Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIDM6XO)

• DOT Name: Leucine-zipper-like transcriptional regulator 1 (LZTR1)
• Synonyms: LZTR-1
• Gene Name: LZTR1
• Related Disease:
  Noonan syndrome
  Noonan syndrome 10
  Schwannomatosis 2
  Aarskog-Scott syndrome, X-linked
  Adult glioblastoma
  Artery stenosis
  Aspiration pneumonia
  Asthma
  Astrocytoma
  Atrial septal defect
  Autism
  Chronic kidney disease
  Cockayne syndrome
  Cornelia de Lange syndrome
  DiGeorge syndrome
  Dowling-Degos disease
  Dubowitz syndrome
  Glioblastoma multiforme
  Glioma
  Glioma susceptibility 1
  Microcephaly
  Myocardial infarction
  Nervous system neoplasm
  Noonan syndrome 2
  Noonan syndrome 4
  Prader-Willi syndrome
  Robinow syndrome
  Schwannomatosis
  Schwannomatosis 1
  Seckel syndrome
  Silver-Russell syndrome
  Gliosarcoma
  Hypertrophic cardiomyopathy
• UniProt ID: LZTR1_HUMAN
• Pfam ID: PF00651 ; PF01344 ; PF13415 ; PF13418
• Sequence:
  MAGPGSTGGQIGAAALAGGARSKVAPSVDFDHSCSDSVEYLTLNFGPFETVHRWRRLPPC
  DEFVGARRSKHTVVAYKDAIYVFGGDNGKTMLNDLLRFDVKDCSWCRAFTTGTPPAPRYH
  HSAVVYGSSMFVFGGYTGDIYSNSNLKNKNDLFEYKFATGQWTEWKIEGRLPVARSAHGA
  TVYSDKLWIFAGYDGNARLNDMWTIGLQDRELTCWEEVAQSGEIPPSCCNFPVAVCRDKM
  FVFSGQSGAKITNNLFQFEFKDKTWTRIPTEHLLRGSPPPPQRRYGHTMVAFDRHLYVFG
  GAADNTLPNELHCYDVDFQTWEVVQPSSDSEVGGAEVPERACASEEVPTLTYEERVGFKK
  SRDVFGLDFGTTSAKQPTQPASELPSGRLFHAAAVISDAMYIFGGTVDNNIRSGEMYRFQ
  FSCYPKCTLHEDYGRLWESRQFCDVEFVLGEKEECVQGHVAIVTARSRWLRRKITQARER
  LAQKLEQEAAPVPREAPGVAAGGARPPLLHVAIREAEARPFEVLMQFLYTDKIKYPRKGH
  VEDVLLIMDVYKLALSFQLCRLEQLCRQYIEASVDLQNVLVVCESAARLQLSQLKEHCLN
  FVVKESHFNQVIMMKEFERLSSPLIVEIVRRKQQPPPRTPLDQPVDIGTSLIQDMKAYLE
  GAGAEFCDITLLLDGHPRPAHKAILAARSSYFEAMFRSFMPEDGQVNISIGEMVPSRQAF
  ESMLRYIYYGEVNMPPEDSLYLFAAPYYYGFYNNRLQAYCKQNLEMNVTVQNVLQILEAA
  DKTQALDMKRHCLHIIVHQFTKVSKLPTLRSLSQQLLLDIIDSLASHISDKQCAELGADI
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS). Is a negative regulator of RAS-MAPK signaling that acts by controlling Ras levels and decreasing Ras association with membranes.

