Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLTA24A)

• DOT Name: NMDA receptor synaptonuclear signaling and neuronal migration factor (NSMF)
• Synonyms: Nasal embryonic luteinizing hormone-releasing hormone factor; Nasal embryonic LHRH factor
• Gene Name: NSMF
• Related Disease:
  Hypogonadism
  Hypogonadotropic hypogonadism 7 with or without anosmia
  Hypogonadotropic hypogonadism 9 with or without anosmia
  Klinefelter syndrome
  Kallmann syndrome
  Hypogonadotropic hypogonadism
  Carcinoma
  Undifferentiated carcinoma
• UniProt ID: NSMF_HUMAN
• Sequence:
  MGAAASRRRALRSEAMSSVAAKVRAARAFGEYLSQSHPENRNGADHLLADAYSGHDGSPE
  MQPAPQNKRRLSLVSNGCYEGSLSEEPSIRKPAGEGPQPRVYTISGEPALLPSPEAEAIE
  LAVVKGRRQRHPHHHSQPLRASPGGSREDVSRPCQSWAGSRQGSKECPGCAQLAPGPTPR
  AFGLDQPPLPETSGRRKKLERMYSVDRVSDDIPIRTWFPKENLFSFQTATTTMQAISVFR
  GYAERKRRKRENDSASVIQRNFRKHLRMVGSRRVKAQTFAERRERSFSRSWSDPTPMKAD
  TSHDSRDSSDLQSSHCTLDEAFEDLDWDTEKGLEAVACDTEGFVPPKVMLISSKVPKAEY
  IPTIIRRDDPSIIPILYDHEHATFEDILEEIERKLNVYHKGAKIWKMLIFCQGGPGHLYL
  LKNKVATFAKVEKEEDMIHFWKRLSRLMSKVNPEPNVIHIMGCYILGNPNGEKLFQNLRT
  LMTPYRVTFESPLELSAQGKQMIETYFDFRLYRLWKSRQHSKLLDFDDVL
• Function: Couples NMDA-sensitive glutamate receptor signaling to the nucleus and triggers long-lasting changes in the cytoarchitecture of dendrites and spine synapse processes. Part of the cAMP response element-binding protein (CREB) shut-off signaling pathway. Stimulates outgrowth of olfactory axons and migration of gonadotropin-releasing hormone (GnRH) and luteinizing-hormone-releasing hormone (LHRH) neuronal cells.
• Tissue Specificity: Highly expressed in adult and fetal brain. Weakly expressed in heart, liver, spleen, testis, small intestine, skeletal muscle, peripheral white blood cells and kidney.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypogonadism	DISICMNI	Strong	Genetic Variation	[1]
Hypogonadotropic hypogonadism 7 with or without anosmia	DISPBWEU	Strong	Genetic Variation	[2]
Hypogonadotropic hypogonadism 9 with or without anosmia	DISG13LO	Strong	Autosomal dominant	[3]
Klinefelter syndrome	DISOUI7W	Strong	Genetic Variation	[2]
Kallmann syndrome	DISO3HDG	moderate	Biomarker	[4]
Hypogonadotropic hypogonadism	DIS8JSKR	Supportive	Autosomal dominant	[5]
Carcinoma	DISH9F1N	Limited	Biomarker	[6]
Undifferentiated carcinoma	DISIAZST	Limited	Biomarker	[6]

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 NMDA receptor synaptonuclear signaling and neuronal migration factor (NSMF).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of NMDA receptor synaptonuclear signaling and neuronal migration factor (NSMF).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of NMDA receptor synaptonuclear signaling and neuronal migration factor (NSMF).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NMDA receptor synaptonuclear signaling and neuronal migration factor (NSMF).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NMDA receptor synaptonuclear signaling and neuronal migration factor (NSMF).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NMDA receptor synaptonuclear signaling and neuronal migration factor (NSMF).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of NMDA receptor synaptonuclear signaling and neuronal migration factor (NSMF).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of NMDA receptor synaptonuclear signaling and neuronal migration factor (NSMF).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of NMDA receptor synaptonuclear signaling and neuronal migration factor (NSMF).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of NMDA receptor synaptonuclear signaling and neuronal migration factor (NSMF).	[16]

References

• [1] The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.Mol Hum Reprod. 2008 Jun;14(6):367-70. doi: 10.1093/molehr/gan027. Epub 2008 May 7.
• [2] Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome.Fertil Steril. 2011 Apr;95(5):1613-20.e1-7. doi: 10.1016/j.fertnstert.2011.01.010. Epub 2011 Feb 15.
• [3] Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). J Hum Genet. 2004;49(5):265-8. doi: 10.1007/s10038-004-0137-4.
• [4] Genetic diagnosis of idiopathic hypogonadotrophic hypogonadism: a new point mutation in the KAL2 gene.Hormones (Athens). 2014 Apr-Jun;13(2):280-5. doi: 10.1007/BF03401342.
• [5] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [6] cDNA microarray profiling of rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 7,12-dimethylbenz[a]anthracene.Carcinogenesis. 2002 Oct;23(10):1561-8. doi: 10.1093/carcin/23.10.1561.
• [7] 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.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] 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.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [13] 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.
• [14] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] 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.
• [16] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.