Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHBA8GT)

• DOT Name: Protein jagunal homolog 1 (JAGN1)
• Gene Name: JAGN1
• Related Disease:
  Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency
  Leukopenia
  Severe congenital neutropenia
• UniProt ID: JAGN1_HUMAN
• PDB ID: 6WVD
• Pfam ID: PF07086
• Sequence:
  MASRAGPRAAGTDGSDFQHRERVAMHYQMSVTLKYEIKKLIYVHLVIWLLLVAKMSVGHL
  RLLSHDQVAMPYQWEYPYLLSILPSLLGLLSFPRNNISYLVLSMISMGLFSIAPLIYGSM
  EMFPAAQQLYRHGKAYRFLFGFSAVSIMYLVLVLAVQVHAWQLYYSKKLLDSWFTSTQEK
  KHK
• Function: Endoplasmic reticulum transmembrane protein involved in vesicle-mediated transport, which is required for neutrophil function. Required for vesicle-mediated transport; it is however unclear whether it is involved in early secretory pathway or intracellular protein transport. Acts as a regulator of neutrophil function, probably via its role in vesicle-mediated transport: required for defense against fungal pathogens and for granulocyte colony-stimulating factor (GM-CSF) signaling pathway; possibly by regulating glycosylation and/or targeting of proteins contributing to the viability and migration of neutrophils.
• Tissue Specificity: Ubiquitously expressed.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency	DISMVYO8	Strong	Autosomal recessive	[1]
Leukopenia	DISJMBMM	Strong	Genetic Variation	[2]
Severe congenital neutropenia	DISES99N	Strong	Biomarker	[2]

2 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 jagunal homolog 1 (JAGN1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein jagunal homolog 1 (JAGN1).	[9]

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 Protein jagunal homolog 1 (JAGN1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein jagunal homolog 1 (JAGN1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein jagunal homolog 1 (JAGN1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein jagunal homolog 1 (JAGN1).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein jagunal homolog 1 (JAGN1).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Protein jagunal homolog 1 (JAGN1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein jagunal homolog 1 (JAGN1).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein jagunal homolog 1 (JAGN1).	[12]

References

• [1] JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. Nat Genet. 2014 Sep;46(9):1021-7. doi: 10.1038/ng.3069. Epub 2014 Aug 17.
• [2] Next-Generation Sequencing Reveals A JAGN1 Mutation in a Syndromic Child With Intermittent Neutropenia.J Pediatr Hematol Oncol. 2019 May;41(4):e266-e269. doi: 10.1097/MPH.0000000000001256.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.