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Noonan syndrome	DIS7Q7DN	Definitive	Autosomal dominant	[1]
Noonan syndrome 10	DISS7QAL	Definitive	Autosomal dominant	[2]
Schwannomatosis 2	DIS9SG3R	Definitive	Autosomal dominant	[3]
Aarskog-Scott syndrome, X-linked	DISNHV62	Strong	Biomarker	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Artery stenosis	DISQU4Q5	Strong	CausalMutation	[6]
Aspiration pneumonia	DIS0DGX4	Strong	CausalMutation	[6]
Asthma	DISW9QNS	Strong	CausalMutation	[6]
Astrocytoma	DISL3V18	Strong	Biomarker	[5]
Atrial septal defect	DISJT76B	Strong	Genetic Variation	[7]
Autism	DISV4V1Z	Strong	Biomarker	[8]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[9]
Cockayne syndrome	DISW6GL2	Strong	Biomarker	[4]
Cornelia de Lange syndrome	DISEQSXO	Strong	Biomarker	[4]
DiGeorge syndrome	DIST1RKO	Strong	Biomarker	[10]
Dowling-Degos disease	DISGTTEP	Strong	Genetic Variation	[11]
Dubowitz syndrome	DISRMNLQ	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Glioma susceptibility 1	DISD5L1R	Strong	Genetic Variation	[12]
Microcephaly	DIS2GRD8	Strong	CausalMutation	[6]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[13]
Nervous system neoplasm	DIS141UP	Strong	Biomarker	[5]
Noonan syndrome 2	DISTDKUR	Strong	Autosomal recessive	[14]
Noonan syndrome 4	DISW145E	Strong	Biomarker	[15]
Prader-Willi syndrome	DISYWMLU	Strong	Biomarker	[4]
Robinow syndrome	DISK1CNU	Strong	Biomarker	[4]
Schwannomatosis	DISDWAM1	Strong	Genetic Variation	[5]
Schwannomatosis 1	DISFDUF2	Strong	Biomarker	[16]
Seckel syndrome	DISEVUBA	Strong	Biomarker	[4]
Silver-Russell syndrome	DISSVJ1D	Strong	Biomarker	[4]
Gliosarcoma	DIS985MG	moderate	SomaticCausalMutation	[17]
Hypertrophic cardiomyopathy	DISQG2AI	moderate	Genetic Variation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Leucine-zipper-like transcriptional regulator 1 (LZTR1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Leucine-zipper-like transcriptional regulator 1 (LZTR1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Leucine-zipper-like transcriptional regulator 1 (LZTR1).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Leucine-zipper-like transcriptional regulator 1 (LZTR1).	[22]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Leucine-zipper-like transcriptional regulator 1 (LZTR1).	[23]

References

• [1] 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.
• [2] LZTR1: Genotype Expansion in Noonan Syndrome. Horm Res Paediatr. 2019;92(4):269-275. doi: 10.1159/000502741. Epub 2019 Sep 18.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination.Science. 2018 Dec 7;362(6419):1177-1182. doi: 10.1126/science.aap7607. Epub 2018 Nov 15.
• [5] Oligo-astrocytoma in LZTR1-related Noonan syndrome.Eur J Med Genet. 2020 Jan;63(1):103617. doi: 10.1016/j.ejmg.2019.01.007. Epub 2019 Jan 19.
• [6] Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.Genet Med. 2018 Oct;20(10):1175-1185. doi: 10.1038/gim.2017.249. Epub 2018 Feb 22.
• [7] Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.Hum Genet. 2019 Jan;138(1):21-35. doi: 10.1007/s00439-018-1951-7. Epub 2018 Oct 27.
• [8] Excess of rare, inherited truncating mutations in autism. Nat Genet. 2015 Jun;47(6):582-8. doi: 10.1038/ng.3303. Epub 2015 May 11.
• [9] Personalized Treatment for Small Renal Tumors: Decision Analysis of Competing Causes of Mortality.Radiology. 2019 Mar;290(3):732-743. doi: 10.1148/radiol.2018181114. Epub 2019 Jan 15.
• [10] Isolation and characterization of a novel gene deleted in DiGeorge syndrome.Hum Mol Genet. 1995 Apr;4(4):541-9. doi: 10.1093/hmg/4.4.541.
• [11] Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.Clin Genet. 2019 Jun;95(6):693-703. doi: 10.1111/cge.13533. Epub 2019 Apr 3.
• [12] LZTR1 is a regulator of RAS ubiquitination and signaling.Science. 2018 Dec 7;362(6419):1171-1177. doi: 10.1126/science.aap8210. Epub 2018 Nov 15.
• [13] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [14] PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019 Nov;51(11):1560-1565. doi: 10.1038/s41588-019-0528-2.
• [15] Evaluation of HDPE and LDPE degradation by fungus, implemented by statistical optimization.Sci Rep. 2017 Jan 4;7:39515. doi: 10.1038/srep39515.
• [16] Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.Nat Genet. 2014 Feb;46(2):182-7. doi: 10.1038/ng.2855. Epub 2013 Dec 22.
• [17] Genomics informs glioblastoma biology.Nat Genet. 2013 Oct;45(10):1105-7. doi: 10.1038/ng.2775.
• [18] Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort.Orphanet J Rare Dis. 2019 Feb 7;14(1):29. doi: 10.1186/s13023-019-1010-z.
• [19] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [20] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [21] 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.
• [22] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [23] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.