Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKDEC1Q)

• DOT Name: Neuroligin-3 (NLGN3)
• Synonyms: Gliotactin homolog
• Gene Name: NLGN3
• Related Disease:
  Autism
  Kidney failure
  Non-insulin dependent diabetes
  Autism, susceptibility to, X-linked 1
  Brain cancer
  Brain disease
  Brain neoplasm
  Congenital hypothyroidism
  Depression
  Glioblastoma multiforme
  Intellectual disability
  Malignant glioma
  Neoplasm
  Schizophrenia
  Sciatic neuropathy
  Sleep disorder
  Hirschsprung disease
  X-linked complex neurodevelopmental disorder
  Adult glioblastoma
  Anxiety
  Anxiety disorder
  Neuroblastoma
  Neurodevelopmental disorder
• UniProt ID: NLGN3_HUMAN
• PDB ID: 8GS3
• Pfam ID: PF00135
• Sequence:
  MWLRLGPPSLSLSPKPTVGRSLCLTLWFLSLALRASTQAPAPTVNTHFGKLRGARVPLPS
  EILGPVDQYLGVPYAAPPIGEKRFLPPEPPPSWSGIRNATHFPPVCPQNIHTAVPEVMLP
  VWFTANLDIVATYIQEPNEDCLYLNVYVPTEDVKRISKECARKPNKKICRKGGSGAKKQG
  EDLADNDGDEDEDIRDSGAKPVMVYIHGGSYMEGTGNMIDGSILASYGNVIVITLNYRVG
  VLGFLSTGDQAAKGNYGLLDQIQALRWVSENIAFFGGDPRRITVFGSGIGASCVSLLTLS
  HHSEGLFQRAIIQSGSALSSWAVNYQPVKYTSLLADKVGCNVLDTVDMVDCLRQKSAKEL
  VEQDIQPARYHVAFGPVIDGDVIPDDPEILMEQGEFLNYDIMLGVNQGEGLKFVEGVVDP
  EDGVSGTDFDYSVSNFVDNLYGYPEGKDTLRETIKFMYTDWADRDNPETRRKTLVALFTD
  HQWVEPSVVTADLHARYGSPTYFYAFYHHCQSLMKPAWSDAAHGDEVPYVFGVPMVGPTD
  LFPCNFSKNDVMLSAVVMTYWTNFAKTGDPNKPVPQDTKFIHTKANRFEEVAWSKYNPRD
  QLYLHIGLKPRVRDHYRATKVAFWKHLVPHLYNLHDMFHYTSTTTKVPPPDTTHSSHITR
  RPNGKTWSTKRPAISPAYSNENAQGSWNGDQDAGPLLVENPRDYSTELSVTIAVGASLLF
  LNVLAFAALYYRKDKRRQEPLRQPSPQRGAGAPELGAAPEEELAALQLGPTHHECEAGPP
  HDTLRLTALPDYTLTLRRSPDDIPLMTPNTITMIPNSLVGLQTLHPYNTFAAGFNSTGLP
  HSHSTTRV
• Function: Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members. Plays a role in synapse function and synaptic signal transmission, and may mediate its effects by clustering other synaptic proteins. May promote the initial formation of synapses, but is not essential for this. May also play a role in glia-glia or glia-neuron interactions in the developing peripheral nervous system.
• Tissue Specificity: Expressed in the blood vessel walls (at protein level). Detected in throughout the brain and in spinal cord. Detected in brain, and at lower levels in pancreas islet beta cells.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Genetic Variation	[1]
Kidney failure	DISOVQ9P	Definitive	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[2]
Autism, susceptibility to, X-linked 1	DISTBQKW	Strong	X-linked recessive	[3]
Brain cancer	DISBKFB7	Strong	Altered Expression	[4]
Brain disease	DIS6ZC3X	Strong	Genetic Variation	[5]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[4]
Congenital hypothyroidism	DISL5XVU	Strong	Genetic Variation	[6]
Depression	DIS3XJ69	Strong	Biomarker	[7]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[8]
Intellectual disability	DISMBNXP	Strong	Biomarker	[9]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[10]
Sciatic neuropathy	DISMGDKX	Strong	Biomarker	[11]
Sleep disorder	DIS3JP1U	Strong	Genetic Variation	[12]
Hirschsprung disease	DISUUSM1	moderate	Genetic Variation	[13]
X-linked complex neurodevelopmental disorder	DISI3QE9	Moderate	X-linked	[14]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[8]
Anxiety	DISIJDBA	Limited	Biomarker	[15]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[15]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[16]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[9]

