Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCLX3ZW)

• DOT Name: Deformed epidermal autoregulatory factor 1 homolog (DEAF1)
• Synonyms: Nuclear DEAF-1-related transcriptional regulator; NUDR; Suppressin; Zinc finger MYND domain-containing protein 5
• Gene Name: DEAF1
• Related Disease:
  Intellectual disability, autosomal dominant 24
  Type-1 diabetes
  Adenocarcinoma
  Advanced cancer
  Autism
  Autism spectrum disorder
  Cerebellar ataxia
  Colorectal carcinoma
  Complex neurodevelopmental disorder
  Constipation
  Depression
  Epilepsy
  Intellectual disability-epilepsy-extrapyramidal syndrome
  Major depressive disorder
  Mental disorder
  Microcephaly
  Neoplasm
  Neurodevelopmental disorder
  Panic disorder
  Smith-Magenis syndrome
  Traveler's diarrhea
  Autosomal dominant non-syndromic intellectual disability
  Mood disorder
  Hepatocellular carcinoma
  Hyperglycemia
  Neuroblastoma
  Type-1/2 diabetes
• UniProt ID: DEAF1_HUMAN
• PDB ID: 2JW6; 4A24; 5UWW
• Pfam ID: PF01342 ; PF01753
• Sequence:
  MEDSDSAAKQLGLAEAAAVAAAAAVAAAAAAAAGGEAEEPVLSRDEDSEEDADSEAERET
  PRVTAVAVMAAEPGHMDMGAEALPGPDEAAAAAAFAEVTTVTVANVGAAADNVFTTSVAN
  AASISGHVLSGRTALQIGDSLNTEKATLIVVHTDGSIVETTGLKGPAAPLTPGPQSPPTP
  LAPGQEKGGTKYNWDPSVYDSELPVRCRNISGTLYKNRLGSGGRGRCIKQGENWYSPTEF
  EAMAGRASSKDWKRSIRYAGRPLQCLIQDGILNPHAASCTCAACCDDMTLSGPVRLFVPY
  KRRKKENELPTTPVKKDSPKNITLLPATAATTFTVTPSGQITTSGALTFDRASTVEATAV
  ISESPAQGDVFAGATVQEASVQPPCRASHPEPHYPGYQDSCQIAPFPEAALPTSHPKIVL
  TSLPALAVPPPTPTKAAPPALVNGLELSEPRSWLYLEEMVNSLLNTAQQLKTLFEQAKHA
  STYREAATNQAKIHADAERKEQSCVNCGREAMSECTGCHKVNYCSTFCQRKDWKDHQHIC
  GQSAAVTVQADEVHVAESVMEKVTV
• Function: Transcription factor that binds to sequence with multiple copies of 5'-TTC[CG]G-3' present in its own promoter and that of the HNRPA2B1 gene. Down-regulates transcription of these genes. Binds to the retinoic acid response element (RARE) 5'-AGGGTTCACCGAAAGTTCA-3'. Activates the proenkephalin gene independently of promoter binding, probably through protein-protein interaction. When secreted, behaves as an inhibitor of cell proliferation, by arresting cells in the G0 or G1 phase. Required for neural tube closure and skeletal patterning. Regulates epithelial cell proliferation and side-branching in the mammary gland. Controls the expression of peripheral tissue antigens in pancreatic lymph nodes. Isoform 1 displays greater transcriptional activity than isoform 4. Isoform 4 may inhibit transcriptional activity of isoform 1 by interacting with isoform 1 and retaining it in the cytoplasm. Transcriptional activator of EIF4G3.
• Tissue Specificity: Expressed in various tissues and cells such as in peripheral mononuclear cells and hormone-secreting pituitary cells. Expression in pancreatic lymph nodes of patients with type 1 diabetes is 20 times higher than in healthy controls. Highly expressed in fetal and adult brain.

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 24	DISH9BXR	Definitive	Autosomal dominant	[1]
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Autism	DISV4V1Z	Strong	Genetic Variation	[4]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Complex neurodevelopmental disorder	DISB9AFI	Strong	Semidominant	[1]
Constipation	DISRQXWI	Strong	Genetic Variation	[6]
Depression	DIS3XJ69	Strong	Genetic Variation	[7]
Epilepsy	DISBB28L	Strong	Genetic Variation	[4]
Intellectual disability-epilepsy-extrapyramidal syndrome	DIS4HTIM	Strong	Autosomal recessive	[8]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[9]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[10]
Microcephaly	DIS2GRD8	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[11]
Panic disorder	DISD3VNY	Strong	Genetic Variation	[10]
Smith-Magenis syndrome	DISG4G6X	Strong	Genetic Variation	[12]
Traveler's diarrhea	DIS4R0UE	Strong	Genetic Variation	[12]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[1]
Mood disorder	DISLVMWO	Disputed	Altered Expression	[13]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[14]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[15]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[16]

3 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 Deformed epidermal autoregulatory factor 1 homolog (DEAF1).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Deformed epidermal autoregulatory factor 1 homolog (DEAF1).	[27]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Deformed epidermal autoregulatory factor 1 homolog (DEAF1).	[27]

