Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF48IID)

• DOT Name: Netrin-G1 (NTNG1)
• Synonyms: Laminet-1
• Gene Name: NTNG1
• Related Disease:
  Anorexia nervosa cachexia
  Bipolar depression
  Bipolar disorder
  Cocaine addiction
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Familial congenital mirror movements
  Head-neck squamous cell carcinoma
  Intellectual disability
  Neoplasm
  Rett syndrome
  Schizophrenia
  Autism
  Neurodevelopmental disorder
  Neuroendocrine neoplasm
  Atypical Rett syndrome
  Syndromic intellectual disability
  Colorectal neoplasm
  Complex neurodevelopmental disorder
  Patent ductus arteriosus
  Stroke
• UniProt ID: NTNG1_HUMAN
• PDB ID: 3ZYJ
• Pfam ID: PF00053 ; PF00055
• Sequence:
  MYLSRFLSIHALWVTVSSVMQPYPLVWGHYDLCKTQIYTEEGKVWDYMACQPESTDMTKY
  LKVKLDPPDITCGDPPETFCAMGNPYMCNNECDASTPELAHPPELMFDFEGRHPSTFWQS
  ATWKEYPKPLQVNITLSWSKTIELTDNIVITFESGRPDQMILEKSLDYGRTWQPYQYYAT
  DCLDAFHMDPKSVKDLSQHTVLEIICTEEYSTGYTTNSKIIHFEIKDRFAFFAGPRLRNM
  ASLYGQLDTTKKLRDFFTVTDLRIRLLRPAVGEIFVDELHLARYFYAISDIKVRGRCKCN
  LHATVCVYDNSKLTCECEHNTTGPDCGKCKKNYQGRPWSPGSYLPIPKGTANTCIPSISS
  IGNCECFGHSNRCSYIDLLNTVICVSCKHNTRGQHCELCRLGYFRNASAQLDDENVCIEC
  YCNPLGSIHDRCNGSGFCECKTGTTGPKCDECLPGNSWHYGCQPNVCDNELLHCQNGGTC
  HNNVRCLCPAAYTGILCEKLRCEEAGSCGSDSGQGAPPHGSPALLLLTTLLGTASPLVF
• Function: Involved in controlling patterning and neuronal circuit formation at the laminar, cellular, subcellular and synaptic levels. Promotes neurite outgrowth of both axons and dendrites.
• Tissue Specificity: Highly expressed in the thalamus, with very low expression, if any, in other tissues.
• KEGG Pathway:
  Axon guidance (hsa04360)
  Cell adhesion molecules (hsa04514)
• Reactome Pathway: Post-translational modification (R-HSA-163125)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anorexia nervosa cachexia	DISFO5RQ	Strong	Biomarker	[1]
Bipolar depression	DISA75FU	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Altered Expression	[2]
Cocaine addiction	DISHTRXG	Strong	Genetic Variation	[3]
Colon cancer	DISVC52G	Strong	Posttranslational Modification	[4]
Colon carcinoma	DISJYKUO	Strong	Posttranslational Modification	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Familial congenital mirror movements	DISJLV92	Strong	Genetic Variation	[6]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[7]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[8]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[9]
Rett syndrome	DISGG5UV	Strong	Biomarker	[10]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[11]
Autism	DISV4V1Z	moderate	Genetic Variation	[8]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[8]
Neuroendocrine neoplasm	DISNPLOO	moderate	Biomarker	[12]
Atypical Rett syndrome	DISWF699	Supportive	Autosomal dominant	[13]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[14]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[15]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[16]
Patent ductus arteriosus	DIS9P8YS	Limited	Biomarker	[17]
Stroke	DISX6UHX	Limited	Biomarker	[18]

8 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 Netrin-G1 (NTNG1).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Netrin-G1 (NTNG1).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Netrin-G1 (NTNG1).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Netrin-G1 (NTNG1).	[22]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Netrin-G1 (NTNG1).	[23]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Netrin-G1 (NTNG1).	[24]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Netrin-G1 (NTNG1).	[25]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Netrin-G1 (NTNG1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Netrin-G1 (NTNG1).	[26]

