Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB04QSU)

• DOT Name: Neurexin-2-beta (NRXN2)
• Synonyms: Neurexin II-beta
• Gene Name: NRXN2
• Related Disease:
  Autism
  Pervasive developmental disorder
  Schizophrenia
  Autism spectrum disorder
  Intellectual disability
  Neurodevelopmental disorder
  Spinal muscular atrophy
  Gout
• UniProt ID: NRX2B_HUMAN
• PDB ID: 4NXR
• Pfam ID: PF02210
• Sequence:
  MPPGGSGPGGCPRRPPALAGPLPPPPPPPPPPLLPLLPLLLLLLLGAAEGARVSSSLSTT
  HHVHHFHSKHGTVPIAINRMPFLTRGGHAGTTYIFGKGGALITYTWPPNDRPSTRMDRLA
  VGFSTHQRSAVLVRVDSASGLGDYLQLHIDQGTVGVIFNVGTDDITIDEPNAIVSDGKYH
  VVRFTRSGGNATLQVDSWPVNERYPAGNFDNERLAIARQRIPYRLGRVVDEWLLDKGRQL
  TIFNSQAAIKIGGRDQGRPFQGQVSGLYYNGLKVLALAAESDPNVRTEGHLRLVGEGPSV
  LLSAETTATTLLADMATTIMETTTTMATTTTRRGRSPTLRDSTTQNTDDLLVASAECPSD
  DEDLEECEPSTGGELILPIITEDSLDPPPVATRSPFVPPPPTFYPFLTGVGATQDTLPPP
  AARRPPSGGPCQAERDDSDCEEPIEASGFASGEVFDSSLPPTDDEDFYTTFPLVTDRTTL
  LSPRKPAPRPNLRTDGATGAPGVLFAPSAPAPNLPAGKMNHRDPLQPLLENPPLGPGAPT
  SFEPRRPPPLRPGVTSAPGFPHLPTANPTGPGERGPPGAVEVIRESSSTTGMVVGIVAAA
  ALCILILLYAMYKYRNRDEGSYQVDQSRNYISNSAQSNGAVVKEKAPAAPKTPSKAKKNK
  DKEYYV
• Function: Neuronal cell surface protein that may be involved in cell recognition and cell adhesion.
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Autosomal dominant	[1]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Autism spectrum disorder	DISXK8NV	moderate	Biomarker	[4]
Intellectual disability	DISMBNXP	moderate	Biomarker	[4]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[5]
Spinal muscular atrophy	DISTLKOB	moderate	Altered Expression	[6]
Gout	DISHC0U7	Limited	Genetic Variation	[7]

4 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 Neurexin-2-beta (NRXN2).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Neurexin-2-beta (NRXN2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neurexin-2-beta (NRXN2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Neurexin-2-beta (NRXN2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neurexin-2-beta (NRXN2).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Neurexin-2-beta (NRXN2).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Neurexin-2-beta (NRXN2).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Neurexin-2-beta (NRXN2).	[13]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Neurexin-2-beta (NRXN2).	[14]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Neurexin-2-beta (NRXN2).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Neurexin-2-beta (NRXN2).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Neurexin-2-beta (NRXN2).	[19]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Deletion of 11q12.3-11q13.1 in a patient with intellectual disability and childhood facial features resembling Cornelia de Lange syndrome.Gene. 2015 Nov 1;572(1):130-134. doi: 10.1016/j.gene.2015.07.016. Epub 2015 Jul 8.
• [3] Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Hum Genet. 2011 Oct;130(4):563-73. doi: 10.1007/s00439-011-0975-z. Epub 2011 Mar 22.
• [4] A de novo 921Kb microdeletion at 11q13.1 including neurexin 2 in a boy with developmental delay, deficits in speech and language without autistic behaviors.Eur J Med Genet. 2018 Oct;61(10):607-611. doi: 10.1016/j.ejmg.2018.04.002. Epub 2018 Apr 11.
• [5] 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.
• [6] Key role of SMN/SYNCRIP and RNA-Motif 7 in spinal muscular atrophy: RNA-Seq and motif analysis of human motor neurons.Brain. 2019 Feb 1;142(2):276-294. doi: 10.1093/brain/awy330.
• [7] GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.Ann Rheum Dis. 2017 May;76(5):869-877. doi: 10.1136/annrheumdis-2016-209632. Epub 2016 Nov 29.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [9] 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.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] 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.
• [12] 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.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [15] 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.
• [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] 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.
• [18] 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.
• [19] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.