Details of Drug Off-Target (DOT)

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

• DOT Name: Neurofascin (NFASC)
• Gene Name: NFASC
• Related Disease:
  Hepatocellular carcinoma
  Alzheimer disease
  Demyelinating polyneuropathy
  Lung cancer
  Lung carcinoma
  Multiple sclerosis
  Neoplasm
  Nephrotic syndrome
  Neurodevelopmental disorder with central and peripheral motor dysfunction
  Non-small-cell lung cancer
  Polyradiculoneuropathy
  Schizophrenia
  Chronic inflammatory demyelinating polyneuropathy
  Cerebellar ataxia
  Diabetic neuropathy
  Hereditary ataxia
  Neurodevelopmental disorder
  Type-1/2 diabetes
• UniProt ID: NFASC_HUMAN
• PDB ID: 3P3Y; 3P40
• Pfam ID: PF13882 ; PF00041 ; PF07679 ; PF00047 ; PF13927
• Sequence:
  MARQPPPPWVHAAFLLCLLSLGGAIEIPMDPSIQNELTQPPTITKQSAKDHIVDPRDNIL
  IECEAKGNPAPSFHWTRNSRFFNIAKDPRVSMRRRSGTLVIDFRSGGRPEEYEGEYQCFA
  RNKFGTALSNRIRLQVSKSPLWPKENLDPVVVQEGAPLTLQCNPPPGLPSPVIFWMSSSM
  EPITQDKRVSQGHNGDLYFSNVMLQDMQTDYSCNARFHFTHTIQQKNPFTLKVLTTRGVA
  ERTPSFMYPQGTASSQMVLRGMDLLLECIASGVPTPDIAWYKKGGDLPSDKAKFENFNKA
  LRITNVSEEDSGEYFCLASNKMGSIRHTISVRVKAAPYWLDEPKNLILAPGEDGRLVCRA
  NGNPKPTVQWMVNGEPLQSAPPNPNREVAGDTIIFRDTQISSRAVYQCNTSNEHGYLLAN
  AFVSVLDVPPRMLSPRNQLIRVILYNRTRLDCPFFGSPIPTLRWFKNGQGSNLDGGNYHV
  YENGSLEIKMIRKEDQGIYTCVATNILGKAENQVRLEVKDPTRIYRMPEDQVARRGTTVQ
  LECRVKHDPSLKLTVSWLKDDEPLYIGNRMKKEDDSLTIFGVAERDQGSYTCVASTELDQ
  DLAKAYLTVLADQATPTNRLAALPKGRPDRPRDLELTDLAERSVRLTWIPGDANNSPITD
  YVVQFEEDQFQPGVWHDHSKYPGSVNSAVLRLSPYVNYQFRVIAINEVGSSHPSLPSERY
  RTSGAPPESNPGDVKGEGTRKNNMEITWTPMNATSAFGPNLRYIVKWRRRETREAWNNVT
  VWGSRYVVGQTPVYVPYEIRVQAENDFGKGPEPESVIGYSGEDYPRAAPTEVKVRVMNST
  AISLQWNRVYSDTVQGQLREYRAYYWRESSLLKNLWVSQKRQQASFPGDRLRGVVSRLFP
  YSNYKLEMVVVNGRGDGPRSETKEFTTPEGVPSAPRRFRVRQPNLETINLEWDHPEHPNG
  IMIGYTLKYVAFNGTKVGKQIVENFSPNQTKFTVQRTDPVSRYRFTLSARTQVGSGEAVT
  EESPAPPNEATPTAAPPTLPPTTVGATGAVSSTDATAIAATTEATTVPIIPTVAPTTIAT
  TTTVATTTTTTAAATTTTESPPTTTSGTKIHESAPDEQSIWNVTVLPNSKWANITWKHNF
  GPGTDFVVEYIDSNHTKKTVPVKAQAQPIQLTDLYPGMTYTLRVYSRDNEGISSTVITFM
  TSTAYTNNQADIATQGWFIGLMCAIALLVLILLIVCFIKRSRGGKYPVREKKDVPLGPED
  PKEEDGSFDYSDEDNKPLQGSQTSLDGTIKQQESDDSLVDYGEGGEGQFNEDGSFIGQYT
  VKKDKEETEGNESSEATSPVNAIYSLA
• Function: Cell adhesion, ankyrin-binding protein which may be involved in neurite extension, axonal guidance, synaptogenesis, myelination and neuron-glial cell interactions.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway:
  Neurofascin interactions (R-HSA-447043)
  Neutrophil degranulation (R-HSA-6798695)
  Interaction between L1 and Ankyrins (R-HSA-445095)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Demyelinating polyneuropathy	DIS7IO4W	Strong	Genetic Variation	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[6]
Neurodevelopmental disorder with central and peripheral motor dysfunction	DIS72RRQ	Strong	Autosomal recessive	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Polyradiculoneuropathy	DIS1KDVQ	Strong	Biomarker	[8]
Schizophrenia	DISSRV2N	Strong	Biomarker	[9]
Chronic inflammatory demyelinating polyneuropathy	DISNGBLD	moderate	Genetic Variation	[10]
Cerebellar ataxia	DIS9IRAV	Limited	Genetic Variation	[3]
Diabetic neuropathy	DISX6VF8	Limited	Biomarker	[11]
Hereditary ataxia	DIS6JNI3	Limited	Genetic Variation	[3]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[3]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[11]

