Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFHT4MO)

• DOT Name: Methyl-CpG-binding domain protein 5 (MBD5)
• Synonyms: Methyl-CpG-binding protein MBD5
• Gene Name: MBD5
• Related Disease:
  Autism
  Complex neurodevelopmental disorder
  Anxiety
  Anxiety disorder
  Autism spectrum disorder
  Bipolar disorder
  Cervical cancer
  Cervical carcinoma
  Childhood acute lymphoblastic leukemia
  Dementia
  Hepatocellular carcinoma
  Intellectual disability, autosomal dominant 1
  Neurodevelopmental disorder
  Non-small-cell lung cancer
  Obesity
  Pervasive developmental disorder
  Schizophrenia
  Sleep disorder
  Velocardiofacial syndrome
  West syndrome
  Familial atrial fibrillation
  Fragile X syndrome
  Intellectual disability
  Isolated congenital microcephaly
  Ptosis
  Smith-Magenis syndrome
  Autosomal dominant non-syndromic intellectual disability
  Epilepsy
  Atrial fibrillation
  Graft-versus-host disease
  Parkinson disease
  Rett syndrome
• UniProt ID: MBD5_HUMAN
• Sequence:
  MNGGKECDGGDKEGGLPAIQVPVGWQRRVDQNGVLYVSPSGSLLSCLEQVKTYLLTDGTC
  KCGLECPLILPKVFNFDPGAAVKQRTAEDVKADEDVTKLCIHKRKIIAVATLHKSMEAPH
  PSLVLTSPGGGTNATPVVPSRAATPRSVRNKSHEGITNSVMPECKNPFKLMIGSSNAMGR
  LYVQELPGSQQQELHPVYPRQRLGSSEHGQKSPFRGSHGGLPSPASSGSQIYGDGSISPR
  TDPLGSPDVFTRSNPGFHGAPNSSPIHLNRTPLSPPSVMLHGSPVQSSCAMAGRTNIPLS
  PTLTTKSPVMKKPMCNFSTNMEIPRAMFHHKPPQGPPPPPPPSCALQKKPLTSEKDPLGI
  LDPIPSKPVNQNPVIINPTSFHSNVHSQVPMMNVSMPPAVVPLPSNLPLPTVKPGHMNHG
  SHVQRVQHSASTSLSPSPVTSPVHMMGTGIGRIEASPQRSRSSSTSSDHGNFMMPPVGPQ
  ATSSGIKVPPRSPRSTIGSPRPSMPSSPSTKSDGHHQYKDIPNPLIAGISNVLNTPSSAA
  FPTASAGSSSVKSQPGLLGMPLNQILNQHNAASFPASSLLSAAAKAQLANQNKLAGNNSS
  SSSNSGAVAGSGNTEGHSTLNTMFPPTANMLLPTGEGQSGRAALRDKLMSQQKDALRKRK
  QPPTTVLSLLRQSQMDSSAVPKPGPDLLRKQGQGSFPISSMSQLLQSMSCQSSHLSSNST
  PGCGASNTALPCSANQLHFTDPSMNSSVLQNIPLRGEAVHCHNANTNFVHSNSPVPNHHL
  AGLINQIQASGNCGMLSQSGMALGNSLHPNPPQSRISTSSTPVIPNSIVSSYNQTSSEAG
  GSGPSSSIAIAGTNHPAITKTTSVLQDGVIVTTAAGNPLQSQLPIGSDFPFVGQEHALHF
  PSNSTSNNHLPHPLNPSLLSSLPISLPVNQQHLLNQNLLNILQPSAGEGDMSSINNTLSN
  HQLTHLQSLLNNNQMFPPNQQQQQLLQGYQNLQAFQGQSTIPCPANNNPMACLFQNFQVR
  MQEDAALLNKRISTQPGLTALPENPNTTLPPFQDTPCELQPRIDPSLGQQVKDGLVVGGP
  GDASVDAIYKAVVDAASKGMQVVITTAVNSTTQISPIPALSAMSAFTASIGDPLNLSSAV
  SAVIHGRNMGGVDHDGRLRNSRGARLPKNLDHGKNVNEGDGFEYFKSASCHTSKKQWDGE
  QSPRGERNRWKYEEFLDHPGHIHSSPCHERPNNVSTLPFLPGEQHPILLPPRNCPGDKIL
  EENFRYNNYKRTMMSFKERLENTVERCAHINGNRPRQSRGFGELLSTAKQDLVLEEQSPS
  SSNSLENSLVKDYIHYNGDFNAKSVNGCVPSPSDAKSISSEDDLRNPDSPSSNELIHYRP
  RTFNVGDLVWGQIKGLTSWPGKLVREDDVHNSCQQSPEEGKVEPEKLKTLTEGLEAYSRV
  RKRNRKSGKLNNHLEAAIHEAMSELDKMSGTVHQIPQGDRQMRPPKPKRRKISR
• Function: Binds to heterochromatin. Does not interact with either methylated or unmethylated DNA (in vitro).
• Tissue Specificity: Detected in heart, placenta, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway: UCH proteinases (R-HSA-5689603)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Genetic Variation	[1]
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[2]
Anxiety	DISIJDBA	Strong	Genetic Variation	[3]
Anxiety disorder	DISBI2BT	Strong	Genetic Variation	[3]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[5]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[5]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[6]
Dementia	DISXL1WY	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Intellectual disability, autosomal dominant 1	DISPIV05	Strong	Autosomal dominant	[8]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Obesity	DIS47Y1K	Strong	Genetic Variation	[11]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[12]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[13]
Sleep disorder	DIS3JP1U	Strong	Biomarker	[14]
Velocardiofacial syndrome	DISOSBTY	Strong	Genetic Variation	[15]
West syndrome	DISLIAU9	Strong	Genetic Variation	[16]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[17]
Fragile X syndrome	DISE8W3A	moderate	Biomarker	[14]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[1]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[18]
Ptosis	DISJZNIY	moderate	Biomarker	[19]
Smith-Magenis syndrome	DISG4G6X	moderate	Genetic Variation	[14]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[8]
Epilepsy	DISBB28L	Disputed	Genetic Variation	[1]
Atrial fibrillation	DIS15W6U	Limited	Biomarker	[17]
Graft-versus-host disease	DIS0QADF	Limited	Biomarker	[20]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[21]
Rett syndrome	DISGG5UV	Limited	Genetic Variation	[22]

