Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDJGBK8)

• DOT Name: Neuroligin-4, X-linked (NLGN4X)
• Synonyms: Neuroligin X; HNLX
• Gene Name: NLGN4X
• Related Disease:
  X-linked complex neurodevelopmental disorder
  X-linked intellectual disability
  Advanced cancer
  Alcohol dependence
  Autism, susceptibility to, X-linked 2
  Brain disease
  Breast cancer
  Breast carcinoma
  Neoplasm
  Non-syndromic ichthyosis
  Paraganglioma
  Tourette syndrome
  Neurodevelopmental disorder
  Recessive X-linked ichthyosis
  Mental disorder
  Schizophrenia
• UniProt ID: NLGNX_HUMAN
• PDB ID: 2WQZ; 2XB6; 3BE8
• Pfam ID: PF00135
• Sequence:
  MSRPQGLLWLPLLFTPVCVMLNSNVLLWLTALAIKFTLIDSQAQYPVVNTNYGKIRGLRT
  PLPNEILGPVEQYLGVPYASPPTGERRFQPPEPPSSWTGIRNTTQFAAVCPQHLDERSLL
  HDMLPIWFTANLDTLMTYVQDQNEDCLYLNIYVPTEDDIHDQNSKKPVMVYIHGGSYMEG
  TGNMIDGSILASYGNVIVITINYRLGILGFLSTGDQAAKGNYGLLDQIQALRWIEENVGA
  FGGDPKRVTIFGSGAGASCVSLLTLSHYSEGLFQKAIIQSGTALSSWAVNYQPAKYTRIL
  ADKVGCNMLDTTDMVECLRNKNYKELIQQTITPATYHIAFGPVIDGDVIPDDPQILMEQG
  EFLNYDIMLGVNQGEGLKFVDGIVDNEDGVTPNDFDFSVSNFVDNLYGYPEGKDTLRETI
  KFMYTDWADKENPETRRKTLVALFTDHQWVAPAVATADLHAQYGSPTYFYAFYHHCQSEM
  KPSWADSAHGDEVPYVFGIPMIGPTELFSCNFSKNDVMLSAVVMTYWTNFAKTGDPNQPV
  PQDTKFIHTKPNRFEEVAWSKYNPKDQLYLHIGLKPRVRDHYRATKVAFWLELVPHLHNL
  NEIFQYVSTTTKVPPPDMTSFPYGTRRSPAKIWPTTKRPAITPANNPKHSKDPHKTGPED
  TTVLIETKRDYSTELSVTIAVGASLLFLNILAFAALYYKKDKRRHETHRRPSPQRNTTND
  IAHIQNEEIMSLQMKQLEHDHECESLQAHDTLRLTCPPDYTLTLRRSPDDIPLMTPNTIT
  MIPNTLTGMQPLHTFNTFSGGQNSTNLPHGHSTTRV
• Function: Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.
• Tissue Specificity: Expressed at highest levels in heart. Expressed at lower levels in liver, skeletal muscle and pancreas and at very low levels in brain.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked complex neurodevelopmental disorder	DISI3QE9	Definitive	X-linked	[1]
X-linked intellectual disability	DISYJBY3	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[4]
Autism, susceptibility to, X-linked 2	DISLVWWZ	Strong	X-linked	[5]
Brain disease	DIS6ZC3X	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[7]
Non-syndromic ichthyosis	DISZ9QBQ	Strong	Genetic Variation	[8]
Paraganglioma	DIS2XXH5	Strong	Genetic Variation	[7]
Tourette syndrome	DISX9D54	Strong	Genetic Variation	[9]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[10]
Recessive X-linked ichthyosis	DISZY56W	moderate	Genetic Variation	[11]
Mental disorder	DIS3J5R8	Limited	Genetic Variation	[12]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Neuroligin-4, X-linked (NLGN4X).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neuroligin-4, X-linked (NLGN4X).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neuroligin-4, X-linked (NLGN4X).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Neuroligin-4, X-linked (NLGN4X).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Neuroligin-4, X-linked (NLGN4X).	[17]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Neuroligin-4, X-linked (NLGN4X).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Neuroligin-4, X-linked (NLGN4X).	[20]

References

• [1] 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.
• [2] X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family.Am J Hum Genet. 2004 Mar;74(3):552-7. doi: 10.1086/382137. Epub 2004 Feb 12.
• [3] Neuroligin 4X overexpression in human breast cancer is associated with poor relapse-free survival.PLoS One. 2017 Dec 15;12(12):e0189662. doi: 10.1371/journal.pone.0189662. eCollection 2017.
• [4] Sex chromosome-wide association analysis suggested male-specific risk genes for alcohol dependence.Psychiatr Genet. 2013 Dec;23(6):233-8. doi: 10.1097/YPG.0b013e328364b8c7.
• [5] 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.
• [6] 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.
• [7] ATRX driver mutation in a composite malignant pheochromocytoma.Cancer Genet. 2016 Jun;209(6):272-7. doi: 10.1016/j.cancergen.2016.04.058. Epub 2016 Apr 26.
• [8] Expanding the genetic spectrum of ANOS1 mutations in patients with congenital hypogonadotropic hypogonadism.Hum Reprod. 2017 Mar 1;32(3):704-711. doi: 10.1093/humrep/dew354.
• [9] Familial deletion within NLGN4 associated with autism and Tourette syndrome.Eur J Hum Genet. 2008 May;16(5):614-8. doi: 10.1038/sj.ejhg.5202006. Epub 2008 Jan 30.
• [10] 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.
• [11] X-linked ichthyosis (steroid sulfatase deficiency) is associated with increased risk of attention deficit hyperactivity disorder, autism and social communication deficits.J Med Genet. 2008 Aug;45(8):519-24. doi: 10.1136/jmg.2008.057729. Epub 2008 Apr 15.
• [12] Mutation screening in the Greek population and evaluation of NLGN3 and NLGN4X genes causal factors for autism.Psychiatr Genet. 2013 Oct;23(5):198-203. doi: 10.1097/YPG.0b013e3283643644.
• [13] Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.Nat Genet. 2018 Mar;50(3):381-389. doi: 10.1038/s41588-018-0059-2. Epub 2018 Feb 26.
• [14] 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.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [17] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [18] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.