Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2O2IUJ)

• DOT Name: MAD2L1-binding protein (MAD2L1BP)
• Synonyms: Caught by MAD2 protein; p31(comet)
• Gene Name: MAD2L1BP
• Related Disease:
  Autosomal dominant optic atrophy, classic form
  Axonal neuropathy
  Peripheral sensory neuropathies
  Advanced cancer
  Amyloidosis
  Cerebellar disorder
  Charcot-Marie-Tooth disease axonal type 2C
  Charcot-Marie-Tooth disease axonal type 2F
  Charcot-Marie-Tooth disease axonal type 2L
  Charcot-Marie-Tooth disease type 1
  Charcot-Marie-Tooth disease type 2
  Charcot-Marie-Tooth disease type 2I
  Distal hereditary motor neuropathy
  Giant axonal neuropathy 1
  Hepatocellular carcinoma
  Hereditary motor and sensory neuropathy
  Hereditary neuropathy with liability to pressure palsies
  Hereditary spastic paraplegia
  Isolated congenital microcephaly
  Neuromuscular disease
  Peripheral neuropathy
  Polyneuropathy
  Spinal muscular atrophy
  Vascular purpura
  Charcot-Marie-Tooth disease type 3
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 2B2
  Corpus callosum, agenesis of
  Hereditary spastic paraplegia 10
  Hereditary spastic paraplegia 17
  Intellectual disability
  Neoplasm
  Nervous system disease
  Neuronopathy, distal hereditary motor, type 5
  Neuropathy, congenital hypomelinating
  Silver-Russell syndrome
• UniProt ID: MD2BP_HUMAN
• PDB ID: 2QYF; 6F0X
• Pfam ID: PF06581
• Sequence:
  MAAPEAEVLSSAAVPDLEWYEKSEETHASQIELLETSSTQEPLNASEAFCPRDCMVPVVF
  PGPVSQEGCCQFTCELLKHIMYQRQQLPLPYEQLKHFYRKPSPQAEEMLKKKPRATTEVS
  SRKCQQALAELESVLSHLEDFFARTLVPRVLILLGGNALSPKEFYELDLSLLAPYSVDQS
  LSTAACLRRLFRAIFMADAFSELQAPPLMGTVVMAQGHRNCGEDWFRPKLNYRVPSRGHK
  LTVTLSCGRPSIRTTAWEDYIWFQAPVTFKGFRE
• Function: May function to silence the spindle checkpoint and allow mitosis to proceed through anaphase by binding MAD2L1 after it has become dissociated from the MAD2L1-CDC20 complex.
• KEGG Pathway: Cell cycle (hsa04110)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant optic atrophy, classic form	DISXUAV9	Definitive	Biomarker	[1]
Axonal neuropathy	DIS5S2BC	Definitive	Genetic Variation	[1]
Peripheral sensory neuropathies	DISYWI6M	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Amyloidosis	DISHTAI2	Strong	Genetic Variation	[4]
Cerebellar disorder	DIS2O7WM	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease axonal type 2C	DIS1S5NJ	Strong	Biomarker	[6]
Charcot-Marie-Tooth disease axonal type 2F	DIS4U2DX	Strong	Genetic Variation	[7]
Charcot-Marie-Tooth disease axonal type 2L	DISO472Y	Strong	Biomarker	[8]
Charcot-Marie-Tooth disease type 1	DIS56F9A	Strong	Biomarker	[9]
Charcot-Marie-Tooth disease type 2	DISR30O9	Strong	Biomarker	[10]
Charcot-Marie-Tooth disease type 2I	DISOJA8B	Strong	Biomarker	[8]
Distal hereditary motor neuropathy	DISGS2ID	Strong	Genetic Variation	[11]
Giant axonal neuropathy 1	DIS3H1TR	Strong	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Hereditary motor and sensory neuropathy	DISR0X2K	Strong	Genetic Variation	[14]
Hereditary neuropathy with liability to pressure palsies	DISY0X1V	Strong	Biomarker	[15]
Hereditary spastic paraplegia	DISGZQV1	Strong	Biomarker	[16]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[5]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[17]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[12]
Polyneuropathy	DISB9G3W	Strong	Biomarker	[2]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[18]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[16]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	moderate	Biomarker	[19]
Charcot marie tooth disease	DIS3BT2L	Limited	Biomarker	[20]
Charcot-Marie-Tooth disease type 2B2	DISNPA2O	Limited	Genetic Variation	[21]
Corpus callosum, agenesis of	DISO9P40	Limited	Genetic Variation	[22]
Hereditary spastic paraplegia 10	DISYFO3L	Limited	Biomarker	[23]
Hereditary spastic paraplegia 17	DISI7Y7F	Limited	Biomarker	[24]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[22]
Neoplasm	DISZKGEW	Limited	Altered Expression	[25]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[26]
Neuronopathy, distal hereditary motor, type 5	DISTSHF6	Limited	Biomarker	[24]
Neuropathy, congenital hypomelinating	DISZUW4L	Limited	Genetic Variation	[27]
Silver-Russell syndrome	DISSVJ1D	Limited	Biomarker	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of MAD2L1-binding protein (MAD2L1BP).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of MAD2L1-binding protein (MAD2L1BP).	[29]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of MAD2L1-binding protein (MAD2L1BP).	[30]
Marinol	DM70IK5	Approved	Marinol decreases the expression of MAD2L1-binding protein (MAD2L1BP).	[31]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of MAD2L1-binding protein (MAD2L1BP).	[32]