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 Neurofascin (NFASC).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Neurofascin (NFASC).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Neurofascin (NFASC).	[25]

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 Neurofascin (NFASC).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neurofascin (NFASC).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neurofascin (NFASC).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Neurofascin (NFASC).	[16]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Neurofascin (NFASC).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Neurofascin (NFASC).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Neurofascin (NFASC).	[20]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Neurofascin (NFASC).	[21]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Neurofascin (NFASC).	[22]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Neurofascin (NFASC).	[23]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Neurofascin (NFASC).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Neurofascin (NFASC).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Neurofascin (NFASC).	[27]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Neurofascin (NFASC).	[28]

References

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• [3] Neurofascin (NFASC) gene mutation causes autosomal recessive ataxia with demyelinating neuropathy.Parkinsonism Relat Disord. 2019 Jun;63:66-72. doi: 10.1016/j.parkreldis.2019.02.045. Epub 2019 Mar 1.
• [4] Copy number variation, increased gene expression, and molecular mechanisms of neurofascin in lung cancer.Mol Carcinog. 2017 Sep;56(9):2076-2085. doi: 10.1002/mc.22664. Epub 2017 May 2.
• [5] Novel forms of neurofascin 155 in the central nervous system: alterations in paranodal disruption models and multiple sclerosis.Brain. 2010 Feb;133(Pt 2):389-405. doi: 10.1093/brain/awp341. Epub 2010 Feb 3.
• [6] Autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy.Curr Opin Neurol. 2019 Oct;32(5):651-657. doi: 10.1097/WCO.0000000000000725.
• [7] Neurofascins are required to establish axonal domains for saltatory conduction. Neuron. 2005 Dec 8;48(5):737-42. doi: 10.1016/j.neuron.2005.10.019.
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• [9] Reduced density of ADAM 12-immunoreactive oligodendrocytes in the anterior cingulate white matter of patients with schizophrenia.World J Biol Psychiatry. 2010 Apr;11(3):556-66. doi: 10.3109/15622970903497936.
• [10] Tongue tremor in neurofascin-155 IgG4 seropositive chronic inflammatory polyradiculoneuropathy.J Neuroimmunol. 2019 May 15;330:178-180. doi: 10.1016/j.jneuroim.2019.01.017. Epub 2019 Jan 29.
• [11] Nodes of Ranvier in skin biopsies of patients with diabetes mellitus.J Peripher Nerv Syst. 2017 Sep;22(3):182-190. doi: 10.1111/jns.12224. Epub 2017 Jun 23.
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• [13] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
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• [15] 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.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [18] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [19] 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.
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• [21] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [22] 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.
• [23] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [24] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [25] 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.
• [26] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
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