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 Deformed epidermal autoregulatory factor 1 homolog (DEAF1).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Deformed epidermal autoregulatory factor 1 homolog (DEAF1).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Deformed epidermal autoregulatory factor 1 homolog (DEAF1).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Deformed epidermal autoregulatory factor 1 homolog (DEAF1).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Deformed epidermal autoregulatory factor 1 homolog (DEAF1).	[22]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Deformed epidermal autoregulatory factor 1 homolog (DEAF1).	[23]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Deformed epidermal autoregulatory factor 1 homolog (DEAF1).	[24]
Heroin diacetylmorphine	DMDBWHY	Approved	Heroin diacetylmorphine decreases the expression of Deformed epidermal autoregulatory factor 1 homolog (DEAF1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Deformed epidermal autoregulatory factor 1 homolog (DEAF1).	[26]

References

• [1] Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems. Am J Hum Genet. 2014 May 1;94(5):649-61. doi: 10.1016/j.ajhg.2014.03.013. Epub 2014 Apr 10.
• [2] Inflammation and hyperglycemia mediate Deaf1 splicing in the pancreatic lymph nodes via distinct pathways during type 1 diabetes.Diabetes. 2015 Feb;64(2):604-17. doi: 10.2337/db14-0803. Epub 2014 Sep 3.
• [3] Altered subcellular localization of suppressin, a novel inhibitor of cell-cycle entry, is an independent prognostic factor in colorectal adenocarcinomas.Clin Cancer Res. 2001 Nov;7(11):3495-503.
• [4] Recessive DEAF1 mutation associates with autism, intellectual disability, basal ganglia dysfunction and epilepsy. J Med Genet. 2015 Sep;52(9):607-11. doi: 10.1136/jmedgenet-2015-103083. Epub 2015 Jun 5.
• [5] Exome sequencing identifies de novo splicing variant in XRCC6 in sporadic case of autism.J Hum Genet. 2020 Mar;65(3):287-296. doi: 10.1038/s10038-019-0707-0. Epub 2019 Dec 12.
• [6] Functional analysis of novel DEAF1 variants identified through clinical exome sequencing expands DEAF1-associated neurodevelopmental disorder (DAND) phenotype.Hum Mutat. 2017 Dec;38(12):1774-1785. doi: 10.1002/humu.23339. Epub 2017 Sep 23.
• [7] rs6295 [C]-Allele Protects Against Depressive Mood in Elderly Endurance Athletes.J Sport Exerc Psychol. 2015 Dec;37(6):637-45. doi: 10.1123/jsep.2015-0111.
• [8] Novel homozygous DEAF1 variant suspected in causing white matter disease, intellectual disability, and microcephaly. Am J Med Genet A. 2014 Jun;164A(6):1565-70. doi: 10.1002/ajmg.a.36482. Epub 2014 Mar 25.
• [9] Increased serotonin-1A (5-HT1A) autoreceptor expression and reduced raphe serotonin levels in deformed epidermal autoregulatory factor-1 (Deaf-1) gene knock-out mice.J Biol Chem. 2012 Feb 24;287(9):6615-27. doi: 10.1074/jbc.M111.293027. Epub 2012 Jan 9.
• [10] 5-HT1A receptors, gene repression, and depression: guilt by association.Neuroscientist. 2004 Dec;10(6):575-93. doi: 10.1177/1073858404267382.
• [11] Impaired memory and marble burying activity in deformed epidermal autoregulatory factor 1 (Deaf1) conditional knockout mice.Behav Brain Res. 2020 Feb 17;380:112383. doi: 10.1016/j.bbr.2019.112383. Epub 2019 Nov 26.
• [12] Exome analysis of Smith-Magenis-like syndrome cohort identifies de novo likely pathogenic variants. Hum Genet. 2017 Apr;136(4):409-420. doi: 10.1007/s00439-017-1767-x. Epub 2017 Feb 17.
• [13] Cell-specific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism.J Neurosci. 2006 Feb 8;26(6):1864-71. doi: 10.1523/JNEUROSCI.2643-05.2006.
• [14] The SMYD3 VNTR 3/3 polymorphism confers an increased risk and poor prognosis of hepatocellular carcinoma in a Chinese population.Pathol Res Pract. 2018 May;214(5):625-630. doi: 10.1016/j.prp.2018.04.005. Epub 2018 Apr 17.
• [15] 17-estradiol-induced regulation of the novel 5-HT1A-related transcription factors NUDR and Freud-1 in SH SY5Y cells.Cell Mol Neurobiol. 2012 May;32(4):517-21. doi: 10.1007/s10571-012-9809-3. Epub 2012 Feb 11.
• [16] Type 1 diabetes in mice and men: gene expression profiling to investigate disease pathogenesis.Immunol Res. 2014 May;58(2-3):340-50. doi: 10.1007/s12026-014-8501-8.
• [17] 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.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] 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.
• [23] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [24] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [25] Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology. 2006 Oct;31(10):2304-12. doi: 10.1038/sj.npp.1301089. Epub 2006 May 3.
• [26] 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.
• [27] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.