Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM9RS9G)

• DOT Name: Transmembrane protein 43 (TMEM43)
• Synonyms: Protein LUMA
• Gene Name: TMEM43
• Related Disease:
  Arrhythmogenic right ventricular dysplasia 5
  Brain neoplasm
  Cardiovascular disease
  Emery-Dreifuss muscular dystrophy 2, autosomal dominant
  Myopathy
  Ventricular tachycardia
  Cardiomyopathy
  Dilated cardiomyopathy
  Emery-Dreifuss muscular dystrophy
  Autosomal dominant Emery-Dreifuss muscular dystrophy
  Arrhythmogenic right ventricular cardiomyopathy
  Auditory neuropathy, autosomal dominant 3
  Breast cancer
  Breast carcinoma
  Emery-Dreifuss muscular dystrophy 7, autosomal dominant
• UniProt ID: TMM43_HUMAN
• Pfam ID: PF07787
• Sequence:
  MAANYSSTSTRREHVKVKTSSQPGFLERLSETSGGMFVGLMAFLLSFYLIFTNEGRALKT
  ATSLAEGLSLVVSPDSIHSVAPENEGRLVHIIGALRTSKLLSDPNYGVHLPAVKLRRHVE
  MYQWVETEESREYTEDGQVKKETRYSYNTEWRSEIINSKNFDREIGHKNPSAMAVESFMA
  TAPFVQIGRFFLSSGLIDKVDNFKSLSLSKLEDPHVDIIRRGDFFYHSENPKYPEVGDLR
  VSFSYAGLSGDDPDLGPAHVVTVIARQRGDQLVPFSTKSGDTLLLLHHGDFSAEEVFHRE
  LRSNSMKTWGLRAAGWMAMFMGLNLMTRILYTLVDWFPVFRDLVNIGLKAFAFCVATSLT
  LLTVAAGWLFYRPLWALLIAGLALVPILVARTRVPAKKLE
• Function: May have an important role in maintaining nuclear envelope structure by organizing protein complexes at the inner nuclear membrane. Required for retaining emerin at the inner nuclear membrane. Plays a role in the modulation of innate immune signaling through the cGAS-STING pathway by interacting with RNF26. In addition, functions as a critical signaling component in mediating NF-kappa-B activation by acting downstream of EGFR and upstream of CARD10. Contributes to passive conductance current in cochlear glia-like supporting cells, mediated by gap junctions and necessary for hearing and speech discrimination.
• Tissue Specificity: Highest expression in placenta. Also found at lower levels in heart, ovary, spleen, small intestine, thymus, prostate and testis.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arrhythmogenic right ventricular dysplasia 5	DISXFDU7	Definitive	Autosomal dominant	[1]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[2]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[3]
Emery-Dreifuss muscular dystrophy 2, autosomal dominant	DIS4FT32	Strong	GermlineCausalMutation	[4]
Myopathy	DISOWG27	Strong	Biomarker	[4]
Ventricular tachycardia	DISIBXJ3	Strong	Genetic Variation	[5]
Cardiomyopathy	DISUPZRG	moderate	Genetic Variation	[6]
Dilated cardiomyopathy	DISX608J	moderate	Genetic Variation	[7]
Emery-Dreifuss muscular dystrophy	DISYTPR5	moderate	Genetic Variation	[8]
Autosomal dominant Emery-Dreifuss muscular dystrophy	DISL8GMY	Supportive	Autosomal dominant	[4]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Disputed	Genetic Variation	[9]
Auditory neuropathy, autosomal dominant 3	DIS88LZ1	Limited	Autosomal dominant	[10]
Breast cancer	DIS7DPX1	Limited	Biomarker	[11]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[11]
Emery-Dreifuss muscular dystrophy 7, autosomal dominant	DISTHIJQ	Limited	Autosomal dominant	[4]

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 Transmembrane protein 43 (TMEM43).	[12]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Transmembrane protein 43 (TMEM43).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transmembrane protein 43 (TMEM43).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Transmembrane protein 43 (TMEM43).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Transmembrane protein 43 (TMEM43).	[17]

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 Transmembrane protein 43 (TMEM43).	[16]

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] TMEM43/LUMA is a key signaling component mediating EGFR-induced NF-B activation and tumor progression.Oncogene. 2017 May 18;36(20):2813-2823. doi: 10.1038/onc.2016.430. Epub 2016 Dec 19.
• [3] The role of epigenetic modifications in cardiovascular disease: A systematic review.Int J Cardiol. 2016 Jun 1;212:174-83. doi: 10.1016/j.ijcard.2016.03.062. Epub 2016 Mar 19.
• [4] TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy. Ann Neurol. 2011 Jun;69(6):1005-13. doi: 10.1002/ana.22338. Epub 2011 Mar 9.
• [5] Ventricular tachycardia ablation in arrhythmogenic right ventricular cardiomyopathy patients with TMEM43 gene mutations.J Cardiovasc Electrophysiol. 2018 Jan;29(1):90-97. doi: 10.1111/jce.13353. Epub 2017 Oct 26.
• [6] Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3.Circulation. 2019 Oct;140(14):1188-1204. doi: 10.1161/CIRCULATIONAHA.119.040366. Epub 2019 Sep 5.
• [7] The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus.Eur Heart J. 2015 Apr 7;36(14):872-81. doi: 10.1093/eurheartj/ehu077. Epub 2014 Mar 4.
• [8] Emerin in health and disease.Semin Cell Dev Biol. 2014 May;29:95-106. doi: 10.1016/j.semcdb.2013.12.008. Epub 2013 Dec 21.
• [9] TMEM43-S358L mutation enhances NF-B-TGF signal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy.Protein Cell. 2019 Feb;10(2):104-119. doi: 10.1007/s13238-018-0563-2. Epub 2018 Jul 6.
• [10] 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.
• [11] Global methylation levels in peripheral blood leukocyte DNA by LUMA and breast cancer: a case-control study in Japanese women.Br J Cancer. 2014 May 27;110(11):2765-71. doi: 10.1038/bjc.2014.223. Epub 2014 May 1.
• [12] 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.
• [13] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.