Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYQ7TYM)

• DOT Name: Cyclic nucleotide-gated cation channel alpha-3 (CNGA3)
• Synonyms: Cone photoreceptor cGMP-gated channel subunit alpha; Cyclic nucleotide-gated channel alpha-3; CNG channel alpha-3; CNG-3; CNG3
• Gene Name: CNGA3
• Related Disease:
  Achromatopsia 2
  CNGA3-related retinopathy
  Achromatopsia
  Cone-rod dystrophy
  Leber congenital amaurosis 9
• UniProt ID: CNGA3_HUMAN
• PDB ID: 3SWY; 7RHS; 8ETP; 8EU3; 8EUC; 8EV8; 8EV9; 8EVA; 8EVB; 8EVC
• Pfam ID: PF16526 ; PF00027 ; PF00520
• Sequence:
  MAKINTQYSHPSRTHLKVKTSDRDLNRAENGLSRAHSSSEETSSVLQPGIAMETRGLADS
  GQGSFTGQGIARLSRLIFLLRRWAARHVHHQDQGPDSFPDRFRGAELKEVSSQESNAQAN
  VGSQEPADRGRSAWPLAKCNTNTSNNTEEEKKTKKKDAIVVDPSSNLYYRWLTAIALPVF
  YNWYLLICRACFDELQSEYLMLWLVLDYSADVLYVLDVLVRARTGFLEQGLMVSDTNRLW
  QHYKTTTQFKLDVLSLVPTDLAYLKVGTNYPEVRFNRLLKFSRLFEFFDRTETRTNYPNM
  FRIGNLVLYILIIIHWNACIYFAISKFIGFGTDSWVYPNISIPEHGRLSRKYIYSLYWST
  LTLTTIGETPPPVKDEEYLFVVVDFLVGVLIFATIVGNVGSMISNMNASRAEFQAKIDSI
  KQYMQFRKVTKDLETRVIRWFDYLWANKKTVDEKEVLKSLPDKLKAEIAINVHLDTLKKV
  RIFQDCEAGLLVELVLKLRPTVFSPGDYICKKGDIGKEMYIINEGKLAVVADDGVTQFVV
  LSDGSYFGEISILNIKGSKSGNRRTANIRSIGYSDLFCLSKDDLMEALTEYPEAKKALEE
  KGRQILMKDNLIDEELARAGADPKDLEEKVEQLGSSLDTLQTRFARLLAEYNATQMKMKQ
  RLSQLESQVKGGGDKPLADGEVPGDATKTEDKQQ
• Function: Visual signal transduction is mediated by a G-protein coupled cascade using cGMP as second messenger. This protein can be activated by cyclic GMP which leads to an opening of the cation channel and thereby causing a depolarization of cone photoreceptors. Induced a flickering channel gating, weakened the outward rectification in the presence of extracellular calcium, increased sensitivity for L-cis diltiazem and enhanced the cAMP efficacy of the channel when coexpressed with CNGB3. Essential for the generation of light-evoked electrical responses in the red-, green- and blue sensitive cones.
• Tissue Specificity: Prominently expressed in retina.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Olfactory transduction (hsa04740)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Achromatopsia 2	DIS4ZTNS	Definitive	Autosomal recessive	[1]
CNGA3-related retinopathy	DISHSSLI	Definitive	Autosomal recessive	[2]
Achromatopsia	DISKL51I	Supportive	Autosomal recessive	[3]
Cone-rod dystrophy	DISY9RWN	Supportive	Autosomal dominant	[4]
Leber congenital amaurosis 9	DIS35YGW	Limited	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cyclic nucleotide-gated cation channel alpha-3 (CNGA3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cyclic nucleotide-gated cation channel alpha-3 (CNGA3).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cyclic nucleotide-gated cation channel alpha-3 (CNGA3).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cyclic nucleotide-gated cation channel alpha-3 (CNGA3).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cyclic nucleotide-gated cation channel alpha-3 (CNGA3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Cyclic nucleotide-gated cation channel alpha-3 (CNGA3).	[11]

References

• [1] Oligocone trichromacy is part of the spectrum of CNGA3-related cone system disorders. Ophthalmic Genet. 2011 Jun;32(2):107-13. doi: 10.3109/13816810.2010.544366. Epub 2011 Jan 26.
• [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] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [4] Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy. Eur J Hum Genet. 2015 Apr;23(4):473-80. doi: 10.1038/ejhg.2014.136. Epub 2014 Jul 23.
• [5] Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis. Hum Mutat. 2011 Dec;32(12):1450-9. doi: 10.1002/humu.21587. Epub 2011 Sep 23.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [8] 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.
• [9] 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.
• [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] 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.