Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJN1JQA)

• DOT Name: Neurexin-1-beta (NRXN1)
• Synonyms: Neurexin I-beta
• Gene Name: NRXN1
• Related Disease:
  Bipolar disorder
  Complex neurodevelopmental disorder
  Epilepsy
  Pitt-Hopkins syndrome
  Acute lymphocytic leukaemia
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Attention deficit hyperactivity disorder
  Autism spectrum disorder
  Brain disease
  Chromosomal disorder
  Chromosome 2p16.3 deletion syndrome
  Depression
  Epilepsy, idiopathic generalized
  Intellectual disability
  Mental disorder
  Multiple sclerosis
  Narcolepsy
  Nicotine dependence
  Non-insulin dependent diabetes
  Pervasive developmental disorder
  Pitt-Hopkins-like syndrome 2
  Specific language impairment
  Tardive dyskinesia
  Tourette syndrome
  Type-1 diabetes
  Alcohol dependence
  Alcohol-induced disorders
  Alcohol-related disorders
  Asperger syndrome
  Autism
  CHARGE syndrome
  Cognitive impairment
  Fragile X syndrome
  Isolated congenital microcephaly
  Psychotic disorder
  Schizophrenia
• UniProt ID: NRX1B_HUMAN
• PDB ID: 3B3Q; 5Z8Y
• Pfam ID: PF02210 ; PF01034
• Sequence:
  MYQRMLRCGAELGSPGGGGGGGGGGGAGGRLALLWIVPLTLSGLLGVAWGASSLGAHHIH
  HFHGSSKHHSVPIAIYRSPASLRGGHAGTTYIFSKGGGQITYKWPPNDRPSTRADRLAIG
  FSTVQKEAVLVRVDSSSGLGDYLELHIHQGKIGVKFNVGTDDIAIEESNAIINDGKYHVV
  RFTRSGGNATLQVDSWPVIERYPAGNNDNERLAIARQRIPYRLGRVVDEWLLDKGRQLTI
  FNSQATIIIGGKEQGQPFQGQLSGLYYNGLKVLNMAAENDANIAIVGNVRLVGEVPSSMT
  TESTATAMQSEMSTSIMETTTTLATSTARRGKPPTKEPISQTTDDILVASAECPSDDEDI
  DPCEPSSGGLANPTRAGGREPYPGSAEVIRESSSTTGMVVGIVAAAALCILILLYAMYKY
  RNRDEGSYHVDESRNYISNSAQSNGAVVKEKQPSSAKSSNKNKKNKDKEYYV
• Function: Neuronal cell surface protein involved in cell recognition and cell adhesion by forming intracellular junctions through binding to neuroligins. Plays a role in formation of synaptic junctions.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Definitive	Biomarker	[1]
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[2]
Epilepsy	DISBB28L	Definitive	Genetic Variation	[3]
Pitt-Hopkins syndrome	DISM1JID	Definitive	Biomarker	[4]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[7]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[8]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[9]
Brain disease	DIS6ZC3X	Strong	Genetic Variation	[10]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[11]
Chromosome 2p16.3 deletion syndrome	DIS28AB0	Strong	Autosomal dominant	[12]
Depression	DIS3XJ69	Strong	Genetic Variation	[13]
Epilepsy, idiopathic generalized	DISODZC9	Strong	Genetic Variation	[14]
Intellectual disability	DISMBNXP	Strong	Biomarker	[15]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[16]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[17]
Narcolepsy	DISLCNLI	Strong	Biomarker	[17]
Nicotine dependence	DISZD9W7	Strong	Genetic Variation	[18]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[19]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[20]
Pitt-Hopkins-like syndrome 2	DISRKSS8	Strong	Autosomal recessive	[21]
Specific language impairment	DISEKRML	Strong	Genetic Variation	[22]
Tardive dyskinesia	DISKA5RC	Strong	Biomarker	[23]
Tourette syndrome	DISX9D54	Strong	Genetic Variation	[24]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[10]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[25]
Alcohol-induced disorders	DIS3SFYT	moderate	Genetic Variation	[25]
Alcohol-related disorders	DIS3K4KK	moderate	Genetic Variation	[25]
Asperger syndrome	DIS7IBSP	moderate	Genetic Variation	[26]
