Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2Z2TCB)

• DOT Name: Acetylcholine receptor subunit alpha (CHRNA1)
• Gene Name: CHRNA1
• Related Disease:
  Congenital myasthenic syndrome 1A
  Lethal multiple pterygium syndrome
  Myasthenic syndrome, congenital, 1B, fast-channel
  Postsynaptic congenital myasthenic syndrome
• UniProt ID: ACHA_HUMAN
• PDB ID: 4ZJS; 5HBT
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MEPWPLLLLFSLCSAGLVLGSEHETRLVAKLFKDYSSVVRPVEDHRQVVEVTVGLQLIQL
  INVDEVNQIVTTNVRLKQQWVDYNLKWNPDDYGGVKKIHIPSEKIWRPDLVLYNNADGDF
  AIVKFTKVLLQYTGHITWTPPAIFKSYCEIIVTHFPFDEQNCSMKLGTWTYDGSVVAINP
  ESDQPDLSNFMESGEWVIKESRGWKHSVTYSCCPDTPYLDITYHFVMQRLPLYFIVNVII
  PCLLFSFLTGLVFYLPTDSGEKMTLSISVLLSLTVFLLVIVELIPSTSSAVPLIGKYMLF
  TMVFVIASIIITVIVINTHHRSPSTHVMPNWVRKVFIDTIPNIMFFSTMKRPSREKQDKK
  IFTEDIDISDISGKPGPPPMGFHSPLIKHPEVKSAIEGIKYIAETMKSDQESNNAAAEWK
  YVAMVMDHILLGVFMLVCIIGTLAVFAGRLIELNQQG
• Function: [Isoform 1]: Upon acetylcholine binding, 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; [Isoform 2]: Non functional acetylcholine receptor alpha subunit which is not integrated into functional acetylcholine-gated cation-selective channels.
• Tissue Specificity: Isoform 1 is only expressed in skeletal muscle. Isoform 2 is constitutively expressed in skeletal muscle, brain, heart, kidney, liver, lung and thymus.
• KEGG Pathway:
  Virion - Ebolavirus and Lyssavirus (hsa03265)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  Highly calcium permeable nicotinic acetylcholine receptors (R-HSA-629597)
  Highly calcium permeable postsynaptic nicotinic acetylcholine receptors (R-HSA-629594)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myasthenic syndrome 1A	DIS4PQM3	Strong	Autosomal dominant	[1]
Lethal multiple pterygium syndrome	DIS668BA	Strong	Autosomal recessive	[2]
Myasthenic syndrome, congenital, 1B, fast-channel	DISOANDX	Strong	Autosomal dominant	[1]
Postsynaptic congenital myasthenic syndrome	DIS92VN2	Supportive	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Acetylcholine receptor subunit alpha (CHRNA1).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Acetylcholine receptor subunit alpha (CHRNA1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Acetylcholine receptor subunit alpha (CHRNA1).	[6]

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] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] 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.
• [4] 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.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] 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.