Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXEL4R7)

• DOT Name: MAGE-like protein 2 (MAGEL2)
• Synonyms: Necdin-like protein 1; Protein nM15
• Gene Name: MAGEL2
• Related Disease:
  Schaaf-Yang syndrome
  Arthrogryposis
  Autism
  Autism spectrum disorder
  Bardet biedl syndrome
  Melanoma
  Mental disorder
  Neurodevelopmental disorder
  Obesity
  Pituitary gland disorder
  Prader-Willi syndrome
  C syndrome
  Intellectual disability
  Pervasive developmental disorder
• UniProt ID: MAGL2_HUMAN
• Pfam ID: PF01454
• Sequence:
  MSQLSKNLGDSSPPAEAPKPPVYSRPTVLMRAPPASSRAPPVPWDPPPIDLQASLAAWQA
  PQPAWEAPQGQLPAPVVPMTQPPALGGPIVPAPPLGGPMGKPPTPGVLMVHPPPPGAPMA
  QPPTPGVLMVHPSAPGAPMAHPPPPGTPMSHPPPPGTPMAHPPPPGTPMAHPPPPGTPMV
  HPPPPGTPMAHPPPPGTPMAHPPPPGTPMAHPPPPGTPMAHPPPPGTPMAQPPAPGVLMA
  QPLTPGVLMVQPAAPGAPMVQPPPAAMMTQPQPSGAPMAKPPGPGVLMIHPPGARAPMTQ
  PPASGAPMAQPAAPPAQPMAPPAQPMASWAPQAQPLILQIQSQVIRAPPQVPQGPQAPPA
  QLATPPGWQATSPGWQATQQGWQATPLTWQTTQVTWQAPAVTWQVPPPMRQGPPPIRPGP
  PPIRPGPPPVRQAPPLIRQAPPVIRQAPPVIRQAPPVIRQAPAVIRQAPPVIRQAPPVIR
  QAPPVIRQAPPLIRQAPPPIRPAPQVLATQPPLWQALPPPPPLRQAPQARLPAPQVQAAP
  QVPTAPPATQVPAAPPAGPQVPQPVLPAPLSAPLSAPQAVHCPSIIWQAPKGQPPVPHEI
  PTSMEFQEVQQTQALAWQAQKAPTHIWQPLPAQEAQRQAPPLVQLEQPFQGAPPSQKAVQ
  IQLPPQQAQASGPQAEVPTLPLQPSWQAPPAVLQAQPGPPVAAANFPLGSAKSLMTPSGE
  CRASSIDRRGSSKERRTSSKERRAPSKDRMIFAATFCAPKAVSAARAHLPAAWKNLPATP
  ETFAPSSSVFPATSQFQPASLNAFKGPSAASETPKSLPYALQDPFACVEALPAVPWVPQP
  NMNASKASQAVPTFLMATAAAPQATATTQEASKTSVEPPRRSGKATRKKKHLEAQEDSRG
  HTLAFHDWQGPRPWENLNLSDWEVQSPIQVSGDWEHPNTPRGLSGWEGPSTSRILSGWEG
  PSASWALSAWEGPSTSRALGLSESPGSSLPVVVSEVASVSPGSSATQDNSKVEAQPLSPL
  DERANALVQFLLVKDQAKVPVQRSEMVKVILREYKDECLDIINRANNKLECAFGYQLKEI
  DTKNHAYIIINKLGYHTGNLVASYLDRPKFGLLMVVLSLIFMKGNCVREDLIFNFLFKLG
  LDVRETNGLFGNTKKLITEVFVRQKYLEYRRIPYTEPAEYEFLWGPRAFLETSKMLVLRF
  LAKLHKKDPQSWPFHYLEALAECEWEDTDEDEPDTGDSAHGPTSRPPPR
• Function: Probably enhances ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases, possibly through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex. Acts as a regulator of retrograde transport via its interaction with VPS35. Recruited to retromer-containing endosomes and promotes the formation of 'Lys-63'-linked polyubiquitin chains at 'Lys-220' of WASHC1 together with TRIM27, leading to promote endosomal F-actin assembly. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer. Significantly promotes the cytoplasmic accumulation of CLOCK.
• Tissue Specificity: Expressed in placenta, fetal and adult brain. Not detected in heart and small intestine, very low levels in fibroblasts. Not expressed in brain of a Prader-Willi patient.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schaaf-Yang syndrome	DIS89BQI	Definitive	Autosomal dominant	[1]
Arthrogryposis	DISC81CM	Strong	Genetic Variation	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[3]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[4]
Bardet biedl syndrome	DISTBNZW	Strong	Biomarker	[5]
Melanoma	DIS1RRCY	Strong	Altered Expression	[6]
Mental disorder	DIS3J5R8	Strong	Biomarker	[7]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[8]
Obesity	DIS47Y1K	Strong	Genetic Variation	[9]
Pituitary gland disorder	DIS7XB48	Strong	Genetic Variation	[2]
Prader-Willi syndrome	DISYWMLU	Strong	Biomarker	[10]
C syndrome	DISMHGXP	moderate	Genetic Variation	[11]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[3]
Pervasive developmental disorder	DIS51975	Limited	Biomarker	[4]

