Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHDYL3H)

• DOT Name: Neuroligin-2 (NLGN2)
• Gene Name: NLGN2
• Related Disease:
  Anxiety
  Anxiety disorder
  Autism spectrum disorder
  Depression
  Intellectual disability
  Major depressive disorder
  Mental disorder
  Neoplasm
  Obesity
  Pervasive developmental disorder
  Schizophrenia
  Sciatic neuropathy
  Uterine fibroids
  Vascular disease
  Epilepsy
  Hirschsprung disease
  Neurodevelopmental disorder
  Status epilepticus seizure
• UniProt ID: NLGN2_HUMAN
• PDB ID: 5XEQ; 8GS4
• Pfam ID: PF00135
• Sequence:
  MWLLALCLVGLAGAQRGGGGPGGGAPGGPGLGLGSLGEERFPVVNTAYGRVRGVRRELNN
  EILGPVVQFLGVPYATPPLGARRFQPPEAPASWPGVRNATTLPPACPQNLHGALPAIMLP
  VWFTDNLEAAATYVQNQSEDCLYLNLYVPTEDGPLTKKRDEATLNPPDTDIRDPGKKPVM
  LFLHGGSYMEGTGNMFDGSVLAAYGNVIVATLNYRLGVLGFLSTGDQAAKGNYGLLDQIQ
  ALRWLSENIAHFGGDPERITIFGSGAGASCVNLLILSHHSEGLFQKAIAQSGTAISSWSV
  NYQPLKYTRLLAAKVGCDREDSAEAVECLRRKPSRELVDQDVQPARYHIAFGPVVDGDVV
  PDDPEILMQQGEFLNYDMLIGVNQGEGLKFVEDSAESEDGVSASAFDFTVSNFVDNLYGY
  PEGKDVLRETIKFMYTDWADRDNGEMRRKTLLALFTDHQWVAPAVATAKLHADYQSPVYF
  YTFYHHCQAEGRPEWADAAHGDELPYVFGVPMVGATDLFPCNFSKNDVMLSAVVMTYWTN
  FAKTGDPNQPVPQDTKFIHTKPNRFEEVVWSKFNSKEKQYLHIGLKPRVRDNYRANKVAF
  WLELVPHLHNLHTELFTTTTRLPPYATRWPPRPPAGAPGTRRPPPPATLPPEPEPEPGPR
  AYDRFPGDSRDYSTELSVTVAVGASLLFLNILAFAALYYKRDRRQELRCRRLSPPGGSGS
  GVPGGGPLLPAAGRELPPEEELVSLQLKRGGGVGADPAEALRPACPPDYTLALRRAPDDV
  PLLAPGALTLLPSGLGPPPPPPPPSLHPFGPFPPPPPTATSHNNTLPHPHSTTRV
• Function: Transmembrane scaffolding protein involved in cell-cell interactions via its interactions with neurexin family members. Mediates cell-cell interactions both in neurons and in other types of cells, such as Langerhans beta cells. Plays a role in synapse function and synaptic signal transmission, especially via gamma-aminobutyric acid receptors (GABA(A) receptors). Functions by recruiting and clustering synaptic proteins. Promotes clustering of postsynaptic GABRG2 and GPHN. Promotes clustering of postsynaptic LHFPL4. Modulates signaling by inhibitory synapses, and thereby plays a role in controlling the ratio of signaling by excitatory and inhibitory synapses and information processing. Required for normal signal amplitude from inhibitory synapses, but is not essential for normal signal frequency. May promote the initial formation of synapses, but is not essential for this. In vitro, triggers the de novo formation of presynaptic structures. Mediates cell-cell interactions between Langerhans beta cells and modulates insulin secretion.
• Tissue Specificity: Expressed in the blood vessel walls. Detected in colon, brain and pancreas islets of Langerhans (at protein level). 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

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anxiety	DISIJDBA	Strong	Altered Expression	[1]
Anxiety disorder	DISBI2BT	Strong	Altered Expression	[1]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[2]
Depression	DIS3XJ69	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	Strong	Biomarker	[4]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[3]
Mental disorder	DIS3J5R8	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Obesity	DIS47Y1K	Strong	Genetic Variation	[1]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[7]
Sciatic neuropathy	DISMGDKX	Strong	Biomarker	[8]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[9]
Vascular disease	DISVS67S	Strong	Biomarker	[6]
Epilepsy	DISBB28L	moderate	Genetic Variation	[2]
Hirschsprung disease	DISUUSM1	moderate	Altered Expression	[10]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[2]
Status epilepticus seizure	DISY3BIC	Limited	Biomarker	[11]

4 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-2 (NLGN2).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Neuroligin-2 (NLGN2).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neuroligin-2 (NLGN2).	[15]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Neuroligin-2 (NLGN2).	[17]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Neuroligin-2 (NLGN2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Neuroligin-2 (NLGN2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Neuroligin-2 (NLGN2).	[13]

References

• [1] 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.
• [2] Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures.Hum Mol Genet. 2013 May 15;22(10):2055-66. doi: 10.1093/hmg/ddt056. Epub 2013 Feb 7.
• [3] Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility.Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):1111-1116. doi: 10.1073/pnas.1719014115. Epub 2018 Jan 16.
• [4] 790Kb microduplication in chromosome band 17p13.1 associated with intellectual disability, afebrile seizures, dysmorphic features, diabetes, and hypothyroidism.Eur J Med Genet. 2012 Mar;55(3):222-4. doi: 10.1016/j.ejmg.2012.01.016. Epub 2012 Feb 6.
• [5] The effect of Neuroligin-2 absence on sleep architecture and electroencephalographic activity in mice.Mol Brain. 2018 Sep 19;11(1):52. doi: 10.1186/s13041-018-0394-3.
• [6] Modulation of Angiopoietin 2 release from endothelial cells and angiogenesis by the synaptic protein Neuroligin 2.Biochem Biophys Res Commun. 2018 Jun 18;501(1):165-171. doi: 10.1016/j.bbrc.2018.04.204. Epub 2018 May 4.
• [7] Synaptic deficits in iPSC-derived cortical interneurons in schizophrenia are mediated by NLGN2 and rescued by N-acetylcysteine.Transl Psychiatry. 2019 Nov 28;9(1):321. doi: 10.1038/s41398-019-0660-x.
• [8] 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.
• [9] Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits.Nat Commun. 2018 Sep 7;9(1):3636. doi: 10.1038/s41467-018-05428-6.
• [10] Down-regulation of fibronectin and the correlated expression of neuroligin in hirschsprung disease.Neurogastroenterol Motil. 2017 Dec;29(12). doi: 10.1111/nmo.13134. Epub 2017 Jun 28.
• [11] Altered synaptic properties during integration of adult-born hippocampal neurons following a seizure insult.PLoS One. 2012;7(4):e35557. doi: 10.1371/journal.pone.0035557. Epub 2012 Apr 23.
• [12] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [13] 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.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [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] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.