Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTILSPJ6)

• DOT Name: Multiple epidermal growth factor-like domains protein 10 (MEGF10)
• Synonyms: Multiple EGF-like domains protein 10
• Gene Name: MEGF10
• Related Disease:
  Alzheimer disease
  Congenital alveolar dysplasia
  MEGF10-related myopathy
  Autism
  Congenital multicore myopathy with external ophthalmoplegia
  Congenital myopathy
  Glioma
  Multiminicore myopathy
  Neuroblastoma
  Schizophrenia
  Myopathy
  Neoplasm
  Respiratory failure
• UniProt ID: MEG10_HUMAN
• Pfam ID: PF07974 ; PF12661 ; PF00053
• Sequence:
  MVISLNSCLSFICLLLCHWIGTASPLNLEDPNVCSHWESYSVTVQESYPHPFDQIYYTSC
  TDILNWFKCTRHRVSYRTAYRHGEKTMYRRKSQCCPGFYESGEMCVPHCADKCVHGRCIA
  PNTCQCEPGWGGTNCSSACDGDHWGPHCTSRCQCKNGALCNPITGACHCAAGFRGWRCED
  RCEQGTYGNDCHQRCQCQNGATCDHVTGECRCPPGYTGAFCEDLCPPGKHGPQCEQRCPC
  QNGGVCHHVTGECSCPSGWMGTVCGQPCPEGRFGKNCSQECQCHNGGTCDAATGQCHCSP
  GYTGERCQDECPVGTYGVLCAETCQCVNGGKCYHVSGACLCEAGFAGERCEARLCPEGLY
  GIKCDKRCPCHLENTHSCHPMSGECACKPGWSGLYCNETCSPGFYGEACQQICSCQNGAD
  CDSVTGKCTCAPGFKGIDCSTPCPLGTYGINCSSRCGCKNDAVCSPVDGSCTCKAGWHGV
  DCSIRCPSGTWGFGCNLTCQCLNGGACNTLDGTCTCAPGWRGEKCELPCQDGTYGLNCAE
  RCDCSHADGCHPTTGHCRCLPGWSGVHCDSVCAEGRWGPNCSLPCYCKNGASCSPDDGIC
  ECAPGFRGTTCQRICSPGFYGHRCSQTCPQCVHSSGPCHHITGLCDCLPGFTGALCNEVC
  PSGRFGKNCAGICTCTNNGTCNPIDRSCQCYPGWIGSDCSQPCPPAHWGPNCIHTCNCHN
  GAFCSAYDGECKCTPGWTGLYCTQRCPLGFYGKDCALICQCQNGADCDHISGQCTCRTGF
  MGRHCEQKCPSGTYGYGCRQICDCLNNSTCDHITGTCYCSPGWKGARCDQAGVIIVGNLN
  SLSRTSTALPADSYQIGAIAGIIILVLVVLFLLALFIIYRHKQKGKESSMPAVTYTPAMR
  VVNADYTISGTLPHSNGGNANSHYFTNPSYHTLTQCATSPHVNNRDRMTVTKSKNNQLFV
  NLKNVNPGKRGPVGDCTGTLPADWKHGGYLNELGAFGLDRSYMGKSLKDLGKNSEYNSSN
  CSLSSSENPYATIKDPPVLIPKSSECGYVEMKSPARRDSPYAEINNSTSANRNVYEVEPT
  VSVVQGVFSNNGRLSQDPYDLPKNSHIPCHYDLLPVRDSSSSPKQEDSGGSSSNSSSSSE
• Function: Membrane receptor involved in phagocytosis by macrophages and astrocytes of apoptotic cells. Receptor for C1q, an eat-me signal, that binds phosphatidylserine expressed on the surface of apoptotic cells. Cooperates with ABCA1 within the process of engulfment. Promotes the formation of large intracellular vacuoles and may be responsible for the uptake of amyloid-beta peptides. Necessary for astrocyte-dependent apoptotic neuron clearance in the developing cerebellum. Plays role in muscle cell proliferation, adhesion and motility. Is also an essential factor in the regulation of myogenesis. Controls the balance between skeletal muscle satellite cells proliferation and differentiation through regulation of the notch signaling pathway. May also function in the mosaic spacing of specific neuron subtypes in the retina through homotypic retinal neuron repulsion. Mosaics provide a mechanism to distribute each cell type evenly across the retina, ensuring that all parts of the visual field have access to a full set of processing elements.
• Tissue Specificity: Expressed in muscle (at protein level).
• KEGG Pathway: Efferocytosis (hsa04148)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Definitive	Biomarker	[1]
Congenital alveolar dysplasia	DIS1IYUN	Definitive	Biomarker	[2]
MEGF10-related myopathy	DIS1N56C	Definitive	Autosomal recessive	[3]
Autism	DISV4V1Z	Strong	Genetic Variation	[4]
Congenital multicore myopathy with external ophthalmoplegia	DIS39ELI	Strong	Genetic Variation	[5]
Congenital myopathy	DISLSK9G	Strong	Genetic Variation	[6]
Glioma	DIS5RPEH	Strong	Biomarker	[7]
Multiminicore myopathy	DISE6VYN	Strong	Genetic Variation	[5]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[8]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[9]
Myopathy	DISOWG27	moderate	Biomarker	[10]
Neoplasm	DISZKGEW	Limited	Altered Expression	[8]
Respiratory failure	DISVMYJO	Limited	Biomarker	[11]