4 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 MAGE-like protein 2 (MAGEL2).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of MAGE-like protein 2 (MAGEL2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of MAGE-like protein 2 (MAGEL2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of MAGE-like protein 2 (MAGEL2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of MAGE-like protein 2 (MAGEL2).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of MAGE-like protein 2 (MAGEL2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of MAGE-like protein 2 (MAGEL2).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of MAGE-like protein 2 (MAGEL2).	[19]

References

• [1] 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.
• [2] Mutations in MAGEL2 and L1CAM Are Associated With Congenital Hypopituitarism and Arthrogryposis.J Clin Endocrinol Metab. 2019 Dec 1;104(12):5737-5750. doi: 10.1210/jc.2019-00631.
• [3] Three patients with Schaaf-Yang syndrome exhibiting arthrogryposis and endocrinological abnormalities.Am J Med Genet A. 2018 Mar;176(3):707-711. doi: 10.1002/ajmg.a.38606. Epub 2018 Jan 23.
• [4] Hormonal, metabolic and skeletal phenotype of Schaaf-Yang syndrome: a comparison to Prader-Willi syndrome.J Med Genet. 2018 May;55(5):307-315. doi: 10.1136/jmedgenet-2017-105024. Epub 2018 Mar 1.
• [5] Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth.Hum Mol Genet. 2005 Mar 1;14(5):627-37. doi: 10.1093/hmg/ddi059. Epub 2005 Jan 13.
• [6] Neural stem cell-like gene expression in a mouse ependymoma cell line transformed by human BK polyomavirus.Cancer Sci. 2011 Jan;102(1):122-9. doi: 10.1111/j.1349-7006.2010.01775.x. Epub 2010 Nov 12.
• [7] Lack of association between MAGEL2 and schizophrenia and mood disorders in the Japanese population.Neuromolecular Med. 2010 Sep;12(3):285-91. doi: 10.1007/s12017-010-8116-8. Epub 2010 May 14.
• [8] mTOR and autophagy pathways are dysregulated in murine and human models of Schaaf-Yang syndrome.Sci Rep. 2019 Nov 4;9(1):15935. doi: 10.1038/s41598-019-52287-2.
• [9] Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy.Orphanet J Rare Dis. 2019 Dec 2;14(1):277. doi: 10.1186/s13023-019-1249-4.
• [10] Magel2 Modulates Bone Remodeling and Mass in Prader-Willi Syndrome by Affecting Oleoyl Serine Levels and Activity.J Bone Miner Res. 2019 Jan;34(1):93-105. doi: 10.1002/jbmr.3591. Epub 2018 Oct 22.
• [11] A De Novo Nonsense Mutation in MAGEL2 in a Patient Initially Diagnosed as Opitz-C: Similarities Between Schaaf-Yang and Opitz-C Syndromes.Sci Rep. 2017 Mar 10;7:44138. doi: 10.1038/srep44138.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.