Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTILAM4I)

• DOT Name: Inner nuclear membrane protein Man1 (LEMD3)
• Synonyms: LEM domain-containing protein 3
• Gene Name: LEMD3
• Related Disease:
  Bone disease
  Buschke-Ollendorff syndrome
  Melorheostosis
  Bone development disease
  Congenital disorder of glycosylation
  Hyperostosis
  Megalencephaly
  Non-small-cell lung cancer
  Osteochondrodysplasia
  PMM2-congenital disorder of glycosylation
  Refractory multiple myeloma
  Skeletal dysplasia
  Skin disease
  Venous thromboembolism
  X-linked Emery-Dreifuss muscular dystrophy
  Isolated osteopoikilosis
  Melorheostosis with osteopoikilosis
  Achondroplasia
  Emery-Dreifuss muscular dystrophy
• UniProt ID: MAN1_HUMAN
• PDB ID: 2CH0; 5ZOJ; 5ZOK
• Pfam ID: PF03020 ; PF09402
• Sequence:
  MAAAAASAPQQLSDEELFSQLRRYGLSPGPVTESTRPVYLKKLKKLREEEQQQHRSGGRG
  NKTRNSNNNNTAAATVAAAGPAAAAAAGMGVRPVSGDLSYLRTPGGLCRISASGPESLLG
  GPGGASAAPAAGSKVLLGFSSDESDVEASPRDQAGGGGRKDRASLQYRGLKAPPAPLAAS
  EVTNSNSAERRKPHSWWGARRPAGPELQTPPGKDGAVEDEEGEGEDGEERDPETEEPLWA
  SRTVNGSRLVPYSCRENYSDSEEEDDDDVASSRQVLKDDSLSRHRPRRTHSKPLPPLTAK
  SAGGRLETSVQGGGGLAMNDRAAAAGSLDRSRNLEEAAAAEQGGGCDQVDSSPVPRYRVN
  AKKLTPLLPPPLTDMDSTLDSSTGSLLKTNNHIGGGAFSVDSPRIYSNSLPPSAAVAASS
  SLRINHANHTGSNHTYLKNTYNKPKLSEPEEELLQQFKREEVSPTGSFSAHYLSMFLLTA
  ACLFFLILGLTYLGMRGTGVSEDGELSIENPFGETFGKIQESEKTLMMNTLYKLHDRLAQ
  LAGDHECGSSSQRTLSVQEAAAYLKDLGPEYEGIFNTSLQWILENGKDVGIRCVGFGPEE
  ELTNITDVQFLQSTRPLMSFWCRFRRAFVTVTHRLLLLCLGVVMVCVVLRYMKYRWTKEE
  EETRQMYDMVVKIIDVLRSHNEACQENKDLQPYMPIPHVRDSLIQPHDRKKMKKVWDRAV
  DFLAANESRVRTETRRIGGADFLVWRWIQPSASCDKILVIPSKVWQGQAFHLDRRNSPPN
  SLTPCLKIRNMFDPVMEIGDQWHLAIQEAILEKCSDNDGIVHIAVDKNSREGCVYVKCLS
  PEYAGKAFKALHGSWFDGKLVTVKYLRLDRYHHRFPQALTSNTPLKPSNKHMNSMSHLRL
  RTGLTNSQGSS
• Function: Can function as a specific repressor of TGF-beta, activin, and BMP signaling through its interaction with the R-SMAD proteins. Antagonizes TGF-beta-induced cell proliferation arrest.
• Tissue Specificity: Heart, brain, placenta, lung, liver and skeletal muscle.
• Reactome Pathway:
  Initiation of Nuclear Envelope (NE) Reformation (R-HSA-2995383)
  Depolymerization of the Nuclear Lamina (R-HSA-4419969)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOG GTPase cycle (R-HSA-9013408)
  RAC3 GTPase cycle (R-HSA-9013423)
  RND3 GTPase cycle (R-HSA-9696264)
  RND2 GTPase cycle (R-HSA-9696270)
  RND1 GTPase cycle (R-HSA-9696273)
  Nuclear Envelope Breakdown (R-HSA-2980766)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone disease	DISE1F82	Definitive	Genetic Variation	[1]
Buschke-Ollendorff syndrome	DIS9J6VP	Definitive	Autosomal dominant	[2]
Melorheostosis	DISIMCL3	Definitive	Autosomal dominant	[3]
Bone development disease	DISVKAZS	Strong	Biomarker	[4]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[5]
Hyperostosis	DIS60EOE	Strong	Genetic Variation	[6]
Megalencephaly	DISYW5SV	Strong	Genetic Variation	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[8]
Osteochondrodysplasia	DIS9SPWW	Strong	Genetic Variation	[9]
PMM2-congenital disorder of glycosylation	DISZRBCA	Strong	Genetic Variation	[5]
Refractory multiple myeloma	DIS606GH	Strong	Genetic Variation	[10]
Skeletal dysplasia	DIS5Z8U6	Strong	Genetic Variation	[9]
Skin disease	DISDW8R6	Strong	Genetic Variation	[11]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[12]
X-linked Emery-Dreifuss muscular dystrophy	DISDPMZ3	Strong	Genetic Variation	[13]
Isolated osteopoikilosis	DIS3ITB6	Supportive	Autosomal dominant	[14]
Melorheostosis with osteopoikilosis	DISNQG58	Supportive	Autosomal dominant	[15]
Achondroplasia	DISYWN2O	Limited	Genetic Variation	[7]
Emery-Dreifuss muscular dystrophy	DISYTPR5	Limited	Biomarker	[16]

