Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZGS8BN)

• DOT Name: Leucine-rich repeat LGI family member 4 (LGI4)
• Synonyms: LGI1-like protein 3; Leucine-rich glioma-inactivated protein 4
• Gene Name: LGI4
• Related Disease:
  Arthrogryposis multiplex congenita 1, neurogenic, with myelin defect
  Autosomal dominant epilepsy with auditory features
  Epilepsy
  Glioma
  Intellectual disability
  Arthrogryposis
  Obsolete hypomyelination neuropathy-arthrogryposis syndrome
  Benign neonatal seizures
  Absence epilepsy
  Absence seizure
  Epilepsy, idiopathic generalized
• UniProt ID: LGI4_HUMAN
• Pfam ID: PF03736 ; PF13855
• Sequence:
  MGGAGILLLLLAGAGVVVAWRPPKGKCPLRCSCSKDSALCEGSPDLPVSFSPTLLSLSLV
  RTGVTQLKAGSFLRIPSLHLLLFTSNSFSVIEDDAFAGLSHLQYLFIEDNEIGSISKNAL
  RGLRSLTHLSLANNHLETLPRFLFRGLDTLTHVDLRGNPFQCDCRVLWLLQWMPTVNASV
  GTGACAGPASLSHMQLHHLDPKTFKCRAIELSWFQTVGESALSVEPFSYQGEPHIVLAQP
  FAGRCLILSWDYSLQRFRPEEELPAASVVSCKPLVLGPSLFVLAARLWGGSQLWARPSPG
  LRLAPTQTLAPRRLLRPNDAELLWLEGQPCFVVADASKAGSTTLLCRDGPGFYPHQSLHA
  WHRDTDAEALELDGRPHLLLASASQRPVLFHWTGGRFERRTDIPEAEDVYATRHFQAGGD
  VFLCLTRYIGDSMVMRWDGSMFRLLQQLPSRGAHVFQPLLIARDQLAILGSDFAFSQVLR
  LEPDKGLLEPLQELGPPALVAPRAFAHITMAGRRFLFAACFKGPTQIYQHHEIDLSA
• Function: Component of Schwann cell signaling pathway(s) that controls axon segregation and myelin formation.
• Tissue Specificity: Widely expressed, with highest expression in brain.
• Reactome Pathway: LGI-ADAM interactions (R-HSA-5682910)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthrogryposis multiplex congenita 1, neurogenic, with myelin defect	DIS12DC6	Strong	Autosomal recessive	[1]
Autosomal dominant epilepsy with auditory features	DISFZN2O	Strong	Genetic Variation	[2]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Arthrogryposis	DISC81CM	moderate	Genetic Variation	[6]
Obsolete hypomyelination neuropathy-arthrogryposis syndrome	DISO9PZY	Supportive	Autosomal recessive	[7]
Benign neonatal seizures	DISWNBHF	Disputed	Genetic Variation	[3]
Absence epilepsy	DISJPOUD	Limited	Genetic Variation	[8]
Absence seizure	DIS4709R	Limited	Genetic Variation	[8]
Epilepsy, idiopathic generalized	DISODZC9	Limited	Biomarker	[8]

4 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 Leucine-rich repeat LGI family member 4 (LGI4).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Leucine-rich repeat LGI family member 4 (LGI4).	[10]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Leucine-rich repeat LGI family member 4 (LGI4).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Leucine-rich repeat LGI family member 4 (LGI4).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Leucine-rich repeat LGI family member 4 (LGI4).	[13]

References

• [1] LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11. Int J Biol Sci. 2008;4(6):387-96. doi: 10.7150/ijbs.4.387. Epub 2008 Oct 21.
• [2] LGI1 mutations in temporal lobe epilepsies.Neurology. 2004 Apr 13;62(7):1115-9. doi: 10.1212/01.wnl.0000118213.94650.81.
• [3] Positive association between benign familial infantile convulsions and LGI4.Brain Dev. 2010 Aug;32(7):538-43. doi: 10.1016/j.braindev.2009.09.006. Epub 2009 Oct 7.
• [4] Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals.Oncogene. 2015 Mar 5;34(10):1270-9. doi: 10.1038/onc.2014.70. Epub 2014 Mar 24.
• [5] The claw paw mutation reveals a role for Lgi4 in peripheral nerve development.Nat Neurosci. 2006 Jan;9(1):76-84. doi: 10.1038/nn1598. Epub 2005 Dec 11.
• [6] A mild phenotype of LGI4-Related arthrogryposis multiplex congenita with intrafamilial variability.Eur J Med Genet. 2020 Mar;63(3):103756. doi: 10.1016/j.ejmg.2019.103756. Epub 2019 Sep 9.
• [7] Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita. Am J Hum Genet. 2017 Apr 6;100(4):659-665. doi: 10.1016/j.ajhg.2017.02.006. Epub 2017 Mar 16.
• [8] Genotypic association of exonic LGI4 polymorphisms and childhood absence epilepsy.Neurogenetics. 2004 Feb;5(1):41-4. doi: 10.1007/s10048-003-0158-8. Epub 2003 Sep 19.
• [9] 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.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] 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.