Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0YLT7L)

• DOT Name: LEM domain-containing protein 2 (LEMD2)
• Synonyms: hLEM2
• Gene Name: LEMD2
• Related Disease:
  Cataract 46 juvenile-onset
  Hutchinson-Gilford progeria syndrome
  Marbach-Rustad progeroid syndrome
  Matthew-Wood syndrome
  Neoplasm
  Schizophrenia
  Early-onset posterior subcapsular cataract
  Total early-onset cataract
  Neuroblastoma
  Emery-Dreifuss muscular dystrophy
• UniProt ID: LEMD2_HUMAN
• Pfam ID: PF03020 ; PF09402
• Sequence:
  MAGLSDLELRRELQALGFQPGPITDTTRDVYRNKLRRLRGEARLRDEERLREEARPRGEE
  RLREEARLREDAPLRARPAAASPRAEPWLSQPASGSAYATPGAYGDIRPSAASWVGSRGL
  AYPARPAQLRRRASVRGSSEEDEDARTPDRATQGPGLAARRWWAASPAPARLPSSLLGPD
  PRPGLRATRAGPAGAARARPEVGRRLERWLSRLLLWASLGLLLVFLGILWVKMGKPSAPQ
  EAEDNMKLLPVDCERKTDEFCQAKQKAALLELLHELYNFLAIQAGNFECGNPENLKSKCI
  PVMEAQEYIANVTSSSSAKFEAALTWILSSNKDVGIWLKGEDQSELVTTVDKVVCLESAH
  PRMGVGCRLSRALLTAVTNVLIFFWCLAFLWGLLILLKYRWRKLEEEEQAMYEMVKKIID
  VVQDHYVDWEQDMERYPYVGILHVRDSLIPPQSRRRMKRVWDRAVEFLASNESRIQTESH
  RVAGEDMLVWRWTKPSSFSDSER
• Function: Nuclear lamina-associated inner nuclear membrane protein that is involved in nuclear structure organization, maintenance of nuclear envelope (NE) integrity and NE reformation after mitosis. Plays a role as transmembrane adapter for the endosomal sorting complexes required for transport (ESCRT), and is thereby involved in ESCRT-mediated NE reformation. Promotes ESCRT-mediated NE closure by recruiting CHMP7 and downstream ESCRT-III proteins IST1/CHMP8 and CHMP2A to the reforming NE during anaphase. During nuclear reassembly, condenses into a liquid-like coating around microtubule spindles and coassembles with CHMP7 to form a macromolecular O-ring seal at the confluence between membranes, chromatin, and the spindle to facilitate early nuclear sealing. Plays a role in the organization of heterochromatin associated with the NE and in the maintenance of NE organization under mechanical stress. Required for embryonic development and involved in regulation of several signaling pathways such as MAPK and AKT. Required for myoblast differentiation involving regulation of ERK signaling. Essential for cardiac homeostasis and proper heart function.
• Tissue Specificity: Ubiquitously expressed, including bone marrow, brain, kidney, colon, skeletal muscle, thymus, testis and uterus.
• Reactome Pathway:
  Initiation of Nuclear Envelope (NE) Reformation (R-HSA-2995383)
  Depolymerization of the Nuclear Lamina (R-HSA-4419969)
  Sealing of the nuclear envelope (NE) by ESCRT-III (R-HSA-9668328)
  Nuclear Envelope Breakdown (R-HSA-2980766)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract 46 juvenile-onset	DISPMBTP	Strong	Autosomal recessive	[1]
Hutchinson-Gilford progeria syndrome	DISY55BU	Strong	Genetic Variation	[2]
Marbach-Rustad progeroid syndrome	DISH0TNR	Strong	Autosomal dominant	[3]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[5]
Early-onset posterior subcapsular cataract	DISB7SJS	Supportive	Autosomal dominant	[1]
Total early-onset cataract	DISACMEZ	Supportive	Autosomal dominant	[1]
Neuroblastoma	DISVZBI4	Disputed	Biomarker	[6]
Emery-Dreifuss muscular dystrophy	DISYTPR5	Limited	Genetic Variation	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	LEM domain-containing protein 2 (LEMD2) affects the response to substance of Mitoxantrone.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of LEM domain-containing protein 2 (LEMD2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of LEM domain-containing protein 2 (LEMD2).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of LEM domain-containing protein 2 (LEMD2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of LEM domain-containing protein 2 (LEMD2).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of LEM domain-containing protein 2 (LEMD2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of LEM domain-containing protein 2 (LEMD2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of LEM domain-containing protein 2 (LEMD2).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of LEM domain-containing protein 2 (LEMD2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of LEM domain-containing protein 2 (LEMD2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of LEM domain-containing protein 2 (LEMD2).	[14]

References

• [1] Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death. Mol Genet Genomic Med. 2015 Nov 14;4(1):77-94. doi: 10.1002/mgg3.181. eCollection 2016 Jan.
• [2] The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping.Am J Hum Genet. 2019 Apr 4;104(4):749-757. doi: 10.1016/j.ajhg.2019.02.021. Epub 2019 Mar 21.
• [3] Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017 Feb 23;542(7642):433-438. doi: 10.1038/nature21062. Epub 2017 Jan 25.
• [4] MT1-MMP as a PET Imaging Biomarker for Pancreas Cancer Management.Contrast Media Mol Imaging. 2018 Aug 26;2018:8382148. doi: 10.1155/2018/8382148. eCollection 2018.
• [5] 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.
• [6] New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma.Cancer Lett. 2019 Apr 1;446:90-102. doi: 10.1016/j.canlet.2019.01.014. Epub 2019 Jan 19.
• [7] Ce-emerin and LEM-2: essential roles in Caenorhabditis elegans development, muscle function, and mitosis.Mol Biol Cell. 2012 Feb;23(4):543-52. doi: 10.1091/mbc.E11-06-0505. Epub 2011 Dec 14.
• [8] 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.
• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [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] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.