Related Disease:
  Intellectual disability
  Aniridia 2
  Anxiety
  Autism spectrum disorder
  Epilepsy
  Gastrointestinal stromal tumour
  Glaucoma/ocular hypertension
  Language disorder
  Riley-Day syndrome
  Schizophrenia
  Focal epilepsy
  Neurodevelopmental disorder
  Aniridia
  Aniridia 1
  Childhood kidney Wilms tumor
  Wilms tumor
• UniProt ID: ELP4_HUMAN
• Pfam ID: PF05625
• Sequence:
  MAAVATCGSVAASTGSAVATASKSNVTSFQRRGPRASVTNDSGPRLVSIAGTRPSVRNGQ
  LLVSTGLPALDQLLGGGLAVGTVLLIEEDKYNIYSPLLFKYFLAEGIVNGHTLLVASAKE
  DPANILQELPAPLLDDKCKKEFDEDVYNHKTPESNIKMKIAWRYQLLPKMEIGPVSSSRF
  GHYYDASKRMPQELIEASNWHGFFLPEKISSTLKVEPCSLTPGYTKLLQFIQNIIYEEGF
  DGSNPQKKQRNILRIGIQNLGSPLWGDDICCAENGGNSHSLTKFLYVLRGLLRTSLSACI
  ITMPTHLIQNKAIIARVTTLSDVVVGLESFIGSERETNPLYKDYHGLIHIRQIPRLNNLI
  CDESDVKDLAFKLKRKLFTIERLHLPPDLSDTVSRSSKMDLAESAKRLGPGCGMMAGGKK
  HLDF
• Function: Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine). The elongator complex catalyzes the formation of carboxymethyluridine in the wobble base at position 34 in tRNAs.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)
• BioCyc Pathway: MetaCyc:ENSG00000109911-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Aniridia 2	DIS6AYPD	Strong	Autosomal dominant	[2]
Anxiety	DISIJDBA	Strong	Genetic Variation	[3]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[1]
Epilepsy	DISBB28L	Strong	Genetic Variation	[1]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[4]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Genetic Variation	[5]
Language disorder	DISTLKP7	Strong	Genetic Variation	[1]
Riley-Day syndrome	DISJZHNP	Strong	Biomarker	[6]
Schizophrenia	DISSRV2N	Strong	Biomarker	[7]
Focal epilepsy	DIS4LY5L	moderate	Biomarker	[8]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[9]
Aniridia	DIS1P333	Limited	Biomarker	[10]
Aniridia 1	DISZ95YB	Limited	Autosomal dominant	[11]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Genetic Variation	[12]
Wilms tumor	DISB6T16	Limited	Genetic Variation	[12]

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 Elongator complex protein 4 (ELP4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Elongator complex protein 4 (ELP4).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Elongator complex protein 4 (ELP4).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Elongator complex protein 4 (ELP4).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Elongator complex protein 4 (ELP4).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Elongator complex protein 4 (ELP4).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Elongator complex protein 4 (ELP4).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Elongator complex protein 4 (ELP4).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Elongator complex protein 4 (ELP4).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Elongator complex protein 4 (ELP4).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Elongator complex protein 4 (ELP4).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Elongator complex protein 4 (ELP4).	[23]

References

• [1] Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation.Hum Mutat. 2015 Sep;36(9):842-50. doi: 10.1002/humu.22816. Epub 2015 Jun 30.
• [2] A novel heterozygous deletion within the 3' region of the PAX6 gene causing isolated aniridia in a large family group. J Clin Neurosci. 2009 Dec;16(12):1610-4. doi: 10.1016/j.jocn.2009.03.022. Epub 2009 Sep 29.
• [3] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [4] Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
• [5] Genome-wide association and admixture analysis of glaucoma in the Women's Health Initiative.Hum Mol Genet. 2014 Dec 15;23(24):6634-43. doi: 10.1093/hmg/ddu364. Epub 2014 Jul 15.
• [6] The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system.Dis Model Mech. 2017 May 1;10(5):605-618. doi: 10.1242/dmm.028258. Epub 2017 Feb 6.
• [7] The effect of implementation intentions on prospective memory performance in patients with schizophrenia: A multinomial modeling approach.Schizophr Res. 2020 Jan;215:120-125. doi: 10.1016/j.schres.2019.11.003. Epub 2019 Nov 26.
• [8] Emerging genetic influences in benign epilepsy with centro-temporal spikes - BECTS.Epilepsy Res. 2012 Sep;101(3):197-201. doi: 10.1016/j.eplepsyres.2012.06.011. Epub 2012 Jul 19.
• [9] Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4).Eur J Hum Genet. 2009 Sep;17(9):1171-81. doi: 10.1038/ejhg.2008.267. Epub 2009 Jan 28.
• [10] PAX6 aniridia syndrome: clinics, genetics, and therapeutics.Curr Opin Ophthalmol. 2017 Sep;28(5):436-447. doi: 10.1097/ICU.0000000000000405.
• [11] A deletion 3' to the PAX6 gene in familial aniridia cases. Mol Vis. 2007 Jul 23;13:1245-50.
• [12] Location of the gene involving the small eye mutation on mouse chromosome 2 suggests homology with human aniridia 2 (AN2).Genomics. 1990 Jun;7(2):270-5. doi: 10.1016/0888-7543(90)90550-e.
• [13] 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.
• [14] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [19] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.