Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4235J2)

• DOT Name: Hemojuvelin (HJV)
• Synonyms: Hemochromatosis type 2 protein; Hemojuvelin BMP coreceptor; RGM domain family member C
• Gene Name: HJV
• Related Disease:
  Cardiomyopathy
  Hemochromatosis type 2A
  Hereditary hemochromatosis
  Androgen insensitivity syndrome
  Astrocytoma
  Beta-thalassemia major
  Breast cancer
  Breast carcinoma
  Chronic kidney disease
  Classic Hodgkin lymphoma
  Duchenne muscular dystrophy
  Essential hypertension
  Huntington disease
  IRIDA syndrome
  Lung squamous cell carcinoma
  Myelodysplastic syndrome
  Non-alcoholic fatty liver disease
  Obesity
  Osteoporosis
  Porphyria cutanea tarda
  Stroke
  Bacterial infection
  Hemochromatosis type 2
  Hypogonadism
  Cholestasis
  Hepatitis C virus infection
  High blood pressure
• UniProt ID: RGMC_HUMAN
• PDB ID: 4UI1; 6Z3L
• Pfam ID: PF06534 ; PF06535
• Sequence:
  MGEPGQSPSPRSSHGSPPTLSTLTLLLLLCGHAHSQCKILRCNAEYVSSTLSLRGGGSSG
  ALRGGGGGGRGGGVGSGGLCRALRSYALCTRRTARTCRGDLAFHSAVHGIEDLMIQHNCS
  RQGPTAPPPPRGPALPGAGSGLPAPDPCDYEGRFSRLHGRPPGFLHCASFGDPHVRSFHH
  HFHTCRVQGAWPLLDNDFLFVQATSSPMALGANATATRKLTIIFKNMQECIDQKVYQAEV
  DNLPVAFEDGSINGGDRPGGSSLSIQTANPGNHVEIQAAYIGTTIIIRQTAGQLSFSIKV
  AEDVAMAFSAEQDLQLCVGGCPPSQRLSRSERNRRGAITIDTARRLCKEGLPVEDAYFHS
  CVFDVLISGDPNFTVAAQAALEDARAFLPDLEKLHLFPSDAGVPLSSATLLAPLLSGLFV
  LWLCIQ
• Function: Acts as a bone morphogenetic protein (BMP) coreceptor. Through enhancement of BMP signaling regulates hepcidin (HAMP) expression and regulates iron homeostasis.
• Tissue Specificity: Adult and fetal liver, heart, and skeletal muscle.
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)
• Reactome Pathway: Netrin-1 signaling (R-HSA-373752)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiomyopathy	DISUPZRG	Definitive	Biomarker	[1]
Hemochromatosis type 2A	DISDG593	Definitive	Autosomal recessive	[2]
Hereditary hemochromatosis	DISVG5MT	Definitive	Genetic Variation	[3]
Androgen insensitivity syndrome	DISUZBBO	Strong	Altered Expression	[4]
Astrocytoma	DISL3V18	Strong	Biomarker	[5]
Beta-thalassemia major	DISW06BV	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[7]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[8]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[9]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Biomarker	[10]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[11]
Huntington disease	DISQPLA4	Strong	Altered Expression	[9]
IRIDA syndrome	DISPN8YW	Strong	Genetic Variation	[12]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[13]
Myelodysplastic syndrome	DISYHNUI	Strong	Posttranslational Modification	[14]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[15]
Obesity	DIS47Y1K	Strong	Biomarker	[16]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[17]
Porphyria cutanea tarda	DISHNFD7	Strong	Genetic Variation	[18]
Stroke	DISX6UHX	Strong	Altered Expression	[4]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[19]
Hemochromatosis type 2	DISYM9UP	Supportive	Autosomal recessive	[20]
Hypogonadism	DISICMNI	Disputed	Biomarker	[1]
Cholestasis	DISDJJWE	Limited	Biomarker	[21]
Hepatitis C virus infection	DISQ0M8R	Limited	Altered Expression	[9]
High blood pressure	DISY2OHH	Limited	Genetic Variation	[11]

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 Hemojuvelin (HJV).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Hemojuvelin (HJV).	[28]

9 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 Hemojuvelin (HJV).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hemojuvelin (HJV).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Hemojuvelin (HJV).	[25]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hemojuvelin (HJV).	[23]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Hemojuvelin (HJV).	[26]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Hemojuvelin (HJV).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Hemojuvelin (HJV).	[29]
Dorsomorphin	DMKYXJW	Investigative	Dorsomorphin decreases the expression of Hemojuvelin (HJV).	[30]
SU9516	DMQHG0R	Investigative	SU9516 decreases the expression of Hemojuvelin (HJV).	[30]

