Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5PU9U1)

DOT Name	Doublesex- and mab-3-related transcription factor 1 (DMRT1)
Synonyms	DM domain expressed in testis protein 1
Gene Name	DMRT1
Related Disease	Embryonal neoplasm ( ) Familial hypocalciuric hypercalcemia 1 ( ) Adult teratoma ( ) Alzheimer disease ( ) Anemia, hypochromic microcytic with iron overload ( ) Coeliac disease ( ) Congenital diaphragmatic hernia ( ) Epithelial ovarian cancer ( ) Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 ( ) Hepatocellular carcinoma ( ) Hereditary hemochromatosis ( ) Hyperglycemia ( ) Inflammatory bowel disease ( ) Iron-deficiency anemia ( ) Kidney cancer ( ) Lung squamous cell carcinoma ( ) Male infertility ( ) Neoplasm ( ) Neoplasm of testis ( ) Non-small-cell lung cancer ( ) Oligospermia ( ) Ovarian cancer ( ) Ovarian neoplasm ( ) Parkinson disease ( ) Renal carcinoma ( ) Testicular cancer ( ) Triple negative breast cancer ( ) Ulcerative colitis ( ) 46,XY complete gonadal dysgenesis ( ) Adrenoleukodystrophy ( ) Age-related macular degeneration ( ) Anemia ( ) Arteriosclerosis ( ) Atherosclerosis ( ) Nephropathy ( ) Retinopathy ( ) Stroke ( ) Teratoma ( ) Type-1/2 diabetes ( ) Hypochromic microcytic anemia ( ) Asthma ( ) Germ cell tumor ( ) Gonadal dysgenesis ( ) Parkinsonian disorder ( ) Seminoma ( ) Tuberculosis ( ) Turner syndrome ( )
UniProt ID	DMRT1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	4YJ0
Pfam ID	PF00751 ; PF12374
Sequence	MPNDEAFSKPSTPSEAPHAPGVPPQGRAGGFGKASGALVGAASGSSAGGSSRGGGSGSGA SDLGAGSKKSPRLPKCARCRNHGYASPLKGHKRFCMWRDCQCKKCNLIAERQRVMAAQVA LRRQQAQEEELGISHPIPLPSAAELLVKRENNGSNPCLMTECSGTSQPPPASVPTTAASE GRMVIQDIPAVTSRGHVENTPDLVSDSTYYSSFYQPSLFPYYNNLYNCPQYSMALAADSA SGEVGNPLGGSPVKNSLRGLPGPYVPGQTGNQWQMKNMENRHAMSSQYRMHSYYPPPSYL GQSVPQFFTFEDAPSYPEARASVFSPPSSQDSGLVSLSSSSPISNKSTKAVLECEPASEP SSFTVTPVIEEDE
Function	Transcription factor that plays a key role in male sex determination and differentiation by controlling testis development and male germ cell proliferation. Plays a central role in spermatogonia by inhibiting meiosis in undifferentiated spermatogonia and promoting mitosis, leading to spermatogonial development and allowing abundant and continuous production of sperm. Acts both as a transcription repressor and activator: prevents meiosis by restricting retinoic acid (RA)-dependent transcription and repressing STRA8 expression and promotes spermatogonial development by activating spermatogonial differentiation genes, such as SOHLH1. Also plays a key role in postnatal sex maintenance by maintaining testis determination and preventing feminization: represses transcription of female promoting genes such as FOXL2 and activates male-specific genes. May act as a tumor suppressor. May also play a minor role in oogenesis.
Tissue Specificity	Testis-specific. Expressed in prostate cancer (at protein level).
