Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSGKO5M)

• DOT Name: Selenoprotein N (SELENON)
• Synonyms: SelN
• Gene Name: SELENON
• Related Disease:
  Rectal carcinoma
  Rigid spine muscular dystrophy 1
  SELENON-related myopathy
  Central core myopathy
  Congenital multicore myopathy with external ophthalmoplegia
  Congenital muscular dystrophy
  Congenital myopathy
  Congenital myopathy 4A, autosomal dominant
  Malignant hyperthermia of anesthesia
  Multiminicore myopathy
  Myopathy
  Neuromuscular disease
  Breast cancer
  Breast carcinoma
  Congenital fiber-type disproportion myopathy
  Desmin-related myopathy with Mallory body-like inclusions
  Rigid spine syndrome
  Respiratory failure
  Arrhythmia
  Cap myopathy
  Congenital myopathy 7A, myosin storage, autosomal dominant
  Muscular dystrophy
  Zebra body myopathy
• UniProt ID: SELN_HUMAN
• Sequence:
  MGRARPGQRGPPSPGPAAQPPAPPRRRARSLALLGALLAAAAAAAVRVCARHAEAQAAAR
  QELALKTLGTDGLFLFSSLDTDGDMYISPEEFKPIAEKLTGSCSVTQTGVQWCSHSSLQP
  QLPWLNUSSCLSLLRSTPAASCEEEELPPDPSEETLTIEARFQPLLPETMTKSKDGFLGV
  SRLALSGLRNWTAAASPSAVFATRHFQPFLPPPGQELGEPWWIIPSELSMFTGYLSNNRF
  YPPPPKGKEVIIHRLLSMFHPRPFVKTRFAPQGAVACLTAISDFYYTVMFRIHAEFQLSE
  PPDFPFWFSPAQFTGHIILSKDATHVRDFRLFVPNHRSLNVDMEWLYGASESSNMEVDIG
  YIPQMELEATGPSVPSVILDEDGSMIDSHLPSGEPLQFVFEEIKWQQELSWEEAARRLEV
  AMYPFKKVSYLPFTEAFDRAKAENKLVHSILLWGALDDQSCUGSGRTLRETVLESSPILT
  LLNESFISTWSLVKELEELQNNQENSSHQKLAGLHLEKYSFPVEMMICLPNGTVVHHINA
  NYFLDITSVKPEEIESNLFSFSSTFEDPSTATYMQFLKEGLRRGLPLLQP
• Function: [Isoform 2]: Plays an important role in cell protection against oxidative stress and in the regulation of redox-related calcium homeostasis. Regulates the calcium level of the ER by protecting the calcium pump ATP2A2 against the oxidoreductase ERO1A-mediated oxidative damage. Within the ER, ERO1A activity increases the concentration of H(2)O(2), which attacks the luminal thiols in ATP2A2 and thus leads to cysteinyl sulfenic acid formation (-SOH) and SEPN1 reduces the SOH back to free thiol (-SH), thus restoring ATP2A2 activity. Acts as a modulator of ryanodine receptor (RyR) activity: protects RyR from oxidation due to increased oxidative stress, or directly controls the RyR redox state, regulating the RyR-mediated calcium mobilization required for normal muscle development and differentiation ; Essential for muscle regeneration and satellite cell maintenance in skeletal muscle.
• Tissue Specificity: Isoform 1 and isoform 2 are expressed in skeletal muscle, brain, lung and placenta. Isoform 2 is also expressed in heart, diaphragm and stomach.

