Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9EVMQY)

• DOT Name: Mastermind-like domain-containing protein 1 (MAMLD1)
• Synonyms: F18; Protein CG1
• Gene Name: MAMLD1
• Related Disease:
  46,XY complete gonadal dysgenesis
  46,XY disorder of sex development
  Anca-associated vasculitis
  Autosomal dominant nonsyndromic hearing loss 5
  Ependymoma
  Gonadal dysgenesis
  Hypospadias
  Hypospadias 2, X-linked
  Partial androgen insensitivity syndrome
  Pituitary adenoma
  Turner syndrome
  Stroke
  Type-1/2 diabetes
  Peroxisome biogenesis disorder
  Chronic renal failure
  End-stage renal disease
  Neoplasm
  X-linked myotubular myopathy
• UniProt ID: MAMD1_HUMAN
• Sequence:
  MDDWKSRLVIKSMLPHFAMVGNRQEPRKLQESGKKPSWMEEEDLSFLYKSSPGRKHQGTV
  KRRQEEDHFQFPDMADGGYPNKIKRPCLEDVTLAMGPGAHPSTACAELQVPPLTINPSPA
  AMGVAGQSLLLENNPMNGNIMGSPFVVPQTTEVGLKGPTVPYYEKINSVPAVDQELQELL
  EELTKIQDPSPNELDLEKILGTKPEEPLVLDHPQATLSTTPKPSVQMSHLESLASSKEFA
  SSCSQVTGMSLQIPSSSTGISYSIPSTSKQIVSPSSSMAQSKSQVQAMLPVALPPLPVPQ
  WHHAHQLKALAASKQGSATKQQGPTPSWSGLPPPGLSPPYRPVPSPHPPPLPLPPPPPPF
  SPQSLMVSCMSSNTLSGSTLRGSPNALLSSMTSSSNAALGPAMPYAPEKLPSPALTQQPQ
  FGPQSSILANLMSSTIKTPQGHLMSALPASNPGPSPPYRPEKLSSPGLPQQSFTPQCSLI
  RSLTPTSNLLSQQQQQQQQQQQANVIFKPISSNSSKTLSMIMQQGMASSSPGATEPFTFG
  NTKPLSHFVSEPGPQKMPSMPTTSRQPSLLHYLQQPTPTQASSATASSTATATLQLQQQQ
  QQQQQQPDHSSFLLQQMMQQPQRFQRSVASDSMPALPRQGCCHLFAWTSAASSVKPQHQH
  GNSFTSRQDPQPGDVSPSNITHVDKACKLGEARHPQVSLGRQPPSCQALGSESFLPGSSF
  AHELARVTSSYSTSEAAPWGSWDPKAWRQVPAPLLPSCDATARGTEIRSYGNDP
• Function: Transactivates the HES3 promoter independently of NOTCH proteins. HES3 is a non-canonical NOTCH target gene which lacks binding sites for RBPJ.
• Tissue Specificity: Expressed in fetal brain, fetal ovary and fetal testis. Expressed in adult brain, ovary, skin, testis, uterus. Highly expressed in skeletal muscle.
• Reactome Pathway:
  Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells (R-HSA-210744)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  NOTCH2 intracellular domain regulates transcription (R-HSA-2197563)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Notch-HLH transcription pathway (R-HSA-350054)
  RUNX3 regulates NOTCH signaling (R-HSA-8941856)
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  NOTCH4 Intracellular Domain Regulates Transcription (R-HSA-9013695)
  Formation of paraxial mesoderm (R-HSA-9793380)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XY complete gonadal dysgenesis	DISLF3LT	Strong	Genetic Variation	[1]
46,XY disorder of sex development	DIS78CGG	Strong	Altered Expression	[2]
Anca-associated vasculitis	DISU3CNU	Strong	Biomarker	[3]
Autosomal dominant nonsyndromic hearing loss 5	DISZ795Z	Strong	Genetic Variation	[4]
Ependymoma	DISUMRNZ	Strong	Genetic Variation	[5]
Gonadal dysgenesis	DISIL2ZI	Strong	Biomarker	[1]
Hypospadias	DIS48CCP	Strong	Biomarker	[6]
Hypospadias 2, X-linked	DISNCV78	Strong	X-linked	[7]
Partial androgen insensitivity syndrome	DISQ1113	Strong	Biomarker	[8]
Pituitary adenoma	DISJ5R1X	Strong	Altered Expression	[3]
Turner syndrome	DIS2035C	Strong	Biomarker	[1]
Stroke	DISX6UHX	moderate	Biomarker	[9]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[9]
Peroxisome biogenesis disorder	DISBQ6QJ	Disputed	Genetic Variation	[10]
Chronic renal failure	DISGG7K6	Limited	Biomarker	[11]
End-stage renal disease	DISXA7GG	Limited	Biomarker	[11]
Neoplasm	DISZKGEW	Limited	Altered Expression	[3]
X-linked myotubular myopathy	DISJ95GS	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mastermind-like domain-containing protein 1 (MAMLD1).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mastermind-like domain-containing protein 1 (MAMLD1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mastermind-like domain-containing protein 1 (MAMLD1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mastermind-like domain-containing protein 1 (MAMLD1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mastermind-like domain-containing protein 1 (MAMLD1).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Mastermind-like domain-containing protein 1 (MAMLD1).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Mastermind-like domain-containing protein 1 (MAMLD1).	[19]
Marinol	DM70IK5	Approved	Marinol increases the expression of Mastermind-like domain-containing protein 1 (MAMLD1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mastermind-like domain-containing protein 1 (MAMLD1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mastermind-like domain-containing protein 1 (MAMLD1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Mastermind-like domain-containing protein 1 (MAMLD1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Mastermind-like domain-containing protein 1 (MAMLD1).	[22]

