Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTY88DL)

• DOT Name: Netrin-G2 (NTNG2)
• Synonyms: Laminet-2
• Gene Name: NTNG2
• Related Disease:
  Atypical Rett syndrome
  Bipolar depression
  Bladder cancer
  Cocaine addiction
  Intellectual disability
  Isolated congenital microcephaly
  Neoplasm
  Neurodevelopmental disorder
  Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia
  Polyneuropathy
  Rett syndrome
  Urinary bladder cancer
  Urinary bladder neoplasm
  Autism
  Syndromic intellectual disability
  Schizophrenia
• UniProt ID: NTNG2_HUMAN
• PDB ID: 3TBD; 3ZYG; 3ZYI
• Pfam ID: PF00053 ; PF00055
• Sequence:
  MLHLLALFLHCLPLASGDYDICKSWVTTDEGPTWEFYACQPKVMRLKDYVKVKVEPSGIT
  CGDPPERFCSHENPYLCSNECDASNPDLAHPPRLMFDKEEEGLATYWQSITWSRYPSPLE
  ANITLSWNKTVELTDDVVMTFEYGRPTVMVLEKSLDNGRTWQPYQFYAEDCMEAFGMSAR
  RARDMSSSSAHRVLCTEEYSRWAGSKKEKHVRFEVRDRFAIFAGPDLRNMDNLYTRLESA
  KGLKEFFTLTDLRMRLLRPALGGTYVQRENLYKYFYAISNIEVIGRCKCNLHANLCSMRE
  GSLQCECEHNTTGPDCGKCKKNFRTRSWRAGSYLPLPHGSPNACATAGSFGNCECYGHSN
  RCSYIDFLNVVTCVSCKHNTRGQHCQHCRLGYYRNGSAELDDENVCIECNCNQIGSVHDR
  CNETGFCECREGAAGPKCDDCLPTHYWRQGCYPNVCDDDQLLCQNGGTCLQNQRCACPRG
  YTGVRCEQPRCDPADDDGGLDCDRAPGAAPRPATLLGCLLLLGLAARLGR
• 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.
• KEGG Pathway:
  Axon guidance (hsa04360)
  Cell adhesion molecules (hsa04514)
• Reactome Pathway: Post-translational modification (R-HSA-163125)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atypical Rett syndrome	DISWF699	Definitive	Genetic Variation	[1]
Bipolar depression	DISA75FU	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Cocaine addiction	DISHTRXG	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[5]
Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia	DISMF0HN	Strong	Autosomal recessive	[6]
Polyneuropathy	DISB9G3W	Strong	Biomarker	[7]
Rett syndrome	DISGG5UV	Strong	Biomarker	[8]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Autism	DISV4V1Z	moderate	Genetic Variation	[9]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[5]
Schizophrenia	DISSRV2N	Disputed	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Netrin-G2 (NTNG2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Netrin-G2 (NTNG2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Netrin-G2 (NTNG2).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Netrin-G2 (NTNG2).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Netrin-G2 (NTNG2).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Netrin-G2 (NTNG2).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Netrin-G2 (NTNG2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Netrin-G2 (NTNG2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Netrin-G2 (NTNG2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Netrin-G2 (NTNG2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Netrin-G2 (NTNG2).	[16]

References

• [1] 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.
• [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] Expression in bladder transitional cell carcinoma by real-time quantitative reverse transcription polymerase chain reaction array of 65 genes at the tumor suppressor locus 9q34.1-2: identification of 5 candidates tumor suppressor genes.Int J Cancer. 2004 Sep 10;111(4):539-42. doi: 10.1002/ijc.20283.
• [4] 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.
• [5] 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.
• [6] Homozygous frameshift variant in NTNG2, encoding a synaptic cell adhesion molecule, in individuals with developmental delay, hypotonia, and autistic features. Neurogenetics. 2019 Oct;20(4):209-213. doi: 10.1007/s10048-019-00583-4. Epub 2019 Aug 2.
• [7] Reduced gene expression of netrin family members in skin and sural nerve specimens of patients with painful peripheral neuropathies.J Neurol. 2019 Nov;266(11):2812-2820. doi: 10.1007/s00415-019-09496-6. Epub 2019 Aug 7.
• [8] 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.
• [9] 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.
• [10] Functional variants of the genes involved in neurodevelopment and susceptibility to schizophrenia in an Armenian population.Hum Immunol. 2011 Sep;72(9):746-8. doi: 10.1016/j.humimm.2011.05.018. Epub 2011 May 24.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] 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.
• [17] 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.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] 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.