8 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 Multiple epidermal growth factor-like domains protein 10 (MEGF10).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Multiple epidermal growth factor-like domains protein 10 (MEGF10).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Multiple epidermal growth factor-like domains protein 10 (MEGF10).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Multiple epidermal growth factor-like domains protein 10 (MEGF10).	[15]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Multiple epidermal growth factor-like domains protein 10 (MEGF10).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Multiple epidermal growth factor-like domains protein 10 (MEGF10).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Multiple epidermal growth factor-like domains protein 10 (MEGF10).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Multiple epidermal growth factor-like domains protein 10 (MEGF10).	[20]

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 Multiple epidermal growth factor-like domains protein 10 (MEGF10).	[18]

References

• [1] Glial Draper Rescues A Toxicity in a Drosophila Model of Alzheimer's Disease.J Neurosci. 2017 Dec 6;37(49):11881-11893. doi: 10.1523/JNEUROSCI.0862-17.2017. Epub 2017 Nov 6.
• [2] Mutations in MEGF10, a regulator of satellite cell myogenesis, cause early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD). Nat Genet. 2011 Nov 20;43(12):1189-92. doi: 10.1038/ng.995.
• [3] 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.
• [4] Genetic variants in the transcription regulatory region of MEGF10 are associated with autism in Chinese Han population.Sci Rep. 2017 May 23;7(1):2292. doi: 10.1038/s41598-017-02348-1.
• [5] Adult-onset respiratory insufficiency, scoliosis, and distal joint hyperlaxity in patients with multiminicore disease due to novel Megf10 mutations.Muscle Nerve. 2016 Jun;53(6):984-8. doi: 10.1002/mus.25054. Epub 2016 Apr 25.
• [6] Mutations in the satellite cell gene MEGF10 cause a recessive congenital myopathy with minicores. Neurogenetics. 2012 May;13(2):115-24. doi: 10.1007/s10048-012-0315-z. Epub 2012 Feb 28.
• [7] MEGF10, a Glioma Survival-Associated Molecular Signature, Predicts IDH Mutation Status.Dis Markers. 2018 May 20;2018:5975216. doi: 10.1155/2018/5975216. eCollection 2018.
• [8] Genome-wide DNA methylation analysis identifies MEGF10 as a novel epigenetically repressed candidate tumor suppressor gene in neuroblastoma.Mol Carcinog. 2017 Apr;56(4):1290-1301. doi: 10.1002/mc.22591. Epub 2016 Nov 29.
• [9] Five novel loci associated with antipsychotic treatment response in patients with schizophrenia: a genome-wide association study.Lancet Psychiatry. 2018 Apr;5(4):327-338. doi: 10.1016/S2215-0366(18)30049-X. Epub 2018 Mar 1.
• [10] The impact of Megf10/Drpr gain-of-function on muscle development inDrosophila.FEBS Lett. 2019 Apr;593(7):680-696. doi: 10.1002/1873-3468.13348. Epub 2019 Mar 12.
• [11] MEGF10 related myopathies: A new case with adult onset disease with prominent respiratory failure and review of reported phenotypes.Neuromuscul Disord. 2018 Jan;28(1):48-53. doi: 10.1016/j.nmd.2017.09.017. Epub 2017 Oct 12.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [14] 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.
• [15] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [16] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [17] 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.
• [18] 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.
• [19] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.