Details of Drug Off-Target (DOT)

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

• DOT Name: Acetylcholine receptor subunit epsilon (CHRNE)
• Gene Name: CHRNE
• Related Disease:
  Congenital myasthenic syndrome
  Hepatitis B virus infection
  Congenital myasthenic syndrome 4A
  Congenital myasthenic syndrome 4B
  Congenital myasthenic syndrome 4C
  Thrombocytopenia
  Postsynaptic congenital myasthenic syndrome
  Hirschsprung disease
• UniProt ID: ACHE_HUMAN
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MARAPLGVLLLLGLLGRGVGKNEELRLYHHLFNNYDPGSRPVREPEDTVTISLKVTLTNL
  ISLNEKEETLTTSVWIGIDWQDYRLNYSKDDFGGIETLRVPSELVWLPEIVLENNIDGQF
  GVAYDANVLVYEGGSVTWLPPAIYRSVCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFTF
  AVDNDGKTINKIDIDTEAYTENGEWAIDFCPGVIRRHHGGATDGPGETDVIYSLIIRRKP
  LFYVINIIVPCVLISGLVLLAYFLPAQAGGQKCTVSINVLLAQTVFLFLIAQKIPETSLS
  VPLLGRFLIFVMVVATLIVMNCVIVLNVSQRTPTTHAMSPRLRHVLLELLPRLLGSPPPP
  EAPRAASPPRRASSVGLLLRAEELILKKPRSELVFEGQRHRQGTWTAAFCQSLGAAAPEV
  RCCVDAVNFVAESTRDQEATGEEVSDWVRMGNALDNICFWAALVLFSVGSSLIFLGAYFN
  RVPDLPYAPCIQP
• Function: After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway: Highly sodium permeable postsynaptic acetylcholine nicotinic receptors (R-HSA-629587)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myasthenic syndrome	DISJLG2T	Definitive	Autosomal recessive	[1]
Hepatitis B virus infection	DISLQ2XY	Definitive	Genetic Variation	[2]
Congenital myasthenic syndrome 4A	DISO8ZXF	Strong	Autosomal dominant	[3]
Congenital myasthenic syndrome 4B	DISAWB4G	Strong	Autosomal recessive	[3]
Congenital myasthenic syndrome 4C	DISWUJS0	Strong	Autosomal recessive	[3]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[4]
Postsynaptic congenital myasthenic syndrome	DIS92VN2	Supportive	Autosomal recessive	[5]
Hirschsprung disease	DISUUSM1	Limited	Biomarker	[6]

3 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 Acetylcholine receptor subunit epsilon (CHRNE).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Acetylcholine receptor subunit epsilon (CHRNE).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Acetylcholine receptor subunit epsilon (CHRNE).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Acetylcholine receptor subunit epsilon (CHRNE).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Acetylcholine receptor subunit epsilon (CHRNE).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Acetylcholine receptor subunit epsilon (CHRNE).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Acetylcholine receptor subunit epsilon (CHRNE).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Acetylcholine receptor subunit epsilon (CHRNE).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Acetylcholine receptor subunit epsilon (CHRNE).	[12]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Acetylcholine receptor subunit epsilon (CHRNE).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Acetylcholine receptor subunit epsilon (CHRNE).	[16]

References

• [1] Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):758-62. doi: 10.1073/pnas.92.3.758.
• [2] A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population.Hum Mol Genet. 2011 Oct 1;20(19):3884-92. doi: 10.1093/hmg/ddr301. Epub 2011 Jul 12.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.Blood. 2019 Dec 5;134(23):2082-2091. doi: 10.1182/blood.2018891192.
• [5] Congenital Myasthenic Syndromes Overview. 2003 May 9 [updated 2021 Dec 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.
• [6] Familial chronic megacolon presenting in childhood or adulthood: Seeking the presumed gene association.Neurogastroenterol Motil. 2019 Apr;31(4):e13550. doi: 10.1111/nmo.13550. Epub 2019 Jan 20.
• [7] 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.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [14] 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.
• [15] 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.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.