References

• [1] Shared Genetic Factors Involved in Celiac Disease, Type 2 Diabetes and Anorexia Nervosa Suggest Common Molecular Pathways for Chronic Diseases.PLoS One. 2016 Aug 2;11(8):e0159593. doi: 10.1371/journal.pone.0159593. eCollection 2016.
• [2] Decreased mRNA expression of netrin-G1 and netrin-G2 in the temporal lobe in schizophrenia and bipolar disorder.Neuropsychopharmacology. 2008 Mar;33(4):933-45. doi: 10.1038/sj.npp.1301457. Epub 2007 May 16.
• [3] Netrin G1: its downregulation in the nucleus accumbens of cocaine-conditioned mice and genetic association in human cocaine dependence.Addict Biol. 2018 Jan;23(1):448-460. doi: 10.1111/adb.12485. Epub 2017 Jan 11.
• [4] Frequent inactivation of axon guidance molecule RGMA in human colon cancer through genetic and epigenetic mechanisms.Gastroenterology. 2009 Jul;137(1):176-87. doi: 10.1053/j.gastro.2009.03.005. Epub 2009 Mar 18.
• [5] Semaphorin-3F suppresses the stemness of colorectal cancer cells by inactivating Rac1.Cancer Lett. 2015 Mar 1;358(1):76-84. doi: 10.1016/j.canlet.2014.12.040. Epub 2014 Dec 18.
• [6] Neural function in DCC mutation carriers with and without mirror movements.Ann Neurol. 2019 Mar;85(3):433-442. doi: 10.1002/ana.25418. Epub 2019 Feb 4.
• [7] Axon guidance molecule semaphorin3A is a novel tumor suppressor in head and neck squamous cell carcinoma.Oncotarget. 2016 Feb 2;7(5):6048-62. doi: 10.18632/oncotarget.6831.
• [8] CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons.Nat Cell Biol. 2012 Sep;14(9):911-23. doi: 10.1038/ncb2566. Epub 2012 Aug 26.
• [9] Hyper-Methylated Loci Persisting from Sessile Serrated Polyps to Serrated Cancers.Int J Mol Sci. 2017 Mar 2;18(3):535. doi: 10.3390/ijms18030535.
• [10] Netrin-G2 dysfunction causes a Rett-like phenotype with areflexia.Hum Mutat. 2020 Feb;41(2):476-486. doi: 10.1002/humu.23945. Epub 2019 Nov 15.
• [11] Replication of NTNG1 association in schizophrenia.Psychiatr Genet. 2014 Dec;24(6):266-8. doi: 10.1097/YPG.0000000000000061.
• [12] The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors.Oncotarget. 2015 Nov 3;6(34):36731-45. doi: 10.18632/oncotarget.5481.
• [13] Netrin G1 mutations are an uncommon cause of atypical Rett syndrome with or without epilepsy. Pediatr Neurol. 2007 Oct;37(4):270-4. doi: 10.1016/j.pediatrneurol.2007.06.002.
• [14] Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder. Am J Hum Genet. 2019 Nov 7;105(5):1048-1056. doi: 10.1016/j.ajhg.2019.09.025. Epub 2019 Oct 24.
• [15] Genomic and epigenomic integration identifies a prognostic signature in colon cancer.Clin Cancer Res. 2011 Mar 15;17(6):1535-45. doi: 10.1158/1078-0432.CCR-10-2509. Epub 2011 Jan 28.
• [16] 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.
• [17] Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling.Cell Death Dis. 2015 Jan 15;6(1):e1592. doi: 10.1038/cddis.2014.557.
• [18] Netrin-1 Promotes Synaptic Formation and Axonal Regeneration via JNK1/c-Jun Pathway after the Middle Cerebral Artery Occlusion.Front Cell Neurosci. 2018 Feb 13;12:13. doi: 10.3389/fncel.2018.00013. eCollection 2018.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [22] 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.
• [23] 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.
• [24] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [25] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [26] 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.
• [27] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.