References

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• [2] Clinical and allelic heterogeneity in a pediatric cohort of 11 patients carrying MFN2 mutation.Brain Dev. 2016 May;38(5):498-506. doi: 10.1016/j.braindev.2015.11.006. Epub 2015 Dec 10.
• [3] Novel insights into breast cancer genetic variance through RNA sequencing.Sci Rep. 2013;3:2256. doi: 10.1038/srep02256.
• [4] Autosomal-dominant transthyretin (TTR)-related amyloidosis is not a frequent CMT2 neuropathy "in disguise".Orphanet J Rare Dis. 2018 Oct 4;13(1):177. doi: 10.1186/s13023-018-0917-0.
• [5] The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25. Neurogenetics. 2018 Dec;19(4):215-225. doi: 10.1007/s10048-018-0555-7. Epub 2018 Jul 24.
• [6] Incidence and Clinical Features of TRPV4-Linked Axonal Neuropathies in a USA Cohort of Charcot-Marie-Tooth Disease Type 2.Neuromolecular Med. 2020 Mar;22(1):68-72. doi: 10.1007/s12017-019-08564-4. Epub 2019 Aug 29.
• [7] A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2F) maps to chromosome 7q11-q21. Eur J Hum Genet. 2001 Aug;9(8):646-50. doi: 10.1038/sj.ejhg.5200686.
• [8] A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24. Hum Genet. 2004 May;114(6):527-33. doi: 10.1007/s00439-004-1102-1. Epub 2004 Mar 12.
• [9] Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies.Hum Mutat. 1999;13(1):11-28. doi: 10.1002/(SICI)1098-1004(1999)13:1<11::AID-HUMU2>3.0.CO;2-A.
• [10] Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene.Neurology. 1998 May;50(5):1397-401. doi: 10.1212/wnl.50.5.1397.
• [11] The CMT2D locus: refined genetic position and construction of a bacterial clone-based physical map.Genome Res. 1999 Jun;9(6):568-74.
• [12] The instability of the BTB-KELCH protein Gigaxonin causes Giant Axonal Neuropathy and constitutes a new penetrant and specific diagnostic test.Acta Neuropathol Commun. 2014 Apr 24;2:47. doi: 10.1186/2051-5960-2-47.
• [13] Mutation analysis of p31comet gene, a negative regulator of Mad2, in human hepatocellular carcinoma.Exp Mol Med. 2007 Aug 31;39(4):508-13. doi: 10.1038/emm.2007.56.
• [14] Severe demyelinating hypertrophic polyneuropathy caused by a de novo frameshift mutation within the intracellular domain of myelin protein zero (MPZ/P0).J Neurol Sci. 2009 Jun 15;281(1-2):113-5. doi: 10.1016/j.jns.2009.03.008. Epub 2009 Apr 3.
• [15] Clinical and genetic spectra in a series of Chinese patients with Charcot-Marie-Tooth disease.Clin Chim Acta. 2015 Dec 7;451(Pt B):263-70. doi: 10.1016/j.cca.2015.10.007. Epub 2015 Oct 8.
• [16] A network biology approach to unraveling inherited axonopathies.Sci Rep. 2019 Feb 8;9(1):1692. doi: 10.1038/s41598-018-37119-z.
• [17] Expanding the spectrum of genes responsible for hereditary motor neuropathies.J Neurol Neurosurg Psychiatry. 2019 Oct;90(10):1171-1179. doi: 10.1136/jnnp-2019-320717. Epub 2019 Jun 5.
• [18] Molecular genetics and mechanisms of disease in distal hereditary motor neuropathies: insights directing future genetic studies.Curr Mol Med. 2011 Nov;11(8):650-65. doi: 10.2174/156652411797536714.
• [19] Cellular characterization of MPZ mutations presenting with diverse clinical phenotypes.J Neurol. 2010 Oct;257(10):1661-8. doi: 10.1007/s00415-010-5590-8. Epub 2010 May 12.
• [20] PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease.J Neurol Neurosurg Psychiatry. 2018 Aug;89(8):870-878. doi: 10.1136/jnnp-2017-317562. Epub 2018 Feb 15.
• [21] A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family.Neurogenetics. 2002 Oct;4(2):93-6. doi: 10.1007/s10048-002-0138-4.
• [22] Charcot-Marie-Tooth disease (CMT): distinctive phenotypic and genotypic features in CMT type 2.J Neurol Sci. 2001 Feb 15;184(1):1-9. doi: 10.1016/s0022-510x(00)00497-4.
• [23] Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.Neuron. 2018 Mar 21;97(6):1267-1288. doi: 10.1016/j.neuron.2018.02.027.
• [24] Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome.J Neurol Sci. 2007 Dec 15;263(1-2):100-6. doi: 10.1016/j.jns.2007.06.047. Epub 2007 Jul 30.
• [25] Coordinated regulation of p31(Comet) and Mad2 expression is required for cellular proliferation.Cell Cycle. 2013 Dec 15;12(24):3824-32. doi: 10.4161/cc.26811. Epub 2013 Oct 15.
• [26] A novel p.Val244Leu mutation in MFN2 leads to Charcot-Marie-Tooth disease type 2.Ital J Pediatr. 2016 Mar 8;42:28. doi: 10.1186/s13052-016-0237-8.
• [27] Screening of the myelin protein zero gene in patients with Charcot-Marie-Tooth disease.Acta Biochim Pol. 2004;51(1):273-80.
• [28] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [29] 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.
• [30] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [31] 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.
• [32] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.