Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0RXMJN)

• DOT Name: cGMP-gated cation channel alpha-1 (CNGA1)
• Synonyms: Cyclic nucleotide-gated cation channel 1; Cyclic nucleotide-gated channel alpha-1; CNG channel alpha-1; CNG-1; CNG1; Cyclic nucleotide-gated channel, photoreceptor; Rod photoreceptor cGMP-gated channel subunit alpha
• Gene Name: CNGA1
• Related Disease:
  CNGA1-related retinopathy
  Retinitis pigmentosa 49
  Retinitis pigmentosa
• UniProt ID: CNGA1_HUMAN
• PDB ID: 7LFT; 7LFW; 7LFX; 7LFY; 7LG1; 7RH9; 7RHG; 7RHH; 7RHI; 7RHJ; 7RHK; 7RHL
• Pfam ID: PF16526 ; PF00027 ; PF00520
• Sequence:
  MKNNIINTQQSFVTMPNVIVPDIEKEIRRMENGACSSFSEDDDSASTSEESENENPHARG
  SFSYKSLRKGGPSQREQYLPGAIALFNVNNSSNKDQEPEEKKKKKKEKKSKSDDKNENKN
  DPEKKKKKKDKEKKKKEEKSKDKKEEEKKEVVVIDPSGNTYYNWLFCITLPVMYNWTMVI
  ARACFDELQSDYLEYWLILDYVSDIVYLIDMFVRTRTGYLEQGLLVKEELKLINKYKSNL
  QFKLDVLSLIPTDLLYFKLGWNYPEIRLNRLLRFSRMFEFFQRTETRTNYPNIFRISNLV
  MYIVIIIHWNACVFYSISKAIGFGNDTWVYPDINDPEFGRLARKYVYSLYWSTLTLTTIG
  ETPPPVRDSEYVFVVVDFLIGVLIFATIVGNIGSMISNMNAARAEFQARIDAIKQYMHFR
  NVSKDMEKRVIKWFDYLWTNKKTVDEKEVLKYLPDKLRAEIAINVHLDTLKKVRIFADCE
  AGLLVELVLKLQPQVYSPGDYICKKGDIGREMYIIKEGKLAVVADDGVTQFVVLSDGSYF
  GEISILNIKGSKAGNRRTANIKSIGYSDLFCLSKDDLMEALTEYPDAKTMLEEKGKQILM
  KDGLLDLNIANAGSDPKDLEEKVTRMEGSVDLLQTRFARILAEYESMQQKLKQRLTKVEK
  FLKPLIDTEFSSIEGPGAESGPIDST
• Function: Subunit of the rod cyclic GMP-gated cation channel, which is involved in the final stage of the phototransduction pathway. When light hits rod photoreceptors, cGMP concentrations decrease causing rapid closure of CNGA1/CNGB1 channels and, therefore, hyperpolarization of the membrane potential.
• Tissue Specificity: Rod cells in the retina.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Phototransduction (hsa04744)
• Reactome Pathway:
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  Activation of the phototransduction cascade (R-HSA-2485179)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
CNGA1-related retinopathy	DISJTA9T	Definitive	Autosomal recessive	[1]
Retinitis pigmentosa 49	DISRDSES	Definitive	Autosomal recessive	[2]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[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 cGMP-gated cation channel alpha-1 (CNGA1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of cGMP-gated cation channel alpha-1 (CNGA1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of cGMP-gated cation channel alpha-1 (CNGA1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of cGMP-gated cation channel alpha-1 (CNGA1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of cGMP-gated cation channel alpha-1 (CNGA1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of cGMP-gated cation channel alpha-1 (CNGA1).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of cGMP-gated cation channel alpha-1 (CNGA1).	[8]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of cGMP-gated cation channel alpha-1 (CNGA1).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of cGMP-gated cation channel alpha-1 (CNGA1).	[11]

References

• [1] 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.
• [2] Autosomal recessive retinitis pigmentosa in a Pakistani family mapped to CNGA1 with identification of a novel mutation. Mol Vis. 2004 Nov 17;10:884-9.
• [3] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. 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] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Progestins regulate genes that can elicit both proliferative and antiproliferative effects in breast cancer cells. Oncol Rep. 2008 Jun;19(6):1627-34.
• [9] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [10] 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.
• [11] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [12] 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.