Autism	DISV4V1Z	Moderate	Autosomal dominant	[27]
CHARGE syndrome	DISKD3CW	moderate	Biomarker	[28]
Cognitive impairment	DISH2ERD	moderate	Biomarker	[28]
Fragile X syndrome	DISE8W3A	moderate	Biomarker	[28]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[29]
Psychotic disorder	DIS4UQOT	Limited	Genetic Variation	[30]
Schizophrenia	DISSRV2N	Limited	Unknown	[31]

9 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 Neurexin-1-beta (NRXN1).	[32]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neurexin-1-beta (NRXN1).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neurexin-1-beta (NRXN1).	[34]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Neurexin-1-beta (NRXN1).	[36]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Neurexin-1-beta (NRXN1).	[37]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Neurexin-1-beta (NRXN1).	[39]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Neurexin-1-beta (NRXN1).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neurexin-1-beta (NRXN1).	[41]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Neurexin-1-beta (NRXN1).	[42]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Neurexin-1-beta (NRXN1).	[35]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Neurexin-1-beta (NRXN1).	[38]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Neurexin-1-beta (NRXN1).	[38]

References

• [1] Genetics of long-term treatment outcome in bipolar disorder.Prog Neuropsychopharmacol Biol Psychiatry. 2016 Feb 4;65:17-24. doi: 10.1016/j.pnpbp.2015.08.008. Epub 2015 Aug 20.
• [2] 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.
• [3] Derivation of familial iPSC lines from three ASD patients carrying NRXN1(+/-) and two controls (NUIGi022-A, NUIGi022-B; NUIGi023-A, NUIGi023-B; NUIGi025-A, NUIGi025-B; NUIGi024-A, NUIGi024-B; NUIGi026-A, NUIGi026-B).Stem Cell Res. 2019 Dec;41:101653. doi: 10.1016/j.scr.2019.101653. Epub 2019 Nov 13.
• [4] Neurexins and neuropsychiatric disorders.Neurosci Res. 2018 Feb;127:53-60. doi: 10.1016/j.neures.2017.10.012. Epub 2017 Dec 6.
• [5] Three-way translocation involving MLL, MLLT1, and a novel third partner, NRXN1, in a patient with acute lymphoblastic leukemia and t(2;19;11) (p12;p13.3;q23).Cancer Genet Cytogenet. 2010 Feb;197(1):32-8. doi: 10.1016/j.cancergencyto.2009.10.009.
• [6] A Parallel Reaction Monitoring Mass Spectrometric Method for Analysis of Potential CSF Biomarkers for Alzheimer's Disease.Proteomics Clin Appl. 2018 Jan;12(1). doi: 10.1002/prca.201700131. Epub 2017 Nov 23.
• [7] Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data.Lancet Neurol. 2007 Apr;6(4):322-8. doi: 10.1016/S1474-4422(07)70037-6.
• [8] Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder.Transl Psychiatry. 2019 Oct 17;9(1):258. doi: 10.1038/s41398-019-0599-y.
• [9] A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function.Sci Rep. 2019 Apr 15;9(1):6024. doi: 10.1038/s41598-019-42635-7.
• [10] Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders.Am J Med Genet B Neuropsychiatr Genet. 2012 Apr;159B(3):354-8. doi: 10.1002/ajmg.b.32036. Epub 2012 Feb 15.
• [11] Disruption of neurexin 1 associated with autism spectrum disorder.Am J Hum Genet. 2008 Jan;82(1):199-207. doi: 10.1016/j.ajhg.2007.09.011.
• [12] Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay. Am J Med Genet B Neuropsychiatr Genet. 2010 Jul;153B(5):983-93. doi: 10.1002/ajmg.b.31064.
• [13] Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality.Exp Cell Res. 2019 Oct 1;383(1):111469. doi: 10.1016/j.yexcr.2019.06.014. Epub 2019 Jul 12.