Reactome Pathway	Transcriptional regulation of testis differentiation (R-HSA-9690406 )

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Embryonal neoplasm	DIS5MQSB	Definitive	Biomarker	[1]
Familial hypocalciuric hypercalcemia 1	DISPW6O5	Definitive	Altered Expression	[2]
Adult teratoma	DISBY81U	Strong	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Anemia, hypochromic microcytic with iron overload	DIST0BXW	Strong	Genetic Variation	[4]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[5]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Biomarker	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[7]
Frontotemporal dementia and/or amyotrophic lateral sclerosis 7	DISDD18L	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[9]
Hereditary hemochromatosis	DISVG5MT	Strong	Biomarker	[10]
Hyperglycemia	DIS0BZB5	Strong	Altered Expression	[11]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[12]
Iron-deficiency anemia	DIS0VQYF	Strong	Biomarker	[10]
Kidney cancer	DISBIPKM	Strong	Altered Expression	[13]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[14]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[15]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Neoplasm of testis	DISK4XHT	Strong	Genetic Variation	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[17]
Oligospermia	DIS6YJF3	Strong	Posttranslational Modification	[18]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[7]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[7]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[19]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[13]
Testicular cancer	DIS6HNYO	Strong	Genetic Variation	[20]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[21]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[22]
46,XY complete gonadal dysgenesis	DISLF3LT	moderate	Genetic Variation	[23]
Adrenoleukodystrophy	DISTUD1F	moderate	Altered Expression	[24]
Age-related macular degeneration	DIS0XS2C	moderate	Genetic Variation	[25]
Anemia	DISTVL0C	moderate	Genetic Variation	[5]
Arteriosclerosis	DISK5QGC	moderate	Biomarker	[26]
Atherosclerosis	DISMN9J3	moderate	Biomarker	[26]
Nephropathy	DISXWP4P	moderate	Biomarker	[26]
Retinopathy	DISB4B0F	moderate	Biomarker	[26]
Stroke	DISX6UHX	moderate	Altered Expression	[27]
Teratoma	DIS6ICY4	moderate	Genetic Variation	[28]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[26]
Hypochromic microcytic anemia	DIS0RMTQ	Disputed	Genetic Variation	[29]
Asthma	DISW9QNS	Limited	Genetic Variation	[30]
Germ cell tumor	DIS62070	Limited	Altered Expression	[31]
Gonadal dysgenesis	DISIL2ZI	Limited	Genetic Variation	[32]
Parkinsonian disorder	DISHGY45	Limited	Genetic Variation	[33]
Seminoma	DIS3J8LJ	Limited	Altered Expression	[31]
Tuberculosis	DIS2YIMD	Limited	Genetic Variation	[34]
Turner syndrome	DIS2035C	Limited	Genetic Variation	[32]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
NAPQI	DM8F5LR	Investigative	Doublesex- and mab-3-related transcription factor 1 (DMRT1) affects the response to substance of NAPQI.	[40]
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4 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Doublesex- and mab-3-related transcription factor 1 (DMRT1).	[35]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Doublesex- and mab-3-related transcription factor 1 (DMRT1).	[36]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Doublesex- and mab-3-related transcription factor 1 (DMRT1).	[37]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Doublesex- and mab-3-related transcription factor 1 (DMRT1).	[38]
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1 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 increases the methylation of Doublesex- and mab-3-related transcription factor 1 (DMRT1).	[39]
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References

1	Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer.Nat Genet. 2010 Jul;42(7):604-7. doi: 10.1038/ng.607. Epub 2010 Jun 13.
2	Duodenal expression of iron transport molecules in patients with hereditary hemochromatosis or iron deficiency.J Cell Mol Med. 2012 Aug;16(8):1816-26. doi: 10.1111/j.1582-4934.2011.01458.x.
3	Ceruloplasmin, a Potential Therapeutic Agent for Alzheimer's Disease.Antioxid Redox Signal. 2018 May 10;28(14):1323-1337. doi: 10.1089/ars.2016.6883. Epub 2017 Oct 17.
4	A novel N491S mutation in the human SLC11A2 gene impairs protein trafficking and in association with the G212V mutation leads to microcytic anemia and liver iron overload.Blood Cells Mol Dis. 2011 Dec 15;47(4):243-8. doi: 10.1016/j.bcmd.2011.07.004. Epub 2011 Aug 26.
5	The DMT1 IVS4+44C>A polymorphism and the risk of iron deficiency anemia in children with celiac disease.PLoS One. 2017 Oct 12;12(10):e0185822. doi: 10.1371/journal.pone.0185822. eCollection 2017.
6	Role of catalytic iron and oxidative stress in nitrofen-induced congenital diaphragmatic hernia and its amelioration by Saireito (TJ-114).J Clin Biochem Nutr. 2017 Nov;61(3):176-182. doi: 10.3164/jcbn.17-17. Epub 2017 Sep 5.
7	The iron chelator desferrioxamine synergizes with chemotherapy for cancer treatment.J Trace Elem Med Biol. 2019 Dec;56:131-138. doi: 10.1016/j.jtemb.2019.07.008. Epub 2019 Aug 19.
8	A novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters.Sci Rep. 2017 Jul 28;7(1):6194. doi: 10.1038/s41598-017-06446-y.
9	Low DMT1 Expression Associates With IncreasedOxidative Phosphorylation and EarlyRecurrence in Hepatocellular Carcinoma.J Surg Res. 2019 Feb;234:343-352. doi: 10.1016/j.jss.2018.11.008.
10	Oral Gavage of Ginger Nanoparticle-Derived Lipid Vectors Carrying Dmt1 siRNA Blunts Iron Loading in Murine Hereditary Hemochromatosis.Mol Ther. 2019 Mar 6;27(3):493-506. doi: 10.1016/j.ymthe.2019.01.003. Epub 2019 Jan 12.
11	Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKC-dependent manner.FASEB J. 2019 Mar;33(3):3549-3561. doi: 10.1096/fj.201801855R. Epub 2018 Nov 13.
12	Divalent metal-ion transporter 1 is decreased in intestinal epithelial cells and contributes to the anemia in inflammatory bowel disease.Sci Rep. 2015 Nov 17;5:16344. doi: 10.1038/srep16344.
13	Molecular pathways: Fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer.Clin Cancer Res. 2013 Jul 1;19(13):3345-52. doi: 10.1158/1078-0432.CCR-13-0304. Epub 2013 Apr 30.
