Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYJ4348)

• DOT Name: Leucine-rich repeat transmembrane neuronal protein 4 (LRRTM4)
• Gene Name: LRRTM4
• Related Disease:
  Peripheral arterial disease
  Schizophrenia
  Acute myelogenous leukaemia
  Age-related macular degeneration
  Macular degeneration
• UniProt ID: LRRT4_HUMAN
• Pfam ID: PF13855
• Sequence:
  MGFHLITQLKGMSVVLVLLPTLLLVMLTGAQRACPKNCRCDGKIVYCESHAFADIPENIS
  GGSQGLSLRFNSIQKLKSNQFAGLNQLIWLYLDHNYISSVDEDAFQGIRRLKELILSSNK
  ITYLHNKTFHPVPNLRNLDLSYNKLQTLQSEQFKGLRKLIILHLRSNSLKTVPIRVFQDC
  RNLDFLDLGYNRLRSLSRNAFAGLLKLKELHLEHNQFSKINFAHFPRLFNLRSIYLQWNR
  IRSISQGLTWTWSSLHNLDLSGNDIQGIEPGTFKCLPNLQKLNLDSNKLTNISQETVNAW
  ISLISITLSGNMWECSRSICPLFYWLKNFKGNKESTMICAGPKHIQGEKVSDAVETYNIC
  SEVQVVNTERSHLVPQTPQKPLIIPRPTIFKPDVTQSTFETPSPSPGFQIPGAEQEYEHV
  SFHKIIAGSVALFLSVAMILLVIYVSWKRYPASMKQLQQHSLMKRRRKKARESERQMNSP
  LQEYYVDYKPTNSETMDISVNGSGPCTYTISGSRECEMPHHMKPLPYYSYDQPVIGYCQA
  HQPLHVTKGYETVSPEQDESPGLELGRDHSFIATIARSAAPAIYLERIAN
• Function: May play a role in the development and maintenance of the vertebrate nervous system. Exhibits strong synaptogenic activity, restricted to excitatory presynaptic differentiation.
• Tissue Specificity: Expressed in neuronal tissues.
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[1]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[3]
Age-related macular degeneration	DIS0XS2C	moderate	Genetic Variation	[4]
Macular degeneration	DISLKKHD	moderate	Genetic Variation	[4]

5 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 transmembrane neuronal protein 4 (LRRTM4).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Leucine-rich repeat transmembrane neuronal protein 4 (LRRTM4).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Leucine-rich repeat transmembrane neuronal protein 4 (LRRTM4).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Leucine-rich repeat transmembrane neuronal protein 4 (LRRTM4).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Leucine-rich repeat transmembrane neuronal protein 4 (LRRTM4).	[10]

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 Leucine-rich repeat transmembrane neuronal protein 4 (LRRTM4).	[9]

References

• [1] Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease.PLoS One. 2016 Apr 15;11(4):e0152670. doi: 10.1371/journal.pone.0152670. eCollection 2016.
• [2] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] LRRTM4-C538Y novel gene mutation is associated with hereditary macular degeneration with novel dysfunction of ON-type bipolar cells.J Hum Genet. 2018 Aug;63(8):893-900. doi: 10.1038/s10038-018-0465-4. Epub 2018 May 14.
• [5] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] 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.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.