Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXC2UR7)

• DOT Name: Acetylcholine receptor subunit gamma (CHRNG)
• Gene Name: CHRNG
• Related Disease:
  Autosomal recessive multiple pterygium syndrome
  CHRNG-associated hypo-akinesia disorder of prenatal onset
  Bone development disease
  Congenital myasthenic syndrome
  Congenital nervous system disorder
  Lethal multiple pterygium syndrome
  Nicotine dependence
  Postsynaptic congenital myasthenic syndrome
  Refractive error
  Transient neonatal myasthenia gravis
  Arthrogryposis
  Fetal akinesia deformation sequence 1
  Rhabdomyosarcoma
  Amyotrophic lateral sclerosis
• UniProt ID: ACHG_HUMAN
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MHGGQGPLLLLLLLAVCLGAQGRNQEERLLADLMQNYDPNLRPAERDSDVVNVSLKLTLT
  NLISLNEREEALTTNVWIEMQWCDYRLRWDPRDYEGLWVLRVPSTMVWRPDIVLENNVDG
  VFEVALYCNVLVSPDGCIYWLPPAIFRSACSISVTYFPFDWQNCSLIFQSQTYSTNEIDL
  QLSQEDGQTIEWIFIDPEAFTENGEWAIQHRPAKMLLDPAAPAQEAGHQKVVFYLLIQRK
  PLFYVINIIAPCVLISSVAILIHFLPAKAGGQKCTVAINVLLAQTVFLFLVAKKVPETSQ
  AVPLISKYLTFLLVVTILIVVNAVVVLNVSLRSPHTHSMARGVRKVFLRLLPQLLRMHVR
  PLAPAAVQDTQSRLQNGSSGWSITTGEEVALCLPRSELLFQQWQRQGLVAAALEKLEKGP
  ELGLSQFCGSLKQAAPAIQACVEACNLIACARHQQSHFDNGNEEWFLVGRVLDRVCFLAM
  LSLFICGTAGIFLMAHYNRVPALPFPGDPRPYLPSPD
• 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

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive multiple pterygium syndrome	DISVK1D4	Definitive	Autosomal recessive	[1]
CHRNG-associated hypo-akinesia disorder of prenatal onset	DISJWQRD	Definitive	Autosomal recessive	[2]
Bone development disease	DISVKAZS	Strong	Biomarker	[3]
Congenital myasthenic syndrome	DISJLG2T	Strong	Biomarker	[1]
Congenital nervous system disorder	DIS2BIP8	Strong	Genetic Variation	[4]
Lethal multiple pterygium syndrome	DIS668BA	Strong	Autosomal recessive	[1]
Nicotine dependence	DISZD9W7	Strong	Genetic Variation	[5]
Postsynaptic congenital myasthenic syndrome	DIS92VN2	Strong	Biomarker	[1]
Refractive error	DISWNEQ1	Strong	Genetic Variation	[6]
Transient neonatal myasthenia gravis	DISEIP0F	Strong	Autosomal recessive	[7]
Arthrogryposis	DISC81CM	moderate	Genetic Variation	[8]
Fetal akinesia deformation sequence 1	DISKDI9L	moderate	Genetic Variation	[4]
Rhabdomyosarcoma	DISNR7MS	moderate	Altered Expression	[9]
Amyotrophic lateral sclerosis	DISF7HVM	Disputed	Altered Expression	[10]

1 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 gamma (CHRNG).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Acetylcholine receptor subunit gamma (CHRNG).	[12]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Acetylcholine receptor subunit gamma (CHRNG).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Acetylcholine receptor subunit gamma (CHRNG).	[14]

References

• [1] Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit. Am J Hum Genet. 2006 Aug;79(2):303-12. doi: 10.1086/506257. Epub 2006 Jun 20.
• [2] 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.
• [3] Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome. Am J Hum Genet. 2006 Aug;79(2):390-5. doi: 10.1086/506256. Epub 2006 Jun 20.
• [4] CHRNG genotype-phenotype correlations in the multiple pterygium syndromes. J Med Genet. 2012 Jan;49(1):21-6. doi: 10.1136/jmedgenet-2011-100378.
• [5] Multiple cholinergic nicotinic receptor genes affect nicotine dependence risk in African and European Americans.Genes Brain Behav. 2010 Oct;9(7):741-50. doi: 10.1111/j.1601-183X.2010.00608.x. Epub 2010 Jul 22.
• [6] Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.Nat Genet. 2013 Mar;45(3):314-8. doi: 10.1038/ng.2554. Epub 2013 Feb 10.
• [7] 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.
• [8] Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin. J Clin Invest. 2016 Feb;126(2):762-78. doi: 10.1172/JCI84457. Epub 2016 Jan 11.
• [9] PAX--FKHR fusion genes and AChR-gamma in Chinese patients with rhabdomyosarcoma: diagnosis using formalin-fixed archival tissues.Int J Surg Pathol. 2009 Feb;17(1):6-15. doi: 10.1177/1066896908323922. Epub 2008 Nov 6.
• [10] Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis.J Neurol. 2019 Dec;266(12):2952-2961. doi: 10.1007/s00415-019-09507-6. Epub 2019 Aug 27.
• [11] 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.
• [12] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [13] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [14] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.