Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5QI5EP)

• DOT Name: Leucine-rich repeat-containing protein 4C (LRRC4C)
• Synonyms: Netrin-G1 ligand; NGL-1
• Gene Name: LRRC4C
• Related Disease:
  Narcolepsy
  Bipolar disorder
  Brain disease
  Autism
  Cyclic hematopoiesis
  Neurodevelopmental disorder
  Myopia
• UniProt ID: LRC4C_HUMAN
• PDB ID: 3ZYJ
• Pfam ID: PF07679 ; PF00560 ; PF13855
• Sequence:
  MLNKMTLHPQQIMIGPRFNRALFDPLLVVLLALQLLVVAGLVRAQTCPSVCSCSNQFSKV
  ICVRKNLREVPDGISTNTRLLNLHENQIQIIKVNSFKHLRHLEILQLSRNHIRTIEIGAF
  NGLANLNTLELFDNRLTTIPNGAFVYLSKLKELWLRNNPIESIPSYAFNRIPSLRRLDLG
  ELKRLSYISEGAFEGLSNLRYLNLAMCNLREIPNLTPLIKLDELDLSGNHLSAIRPGSFQ
  GLMHLQKLWMIQSQIQVIERNAFDNLQSLVEINLAHNNLTLLPHDLFTPLHHLERIHLHH
  NPWNCNCDILWLSWWIKDMAPSNTACCARCNTPPNLKGRYIGELDQNYFTCYAPVIVEPP
  ADLNVTEGMAAELKCRASTSLTSVSWITPNGTVMTHGAYKVRIAVLSDGTLNFTNVTVQD
  TGMYTCMVSNSVGNTTASATLNVTAATTTPFSYFSTVTVETMEPSQDEARTTDNNVGPTP
  VVDWETTNVTTSLTPQSTRSTEKTFTIPVTDINSGIPGIDEVMKTTKIIIGCFVAITLMA
  AVMLVIFYKMRKQHHRQNHHAPTRTVEIINVDDEITGDTPMESHLPMPAIEHEHLNHYNS
  YKSPFNHTTTVNTINSIHSSVHEPLLIRMNSKDNVQETQI
• Function: May promote neurite outgrowth of developing thalamic neurons.
• Tissue Specificity: Highly expressed in the cerebral cortex, including frontal, parietal and occipital lobes. Putamen, amygdala, hippocampus and medulla oblongata show moderate expression. Caudate nucleus and thalamus express small amounts, whereas other brain regions show very weak or no expression.
• KEGG Pathway:
  Axon guidance (hsa04360)
  Cell adhesion molecules (hsa04514)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[1]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[2]
Brain disease	DIS6ZC3X	Strong	Biomarker	[2]
Autism	DISV4V1Z	moderate	Biomarker	[3]
Cyclic hematopoiesis	DISQQOM4	moderate	Genetic Variation	[3]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[3]
Myopia	DISK5S60	Limited	Genetic Variation	[4]

6 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 Leucine-rich repeat-containing protein 4C (LRRC4C).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Leucine-rich repeat-containing protein 4C (LRRC4C).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Leucine-rich repeat-containing protein 4C (LRRC4C).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Leucine-rich repeat-containing protein 4C (LRRC4C).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Leucine-rich repeat-containing protein 4C (LRRC4C).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Leucine-rich repeat-containing protein 4C (LRRC4C).	[12]

2 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 affects the methylation of Leucine-rich repeat-containing protein 4C (LRRC4C).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Leucine-rich repeat-containing protein 4C (LRRC4C).	[10]

References

• [1] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [2] NGL-1/LRRC4C-Mutant Mice Display Hyperactivity and Anxiolytic-Like Behavior Associated With Widespread Suppression of Neuronal Activity.Front Mol Neurosci. 2019 Oct 11;12:250. doi: 10.3389/fnmol.2019.00250. eCollection 2019.
• [3] Implication of LRRC4C and DPP6 in neurodevelopmental disorders.Am J Med Genet A. 2017 Feb;173(2):395-406. doi: 10.1002/ajmg.a.38021. Epub 2016 Oct 19.
• [4] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.