14	Frequent silence of chromosome 9p, homozygous DOCK8, DMRT1 and DMRT3 deletion at 9p24.3 in squamous cell carcinoma of the lung.Int J Oncol. 2010 Aug;37(2):327-35.
15	DMRT1 mutations are rarely associated with male infertility.Fertil Steril. 2014 Sep;102(3):816-820.e3. doi: 10.1016/j.fertnstert.2014.05.022. Epub 2014 Jun 14.
16	Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14.Nat Genet. 2013 Jun;45(6):686-9. doi: 10.1038/ng.2635. Epub 2013 May 12.
17	CRISP-R/Cas9 Mediated Deletion of Copper Transport Genes CTR1 and DMT1 in NSCLC Cell Line H1299. Biological and Pharmacological Consequences.Cells. 2019 Apr 6;8(4):322. doi: 10.3390/cells8040322.
18	Alterations of testis-specific promoter methylation in cell-free seminal deoxyribonucleic acid of idiopathic nonobstructive azoospermic men with different testicular phenotypes.Fertil Steril. 2016 Nov;106(6):1331-1337. doi: 10.1016/j.fertnstert.2016.07.006. Epub 2016 Aug 3.
19	Is the 1254T>C polymorphism in the DMT1 gene associated with Parkinson's disease?.Neurosci Lett. 2015 May 6;594:51-4. doi: 10.1016/j.neulet.2015.03.054. Epub 2015 Mar 26.
20	A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility.Hum Mol Genet. 2011 Aug 1;20(15):3109-17. doi: 10.1093/hmg/ddr207. Epub 2011 May 6.
21	Deferoxamine-inducedhigh expression of TfR1 and DMT1 enhanced iron uptake intriple-negative breast cancer cells by activatingIL-6/PI3K/AKTpathway.Onco Targets Ther. 2019 May 31;12:4359-4377. doi: 10.2147/OTT.S193507. eCollection 2019.
22	Increased DMT1 and FPN1 expression with enhanced iron absorption in ulcerative colitis human colon.Am J Physiol Cell Physiol. 2020 Feb 1;318(2):C263-C271. doi: 10.1152/ajpcell.00128.2019. Epub 2019 Nov 13.
23	Chromosome 9p deletion syndrome and sex reversal: novel findings and redefinition of the critically deleted regions.Am J Med Genet A. 2012 Sep;158A(9):2266-71. doi: 10.1002/ajmg.a.35489. Epub 2012 Jul 20.
24	Role of duodenal iron transporters and hepcidin in patients with alcoholic liver disease.J Cell Mol Med. 2014 Sep;18(9):1840-50. doi: 10.1111/jcmm.12310. Epub 2014 Jun 3.
25	An association between environmental factors and the IVS4+44C>A polymorphism of the DMT1 gene in age-related macular degeneration.Graefes Arch Clin Exp Ophthalmol. 2012 Jul;250(7):1057-65. doi: 10.1007/s00417-012-1966-z. Epub 2012 Feb 29.
26	The role and function of HDL in patients with diabetes mellitus and the related cardiovascular risk.Lipids Health Dis. 2017 Oct 30;16(1):207. doi: 10.1186/s12944-017-0594-3.
27	1B/(-)IRE DMT1 expression during brain ischemia contributes to cell death mediated by NF-B/RelA acetylation at Lys310.PLoS One. 2012;7(5):e38019. doi: 10.1371/journal.pone.0038019. Epub 2012 May 29.
28	Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line.Dev Biol. 2013 May 1;377(1):67-78. doi: 10.1016/j.ydbio.2013.02.014. Epub 2013 Mar 6.
29	H(+)-coupled divalent metal-ion transporter-1: functional properties, physiological roles and therapeutics.Curr Top Membr. 2012;70:169-214. doi: 10.1016/B978-0-12-394316-3.00005-3.
30	Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages.J Allergy Clin Immunol. 2016 Aug;138(2):421-31. doi: 10.1016/j.jaci.2015.12.1305. Epub 2016 Feb 20.
31	Protein expression of the transcription factors DMRT1, TCLF5, and OCT4 in selected germ cell neoplasms of the testis.Hum Pathol. 2018 Dec;82:68-75. doi: 10.1016/j.humpath.2018.07.019. Epub 2018 Jul 29.
32	9p partial monosomy and disorders of sex development: review and postulation of a pathogenetic mechanism.Am J Med Genet A. 2013 Aug;161A(8):1882-96. doi: 10.1002/ajmg.a.36018. Epub 2013 Jul 3.
33	Iron transport in Parkinson's disease.Parkinsonism Relat Disord. 2009 Dec;15 Suppl 3:S209-11. doi: 10.1016/S1353-8020(09)70816-8.
34	SLC11A1 (NRAMP1) but not SLC11A2 (NRAMP2) polymorphisms are associated with susceptibility to tuberculosis in a high-incidence community in South Africa.Int J Tuberc Lung Dis. 2004 Dec;8(12):1464-71.
35	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
36	Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
37	Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
38	Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
39	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.
40	Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicol Sci. 2011 Mar;120(1):33-41. doi: 10.1093/toxsci/kfq375. Epub 2010 Dec 22.