Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLUUP7C)

• DOT Name: Acetylcholine receptor subunit delta (CHRND)
• Gene Name: CHRND
• Related Disease:
  Congenital myasthenic syndrome 3A
  Congenital myasthenic syndrome 3B
  Congenital myasthenic syndrome 3C
  LambertEaton myasthenic syndrome
  Lethal multiple pterygium syndrome
  Neuromuscular disease
  Nicotine dependence
  Fetal akinesia deformation sequence 1
  Postsynaptic congenital myasthenic syndrome
  Congenital myasthenic syndrome
  Myasthenia gravis
• UniProt ID: ACHD_HUMAN
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MEGPVLTLGLLAALAVCGSWGLNEEERLIRHLFQEKGYNKELRPVAHKEESVDVALALTL
  SNLISLKEVEETLTTNVWIEHGWTDNRLKWNAEEFGNISVLRLPPDMVWLPEIVLENNND
  GSFQISYSCNVLVYHYGFVYWLPPAIFRSSCPISVTYFPFDWQNCSLKFSSLKYTAKEIT
  LSLKQDAKENRTYPVEWIIIDPEGFTENGEWEIVHRPARVNVDPRAPLDSPSRQDITFYL
  IIRRKPLFYIINILVPCVLISFMVNLVFYLPADSGEKTSVAISVLLAQSVFLLLISKRLP
  ATSMAIPLIGKFLLFGMVLVTMVVVICVIVLNIHFRTPSTHVLSEGVKKLFLETLPELLH
  MSRPAEDGPSPGALVRRSSSLGYISKAEEYFLLKSRSDLMFEKQSERHGLARRLTTARRP
  PASSEQAQQELFNELKPAVDGANFIVNHMRDQNNYNEEKDSWNRVARTVDRLCLFVVTPV
  MVVGTAWIFLQGVYNQPPPQPFPGDPYSYNVQDKRFI
• 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

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myasthenic syndrome 3A	DISCEFP2	Strong	Autosomal dominant	[1]
Congenital myasthenic syndrome 3B	DISCENXT	Strong	Autosomal recessive	[1]
Congenital myasthenic syndrome 3C	DISL15RW	Strong	Autosomal recessive	[1]
LambertEaton myasthenic syndrome	DISN0Q7Q	Strong	Genetic Variation	[2]
Lethal multiple pterygium syndrome	DIS668BA	Strong	Autosomal recessive	[3]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[4]
Nicotine dependence	DISZD9W7	Strong	Genetic Variation	[5]
Fetal akinesia deformation sequence 1	DISKDI9L	moderate	Biomarker	[6]
Postsynaptic congenital myasthenic syndrome	DIS92VN2	Supportive	Autosomal recessive	[7]
Congenital myasthenic syndrome	DISJLG2T	Limited	Genetic Variation	[2]
Myasthenia gravis	DISELRCI	Limited	Genetic Variation	[8]

4 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 delta (CHRND).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Acetylcholine receptor subunit delta (CHRND).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Acetylcholine receptor subunit delta (CHRND).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Acetylcholine receptor subunit delta (CHRND).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Acetylcholine receptor subunit delta (CHRND).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Acetylcholine receptor subunit delta (CHRND).	[13]

References

• [1] 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.
• [2] New compound heterozygous variants of the cholinergic receptor nicotinic delta subunit gene in a Chinese male with congenital myasthenic syndrome: A case report.Medicine (Baltimore). 2017 Dec;96(51):e8981. doi: 10.1097/MD.0000000000008981.
• [3] Acetylcholine receptor delta subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita. J Clin Invest. 2001 Jul;108(1):125-30. doi: 10.1172/JCI12935.
• [4] Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth.Orphanet J Rare Dis. 2015 Nov 17;10:148. doi: 10.1186/s13023-015-0364-0.
• [5] Peer smoking and the nicotinic receptor genes: an examination of genetic and environmental risks for nicotine dependence.Addiction. 2010 Nov;105(11):2014-22. doi: 10.1111/j.1360-0443.2010.03074.x. Epub 2010 Sep 15.
• [6] Germline mutation in DOK7 associated with fetal akinesia deformation sequence. J Med Genet. 2009 May;46(5):338-40. doi: 10.1136/jmg.2008.065425. Epub 2009 Mar 3.
• [7] 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.
• [8] Association of the gene encoding the delta-subunit of the muscle acetylcholine receptor (CHRND) with acquired autoimmune myasthenia gravis.Genes Immun. 2004 Jan;5(1):80-3. doi: 10.1038/sj.gene.6364041.
• [9] 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.
• [10] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [11] 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.
• [12] 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.
• [13] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [14] 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.