Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCYSU28)

• DOT Name: Immediate early response 3-interacting protein 1 (IER3IP1)
• Gene Name: IER3IP1
• Related Disease:
  Childhood epilepsy with centrotemporal spikes
  Epilepsy
  Long QT syndrome 1
  Microcephaly, epilepsy, and diabetes syndrome 1
  Neonatal diabetes mellitus
  Obsolete primary microcephaly-epilepsy-permanent neonatal diabetes syndrome
  Permanent neonatal diabetes mellitus
  Type-1/2 diabetes
  Intellectual disability
  Microcephaly, epilepsy, and diabetes syndrome
• UniProt ID: IR3IP_HUMAN
• Pfam ID: PF08571
• Sequence:
  MAFTLYSLLQAALLCVNAIAVLHEERFLKNIGWGTDQGIGGFGEEPGIKSQLMNLIRSVR
  TVMRVPLIIVNSIAIVLLLLFG
• Function: Regulator of endoplasmic reticulum secretion that acts as a key determinant of brain size. Required for secretion of extracellular matrix proteins. Required for correct brain development by depositing sufficient extracellular matrix proteins for tissue integrity and the proliferation of neural progenitors. Acts as a regulator of the unfolded protein response (UPR).
• Tissue Specificity: Highest levels in heart, skeletal muscle, and kidney.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Strong	CausalMutation	[1]
Epilepsy	DISBB28L	Strong	Genetic Variation	[2]
Long QT syndrome 1	DISXK5OU	Strong	Genetic Variation	[3]
Microcephaly, epilepsy, and diabetes syndrome 1	DIS5YFVN	Strong	Autosomal recessive	[2]
Neonatal diabetes mellitus	DISFHF9K	Strong	Genetic Variation	[4]
Obsolete primary microcephaly-epilepsy-permanent neonatal diabetes syndrome	DISK2F5H	Strong	Autosomal recessive	[5]
Permanent neonatal diabetes mellitus	DIS5AEXS	Strong	Genetic Variation	[6]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[6]
Intellectual disability	DISMBNXP	Limited	Biomarker	[4]
Microcephaly, epilepsy, and diabetes syndrome	DISMC1NE	Limited	Biomarker	[4]

7 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 Immediate early response 3-interacting protein 1 (IER3IP1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Immediate early response 3-interacting protein 1 (IER3IP1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Immediate early response 3-interacting protein 1 (IER3IP1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Immediate early response 3-interacting protein 1 (IER3IP1).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Immediate early response 3-interacting protein 1 (IER3IP1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Immediate early response 3-interacting protein 1 (IER3IP1).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Immediate early response 3-interacting protein 1 (IER3IP1).	[15]

2 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 affects the methylation of Immediate early response 3-interacting protein 1 (IER3IP1).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Immediate early response 3-interacting protein 1 (IER3IP1).	[13]

References

• [1] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [2] Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors. Am J Hum Genet. 2011 Aug 12;89(2):265-76. doi: 10.1016/j.ajhg.2011.07.006.
• [3] A homozygous IER3IP1 mutation causes microcephaly with simplified gyral pattern, epilepsy, and permanent neonatal diabetes syndrome (MEDS).Am J Med Genet A. 2012 Nov;158A(11):2788-96. doi: 10.1002/ajmg.a.35583. Epub 2012 Sep 18.
• [4] Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: insights into the natural history of a rare disorder.Pediatr Diabetes. 2014 May;15(3):252-6. doi: 10.1111/pedi.12086. Epub 2013 Oct 21.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] IER3IP1 deficiency leads to increased -cell death and decreased -cell proliferation.Oncotarget. 2017 May 25;8(34):56768-56779. doi: 10.18632/oncotarget.18179. eCollection 2017 Aug 22.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [13] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [14] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.