• [14] Copy number variations and susceptibility to lateral temporal epilepsy: a study of 21 pedigrees.Epilepsia. 2014 Oct;55(10):1651-8. doi: 10.1111/epi.12767. Epub 2014 Sep 19.
• [15] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [16] Two rare deletions upstream of the NRXN1 gene (2p16.3) affecting the non-coding mRNA AK127244 segregate with diverse psychopathological phenotypes in a family.Eur J Med Genet. 2015 Dec;58(12):650-3. doi: 10.1016/j.ejmg.2015.11.004. Epub 2015 Nov 10.
• [17] Whole-Proteome Peptide Microarrays for Profiling Autoantibody Repertoires within Multiple Sclerosis and Narcolepsy.J Proteome Res. 2017 Mar 3;16(3):1300-1314. doi: 10.1021/acs.jproteome.6b00916. Epub 2017 Feb 9.
• [18] SNPs in NRXN1 and CHRNA5 are associated to smoking and regulation of GABAergic and glutamatergic pathways.Pharmacogenomics. 2016 Jul;17(10):1145-1158. doi: 10.2217/pgs-2016-0020. Epub 2016 Jun 29.
• [19] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [20] NRXN1 deletion syndrome; phenotypic and penetrance data from 34 families.Eur J Med Genet. 2019 Mar;62(3):204-209. doi: 10.1016/j.ejmg.2018.07.015. Epub 2018 Jul 18.
• [21] CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet. 2009 Nov;85(5):655-66. doi: 10.1016/j.ajhg.2009.10.004. Epub 2009 Nov 5.
• [22] Neuronal cell adhesion genes: Key players in risk for schizophrenia, bipolar disorder and other neurodevelopmental brain disorders?.Cell Adh Migr. 2010 Oct-Dec;4(4):511-4. doi: 10.4161/cam.4.4.12460.
• [23] Association study between the neurexin-1 gene and tardive dyskinesia.Hum Psychopharmacol. 2017 Jan;32(1). doi: 10.1002/hup.2568.
• [24] Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome. Neuron. 2017 Jun 21;94(6):1101-1111.e7. doi: 10.1016/j.neuron.2017.06.010.
• [25] A genome-wide association study of behavioral disinhibition.Behav Genet. 2013 Sep;43(5):363-73. doi: 10.1007/s10519-013-9606-x. Epub 2013 Aug 14.
• [26] A synaptic trek to autism.Curr Opin Neurobiol. 2009 Apr;19(2):231-4. doi: 10.1016/j.conb.2009.06.003. Epub 2009 Jun 21.
• [27] Mutation analysis of the NRXN1 gene in autism spectrum disorders. Balkan J Med Genet. 2017 Mar 8;19(2):17-22. doi: 10.1515/bjmg-2016-0031. eCollection 2016 Dec 1.
• [28] Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.Am J Hum Genet. 2013 Aug 8;93(2):249-63. doi: 10.1016/j.ajhg.2013.06.012. Epub 2013 Jul 11.
• [29] A complex microcephaly syndrome in a Pakistani family associated with a novel missense mutation in RBBP8 and a heterozygous deletion in NRXN1.Gene. 2014 Mar 15;538(1):30-5. doi: 10.1016/j.gene.2014.01.027. Epub 2014 Jan 16.
• [30] NRXN1 is associated with enlargement of the temporal horns of the lateral ventricles in psychosis.Transl Psychiatry. 2019 Sep 17;9(1):230. doi: 10.1038/s41398-019-0564-9.
• [31] 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.
• [32] Evaluation of mRNA markers in differentiating human SH-SY5Y cells for estimation of developmental neurotoxicity. Neurotoxicology. 2023 Jul;97:65-77. doi: 10.1016/j.neuro.2023.05.011. Epub 2023 May 18.
• [33] 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.
• [34] 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.
• [35] 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.
• [36] 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.
• [37] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [38] 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.
• [39] Early Transcriptomic Changes upon Thalidomide Exposure Influence the Later Neuronal Development in Human Embryonic Stem Cell-Derived Spheres. Int J Mol Sci. 2020 Aug 3;21(15):5564. doi: 10.3390/ijms21155564.
• [40] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [41] 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.
• [42] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.