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 Methyl-CpG-binding domain protein 5 (MBD5).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Methyl-CpG-binding domain protein 5 (MBD5).	[36]

14 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 Methyl-CpG-binding domain protein 5 (MBD5).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[26]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[27]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[28]
Marinol	DM70IK5	Approved	Marinol increases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[29]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[30]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[31]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[32]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Methyl-CpG-binding domain protein 5 (MBD5).	[32]

References

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• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.Mol Psychiatry. 2014 Mar;19(3):368-79. doi: 10.1038/mp.2013.42. Epub 2013 Apr 16.
• [4] Diagnostic exome sequencing identifies a heterozygous MBD5 frameshift mutation in a family with intellectual disability and epilepsy.Eur J Med Genet. 2017 Oct;60(10):559-564. doi: 10.1016/j.ejmg.2017.08.003. Epub 2017 Aug 12.
• [5] Expression levels of resistant genes affect cervical cancer prognosis.Mol Med Rep. 2017 May;15(5):2802-2806. doi: 10.3892/mmr.2017.6328. Epub 2017 Mar 15.
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• [7] Human hepatocellular carcinoma cell lines exhibit multidrug resistance unrelated to MRD1 gene expression.J Cell Sci. 1991 Mar;98 ( Pt 3):317-22. doi: 10.1242/jcs.98.3.317.
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• [9] Burden of de novo mutations and inherited rare single nucleotide variants in children with sensory processing dysfunction.BMC Med Genomics. 2018 May 25;11(1):50. doi: 10.1186/s12920-018-0362-x.
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• [11] A cryptic microdeletion including MBD5 occurring within the breakpoint of a reciprocal translocation between chromosomes 2 and 5 in a patient with developmental delay and obesity.Am J Med Genet A. 2013 Apr;161A(4):850-5. doi: 10.1002/ajmg.a.35768. Epub 2013 Mar 12.
• [12] Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder.Eur J Hum Genet. 2014 Jan;22(1):57-63. doi: 10.1038/ejhg.2013.67. Epub 2013 May 1.
• [13] High-resolution copy number variation analysis of schizophrenia in Japan.Mol Psychiatry. 2017 Mar;22(3):430-440. doi: 10.1038/mp.2016.88. Epub 2016 May 31.
• [14] MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.Eur J Hum Genet. 2015 Jun;23(6):781-9. doi: 10.1038/ejhg.2014.200. Epub 2014 Oct 1.
• [15] Schizophrenia two-hit hypothesis in velo-cardio facial syndrome.Am J Med Genet B Neuropsychiatr Genet. 2013 Mar;162B(2):177-82. doi: 10.1002/ajmg.b.32129. Epub 2013 Jan 17.
• [16] A genomic copy number variant analysis implicates the MBD5 and HNRNPU genes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion.BMC Med Genet. 2014 May 29;15:62. doi: 10.1186/1471-2350-15-62.
• [17] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [18] Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures.Eur J Hum Genet. 2010 Apr;18(4):436-41. doi: 10.1038/ejhg.2009.199. Epub 2009 Nov 11.
• [19] Surgical Predictors of Reduced Marginal Reflex Distance After Upper Blepharoplasty.Ophthalmic Plast Reconstr Surg. 2019 Nov/Dec;35(6):566-568. doi: 10.1097/IOP.0000000000001376.
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• [21] Association between MDR1 gene polymorphisms and Parkinson's disease in Asian and Caucasian populations: a meta-analysis.J Neurol Sci. 2016 Sep 15;368:255-62. doi: 10.1016/j.jns.2016.07.041. Epub 2016 Jul 18.
• [22] The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype.Eur J Hum Genet. 2010 Feb;18(2):163-70. doi: 10.1038/ejhg.2009.152. Epub 2009 Oct 7.
• [23] 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.
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• [25] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [26] 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.
• [27] 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.
• [28] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [29] 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.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [31] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [32] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [33] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [34] 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.
• [35] 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.
• [36] 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.
• [37] 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.