References

• [1] A novel hemizygous mutation of MAMLD1 in a patient with 46,XY complete gonadal dysgenesis.Sex Dev. 2015;9(2):80-5. doi: 10.1159/000371603. Epub 2015 Feb 3.
• [2] NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development. Genet Med. 2017 Apr;19(4):367-376. doi: 10.1038/gim.2016.118. Epub 2016 Aug 4.
• [3] Attenuation of MAMLD1 Expression Suppresses the Growth and Migratory Properties of Gonadotroph Pituitary Adenomas.Pathol Oncol Res. 2020 Apr;26(2):937-946. doi: 10.1007/s12253-019-00615-2. Epub 2019 Mar 25.
• [4] Refined mapping of a gene for autosomal dominant progressive sensorineural hearing loss (DFNA5) to a 2-cM region, and exclusion of a candidate gene that is expressed in the cochlea.Eur J Hum Genet. 1997 Nov-Dec;5(6):397-405.
• [5] Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features.Brain Pathol. 2019 Mar;29(2):205-216. doi: 10.1111/bpa.12659. Epub 2018 Nov 11.
• [6] Family History is Underestimated in Children with Isolated Hypospadias: A French Multicenter Report of 88 Families.J Urol. 2018 Oct;200(4):890-894. doi: 10.1016/j.juro.2018.04.072. Epub 2018 Apr 30.
• [7] 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.
• [8] 'Idiopathic' partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine disruptor chemicals?.Eur J Endocrinol. 2011 Oct;165(4):579-87. doi: 10.1530/EJE-11-0580. Epub 2011 Jul 25.
• [9] Clinical and molecular epidemiology of community-onset, extended-spectrum beta-lactamase-producing Escherichia coli infections in Thailand: a case-case-control study.Am J Infect Control. 2007 Nov;35(9):606-12. doi: 10.1016/j.ajic.2007.05.008.
• [10] Peroxisome biogenesis and molecular defects in peroxisome assembly disorders.Cell Biochem Biophys. 2000;32 Spring:155-64. doi: 10.1385/cbb:32:1-3:155.
• [11] A grading system that predicts the risk of dialysis induction in IgA nephropathy patients based on the combination of the clinical and histological severity.Clin Exp Nephrol. 2019 Jan;23(1):16-25. doi: 10.1007/s10157-018-1657-0. Epub 2018 Oct 26.
• [12] Cloning and characterization of an alternatively spliced gene in proximal Xq28 deleted in two patients with intersexual genitalia and myotubular myopathy.Genomics. 1997 May 1;41(3):458-62. doi: 10.1006/geno.1997.4662.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [18] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [19] 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.
• [20] 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.
• [21] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [22] 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.
• [23] 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.
• [24] 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.