10 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 Neuroligin-3 (NLGN3).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neuroligin-3 (NLGN3).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Neuroligin-3 (NLGN3).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Neuroligin-3 (NLGN3).	[20]
Marinol	DM70IK5	Approved	Marinol increases the expression of Neuroligin-3 (NLGN3).	[21]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Neuroligin-3 (NLGN3).	[22]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Neuroligin-3 (NLGN3).	[23]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Neuroligin-3 (NLGN3).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Neuroligin-3 (NLGN3).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Neuroligin-3 (NLGN3).	[24]

2 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 decreases the methylation of Neuroligin-3 (NLGN3).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Neuroligin-3 (NLGN3).	[27]

References

• [1] Colonic dilation and altered ex vivo gastrointestinal motility in the neuroligin-3 knockout mouse.Autism Res. 2020 May;13(5):691-701. doi: 10.1002/aur.2109. Epub 2019 Apr 19.
• [2] Cognitive, emotional and social phenotyping of mice in an observer-independent setting.Neurobiol Learn Mem. 2018 Apr;150:136-150. doi: 10.1016/j.nlm.2018.02.023. Epub 2018 Feb 21.
• [3] Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet. 2003 May;34(1):27-9. doi: 10.1038/ng1136.
• [4] Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma.Nature. 2017 Sep 28;549(7673):533-537. doi: 10.1038/nature24014. Epub 2017 Sep 20.
• [5] Trafficking of cholinesterases and neuroligins mutant proteins. An association with autism.Chem Biol Interact. 2008 Sep 25;175(1-3):349-51. doi: 10.1016/j.cbi.2008.04.023. Epub 2008 Apr 29.
• [6] Neuroligin trafficking deficiencies arising from mutations in the alpha/beta-hydrolase fold protein family.J Biol Chem. 2010 Sep 10;285(37):28674-82. doi: 10.1074/jbc.M110.139519. Epub 2010 Jul 8.
• [7] Suppression of NLRP3 inflammasome attenuates stress-induced depression-like behavior in NLGN3-deficient mice.Biochem Biophys Res Commun. 2018 Jul 2;501(4):933-940. doi: 10.1016/j.bbrc.2018.05.085. Epub 2018 May 21.
• [8] Glioblastoma recurrence correlates with NLGN3 levels.Cancer Med. 2018 Jul;7(7):2848-2859. doi: 10.1002/cam4.1538. Epub 2018 May 18.
• [9] Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment.Hum Mutat. 2019 Nov;40(11):2021-2032. doi: 10.1002/humu.23836. Epub 2019 Jul 29.
• [10] Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity.Am J Med Genet A. 2017 Jan;173(1):213-216. doi: 10.1002/ajmg.a.37977. Epub 2016 Nov 16.
• [11] Down-regulation of mRNAs for synaptic adhesion molecules neuroligin-2 and -3 and synCAM1 in spinal motoneurons after axotomy.J Comp Neurol. 2007 Jul 10;503(2):308-18. doi: 10.1002/cne.21382.
• [12] Sleep/Wake Physiology and Quantitative Electroencephalogram Analysis of the Neuroligin-3 Knockout Rat Model of Autism Spectrum Disorder.Sleep. 2017 Oct 1;40(10). doi: 10.1093/sleep/zsx138.
• [13] Significance of neurexin and neuroligin polymorphisms in regulating risk of Hirschsprung's disease.J Investig Med. 2018 Jun;66(5):1-8. doi: 10.1136/jim-2017-000623. Epub 2018 Apr 4.
• [14] 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.
• [15] High resolution magnetic resonance imaging for characterization of the neuroligin-3 knock-in mouse model associated with autism spectrum disorder.PLoS One. 2014 Oct 9;9(10):e109872. doi: 10.1371/journal.pone.0109872. eCollection 2014.
• [16] NLGN3 promotes neuroblastoma cell proliferation and growth through activating PI3K/AKT pathway.Eur J Pharmacol. 2019 Aug 15;857:172423. doi: 10.1016/j.ejphar.2019.172423. Epub 2019 May 28.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] 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.
• [19] Redox/methylation mediated abnormal DNA methylation as regulators of ambient fine particulate matter-induced neurodevelopment related impairment in human neuronal cells. Sci Rep. 2016 Sep 14;6:33402. doi: 10.1038/srep33402.
• [20] 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.
• [21] 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.
• [22] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [23] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [24] 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.
• [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] 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.
• [27] 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.