References

• [1] Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease.Blood. 2018 Jul 5;132(1):101-110. doi: 10.1182/blood-2018-02-830562. Epub 2018 May 9.
• [2] Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood. 2004 Jun 1;103(11):4317-21. doi: 10.1182/blood-2004-01-0192. Epub 2004 Feb 24.
• [3] Genotypic and phenotypic spectra of hemojuvelin mutations in primary hemochromatosis patients: a systematic review.Orphanet J Rare Dis. 2019 Jul 8;14(1):171. doi: 10.1186/s13023-019-1097-2.
• [4] The functional role of hemojuvelin in acute ischemic stroke.J Cereb Blood Flow Metab. 2020 Jun;40(6):1316-1327. doi: 10.1177/0271678X19861448. Epub 2019 Jul 15.
• [5] Expression of iron-related genes in human brain and brain tumors.BMC Neurosci. 2009 Apr 22;10:36. doi: 10.1186/1471-2202-10-36.
• [6] Downregulation of hepcidin and haemojuvelin expression in the hepatocyte cell-line HepG2 induced by thalassaemic sera.Br J Haematol. 2006 Oct;135(1):129-38. doi: 10.1111/j.1365-2141.2006.06258.x. Epub 2006 Aug 25.
• [7] Potential prognostic value of repulsive guidance molecules in breast cancer.Anticancer Res. 2011 May;31(5):1703-11.
• [8] Effect of atorvastatin on iron metabolism regulation in patients with chronic kidney disease - a randomized double blind crossover study.Ren Fail. 2018 Nov;40(1):700-709. doi: 10.1080/0886022X.2018.1535983.
• [9] Relationship of serum haemojuvelin and hepcidin levels with iron level and erythropoietin requirement in prevalent hepatitis C virus positive haemodialysis patients.Nephrology (Carlton). 2018 Apr;23(4):323-330. doi: 10.1111/nep.13010.
• [10] Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age-related muscle wasting.J Cachexia Sarcopenia Muscle. 2019 Jun;10(3):557-573. doi: 10.1002/jcsm.12414. Epub 2019 Mar 18.
• [11] Minor variant of rs 16827043 in the iron regulator hemojuvelin gene (HJV) contributes to hypertension: The TAMRISK study.Medicine (Baltimore). 2017 Feb;96(5):e6052. doi: 10.1097/MD.0000000000006052.
• [12] A novel mutation Gly603Arg of TMPRSS6 in a Korean female with iron-refractory iron deficiency anemia.Pediatr Blood Cancer. 2012 Apr;58(4):640-2. doi: 10.1002/pbc.23190. Epub 2011 May 25.
• [13] Identification of key genes and long noncoding RNAs in celecoxibtreated lung squamous cell carcinoma cell line by RNAsequencing.Mol Med Rep. 2018 May;17(5):6456-6464. doi: 10.3892/mmr.2018.8656. Epub 2018 Mar 1.
• [14] Decitabine treatment could ameliorate primary iron-overload in myelodysplastic syndrome patients.Cancer Invest. 2015 Apr;33(4):98-106. doi: 10.3109/07357907.2014.1001895. Epub 2015 Feb 20.
• [15] Pathways underlying iron accumulation in human nonalcoholic fatty liver disease.Am J Clin Nutr. 2008 May;87(5):1374-83. doi: 10.1093/ajcn/87.5.1374.
• [16] Hemojuvelin: a new link between obesity and iron homeostasis.Obesity (Silver Spring). 2011 Aug;19(8):1545-51. doi: 10.1038/oby.2011.12. Epub 2011 Feb 10.
• [17] Osteoporosis in HFE2 juvenile hemochromatosis. A case report and review of the literature.Osteoporos Int. 2006 Jan;17(1):150-5. doi: 10.1007/s00198-005-1920-6. Epub 2005 Jul 5.
• [18] Down-regulation of hepcidin in porphyria cutanea tarda.Blood. 2008 Dec 1;112(12):4723-8. doi: 10.1182/blood-2008-02-138222. Epub 2008 Sep 22.
• [19] Hemojuvelin regulates the innate immune response to peritoneal bacterial infection in mice.Cell Discov. 2017 Aug 15;3:17028. doi: 10.1038/celldisc.2017.28. eCollection 2017.
• [20] Juvenile Hemochromatosis. 2005 Feb 17 [updated 2020 Jan 9]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [21] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [22] 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.
• [23] 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.
• [24] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [25] 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.
• [26] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [27] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [28] 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.
• [29] 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.
• [30] A HAMP promoter bioassay system for identifying chemical compounds that modulate hepcidin expression. Exp Hematol. 2015 May;43(5):404-413.e5. doi: 10.1016/j.exphem.2015.01.005. Epub 2015 Jan 26.