4 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 Inner nuclear membrane protein Man1 (LEMD3).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inner nuclear membrane protein Man1 (LEMD3).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Inner nuclear membrane protein Man1 (LEMD3).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Inner nuclear membrane protein Man1 (LEMD3).	[20]

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 Inner nuclear membrane protein Man1 (LEMD3).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Inner nuclear membrane protein Man1 (LEMD3).	[22]

References

• [1] Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke-Ollendorff syndrome, but not sporadic melorheostosis.J Bone Miner Res. 2007 Feb;22(2):243-50. doi: 10.1359/jbmr.061102.
• [2] Melorheostosis in a patient with familial osteopoikilosis. Am J Med Genet. 1997 Oct 3;72(1):43-6. doi: 10.1002/(sici)1096-8628(19971003)72:1<43::aid-ajmg9>3.0.co;2-w.
• [3] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [4] Novel Somatic Mutation in LEMD3 Splice Site Results in Buschke-Ollendorff Syndrome with Polyostotic Melorheostosis and Osteopoikilosis.Pediatr Dermatol. 2015 Sep-Oct;32(5):e219-20. doi: 10.1111/pde.12634. Epub 2015 Jul 2.
• [5] N-glycosylation deficiency reduces ICAM-1 induction and impairs inflammatory response.Glycobiology. 2014 Apr;24(4):392-8. doi: 10.1093/glycob/cwu006. Epub 2014 Jan 28.
• [6] The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation.J Cell Biochem. 2017 Dec;118(12):4425-4435. doi: 10.1002/jcb.26096. Epub 2017 Jul 31.
• [7] Mutations of the fibroblast growth factor receptor-3 gene in achondroplasia.Horm Res. 1996;45(1-2):108-10. doi: 10.1159/000184768.
• [8] Wnt signaling pathway pharmacogenetics in non-small cell lung cancer.Pharmacogenomics J. 2014 Dec;14(6):509-22. doi: 10.1038/tpj.2014.21. Epub 2014 Jul 1.
• [9] Melorheostosis: Exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS.Bone. 2017 Aug;101:145-155. doi: 10.1016/j.bone.2017.04.010. Epub 2017 Apr 21.
• [10] Osteopoikilosis and multiple exostoses caused by novel mutations in LEMD3 and EXT1 genes respectively--coincidence within one family.BMC Med Genet. 2010 Jul 9;11:110. doi: 10.1186/1471-2350-11-110.
• [11] Essential roles of LEM-domain protein MAN1 during organogenesis in Xenopus laevis and overlapping functions of emerin.Eur J Cell Biol. 2013 Aug-Sep;92(8-9):280-94. doi: 10.1016/j.ejcb.2013.10.008. Epub 2013 Nov 1.
• [12] Identification of unique venous thromboembolism-susceptibility variants in African-Americans.Thromb Haemost. 2017 Apr 3;117(4):758-768. doi: 10.1160/TH16-08-0652. Epub 2017 Feb 16.
• [13] Muscular Dystrophy Mutations Impair the Nuclear Envelope Emerin Self-assembly Properties.ACS Chem Biol. 2015 Dec 18;10(12):2733-42. doi: 10.1021/acschembio.5b00648. Epub 2015 Oct 5.
• [14] Identification of a novel LEMD3 Y871X mutation in a three-generation family with osteopoikilosis and review of the literature. J Endocrinol Invest. 2016 Jun;39(6):679-85. doi: 10.1007/s40618-015-0419-z. Epub 2015 Dec 22.
• [15] Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet. 2004 Nov;36(11):1213-8. doi: 10.1038/ng1453. Epub 2004 Oct 17.
• [16] MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in Caenorhabditis elegans.Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4598-603. doi: 10.1073/pnas.0730821100. Epub 2003 Apr 8.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] 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.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] 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.
• [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] 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.