Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT43JC9A)

• DOT Name: Magnesium transporter NIPA4 (NIPAL4)
• Synonyms: Ichthyin; NIPA-like protein 4; Non-imprinted in Prader-Willi/Angelman syndrome region protein 4
• Gene Name: NIPAL4
• Related Disease:
  Arthropathy
  Autosomal recessive congenital ichthyosis 6
  Autosomal recessive congenital ichthyosis
  Congenital ichthyosiform erythroderma
  Lamellar ichthyosis
• UniProt ID: NIPA4_HUMAN
• Pfam ID: PF05653
• Sequence:
  MELRVSNTSCENGSLLHLYCSSQEVLCQIVNDLSPEVPSNATFHSWQERIRQNYGFYIGL
  GLAFLSSFLIGSSVILKKKGLLRLVATGATRAVDGGFGYLKDAMWWAGFLTMAAGEVANF
  GAYAFAPATVVTPLGALSVLISAILSSYFLRESLNLLGKLGCVICVAGSTVMVIHAPEEE
  KVTTIMEMASKMKDTGFIVFAVLLLVSCLILIFVIAPRYGQRNILIYIIICSVIGAFSVA
  AVKGLGITIKNFFQGLPVVRHPLPYILSLILALSLSTQVNFLNRALDIFNTSLVFPIYYV
  FFTTVVVTSSIILFKEWYSMSAVDIAGTLSGFVTIILGVFMLHAFKDLDISCASLPHMHK
  NPPPSPAPEPTVIRLEDKNVLVDNIELASTSSPEEKPKVFIIHS
• Function: Acts as a Mg(2+) transporter. Can also transport other divalent cations such as Ba(2+), Sr(2+) and Fe(2+) but to a much less extent than Mg(2+). May be a receptor for ligands (trioxilins A3 and B3) from the hepoxilin pathway.
• Tissue Specificity: Highly expressed in brain, lung, stomach, keratinocytes and leukocytes, and in all other tissues tested except liver, thyroid and fetal brain.
• Reactome Pathway: Miscellaneous transport and binding events (R-HSA-5223345)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthropathy	DISVEERK	Definitive	Genetic Variation	[1]
Autosomal recessive congenital ichthyosis 6	DIS9HRE9	Definitive	Autosomal recessive	[2]
Autosomal recessive congenital ichthyosis	DISVMSR6	Strong	Altered Expression	[3]
Congenital ichthyosiform erythroderma	DISV8HQX	Supportive	Autosomal recessive	[3]
Lamellar ichthyosis	DIS714UN	Supportive	Autosomal recessive	[4]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Magnesium transporter NIPA4 (NIPAL4).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Magnesium transporter NIPA4 (NIPAL4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Magnesium transporter NIPA4 (NIPAL4).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Magnesium transporter NIPA4 (NIPAL4).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Magnesium transporter NIPA4 (NIPAL4).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Magnesium transporter NIPA4 (NIPAL4).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Magnesium transporter NIPA4 (NIPAL4).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Magnesium transporter NIPA4 (NIPAL4).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Magnesium transporter NIPA4 (NIPAL4).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Magnesium transporter NIPA4 (NIPAL4).	[14]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Magnesium transporter NIPA4 (NIPAL4).	[15]

References

• [1] Autosomal recessive congenital ichthyosis due to homozygous variants in NIPAL4 with a dramatic response to ustekinumab.Pediatr Dermatol. 2019 Nov;36(6):1002-1003. doi: 10.1111/pde.13995. Epub 2019 Sep 18.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] NIPAL4/ichthyin is expressed in the granular layer of human epidermis and mutated in two Pakistani families with autosomal recessive ichthyosis. Dermatology. 2010;220(1):8-14. doi: 10.1159/000265757. Epub 2009 Dec 10.
• [4] Inherited ichthyoses/generalized Mendelian disorders of cornification. Eur J Hum Genet. 2013 Feb;21(2):123-33. doi: 10.1038/ejhg.2012.121. Epub 2012 Jun 27.
• [5] 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.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [9] 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.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [12] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [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] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.