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rectal carcinoma	DIS8FRR7	Definitive	Genetic Variation	[1]
Rigid spine muscular dystrophy 1	DISHZE8T	Definitive	Biomarker	[2]
SELENON-related myopathy	DISKAULK	Definitive	Autosomal recessive	[3]
Central core myopathy	DIS18AZZ	Strong	Genetic Variation	[4]
Congenital multicore myopathy with external ophthalmoplegia	DIS39ELI	Strong	Genetic Variation	[5]
Congenital muscular dystrophy	DISKY7OY	Strong	Genetic Variation	[6]
Congenital myopathy	DISLSK9G	Strong	Biomarker	[2]
Congenital myopathy 4A, autosomal dominant	DISU53TI	Strong	Autosomal recessive	[7]
Malignant hyperthermia of anesthesia	DISYC9XI	Strong	Genetic Variation	[8]
Multiminicore myopathy	DISE6VYN	Strong	Genetic Variation	[5]
Myopathy	DISOWG27	Strong	Genetic Variation	[2]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[9]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[10]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[10]
Congenital fiber-type disproportion myopathy	DISU9T2M	Supportive	Autosomal dominant	[11]
Desmin-related myopathy with Mallory body-like inclusions	DISR27TF	Supportive	Autosomal recessive	[12]
Rigid spine syndrome	DISA1BDS	Supportive	Autosomal recessive	[13]
Respiratory failure	DISVMYJO	Disputed	Genetic Variation	[14]
Arrhythmia	DISFF2NI	Limited	Genetic Variation	[15]
Cap myopathy	DIS4S4WQ	Limited	Biomarker	[16]
Congenital myopathy 7A, myosin storage, autosomal dominant	DISUV37B	Limited	Genetic Variation	[16]
Muscular dystrophy	DISJD6P7	Limited	Genetic Variation	[17]
Zebra body myopathy	DISMCSNK	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Selenoprotein N (SELENON).	[18]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Selenoprotein N (SELENON).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Selenoprotein N (SELENON).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Selenoprotein N (SELENON).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Selenoprotein N (SELENON).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Selenoprotein N (SELENON).	[23]

References

• [1] Genetic variation in selenoprotein genes, lifestyle, and risk of colon and rectal cancer.PLoS One. 2012;7(5):e37312. doi: 10.1371/journal.pone.0037312. Epub 2012 May 17.
• [2] SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance.Redox Biol. 2019 Jun;24:101176. doi: 10.1016/j.redox.2019.101176. Epub 2019 Mar 23.
• [3] 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.
• [4] Mutations in MYH7 cause Multi-minicore Disease (MmD) with variable cardiac involvement.Neuromuscul Disord. 2012 Dec;22(12):1096-104. doi: 10.1016/j.nmd.2012.06.007. Epub 2012 Jul 10.
• [5] Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related myopathies.Hum Mutat. 2019 Jul;40(7):962-974. doi: 10.1002/humu.23745. Epub 2019 Apr 1.
• [6] Prevalence of congenital muscular dystrophy in Italy: a population study.Neurology. 2015 Mar 3;84(9):904-11. doi: 10.1212/WNL.0000000000001303. Epub 2015 Feb 4.
• [7] Satellite cell loss and impaired muscle regeneration in selenoprotein N deficiency. Hum Mol Genet. 2011 Feb 15;20(4):694-704. doi: 10.1093/hmg/ddq515. Epub 2010 Dec 2.
• [8] Multi-minicore Disease.Orphanet J Rare Dis. 2007 Jul 13;2:31. doi: 10.1186/1750-1172-2-31.
• [9] Selenoprotein function and muscle disease.Biochim Biophys Acta. 2009 Nov;1790(11):1569-74. doi: 10.1016/j.bbagen.2009.03.002. Epub 2009 Mar 11.
• [10] SEPP1 influences breast cancer risk among women with greater native american ancestry: the breast cancer health disparities study.PLoS One. 2013 Nov 20;8(11):e80554. doi: 10.1371/journal.pone.0080554. eCollection 2013.
• [11] Congenital Fiber-Type Disproportion C RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2007 Jan 12 [updated 2013 Apr 11]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [12] Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene. Ann Neurol. 2004 May;55(5):676-86. doi: 10.1002/ana.20077.
• [13] Congenital Muscular Dystrophy Overview C RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2001 Jan 22 [updated 2012 Aug 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [14] SEPN1-related myopathy in three patients: novel mutations and diagnostic clues.Eur J Pediatr. 2016 Aug;175(8):1113-8. doi: 10.1007/s00431-015-2685-3. Epub 2016 Jan 16.
• [15] Risk of arrhythmia in type I myotonic dystrophy: the role of clinical and genetic variables.J Neurol Neurosurg Psychiatry. 2009 Jul;80(7):790-3. doi: 10.1136/jnnp.2008.162594. Epub 2009 Feb 22.
• [16] Congenital myopathies.Curr Opin Neurol. 2007 Oct;20(5):583-9. doi: 10.1097/WCO.0b013e3282ef6e69.
• [17] A novel mutation in SEPN1 causing rigid spine muscular dystrophy 1: a Case report.BMC Med Genet. 2019 Jan 14;20(1):13. doi: 10.1186/s12881-018-0743-1.
• [18] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [19] 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.
• [20] 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.
• [21] 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.
• [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.
• [23] 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.