Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGR3KO5)

• DOT Name: Cyclic nucleotide-gated cation channel beta-3 (CNGB3)
• Synonyms: Cone photoreceptor cGMP-gated channel subunit beta; Cyclic nucleotide-gated cation channel modulatory subunit; Cyclic nucleotide-gated channel beta-3; CNG channel beta-3
• Gene Name: CNGB3
• Related Disease:
  Achromatopsia 3
  CNGB3-related retinopathy
  Achromatopsia
  Cone dystrophy
  Severe early-childhood-onset retinal dystrophy
• UniProt ID: CNGB3_HUMAN
• PDB ID: 7RHS; 8ETP; 8EU3; 8EUC; 8EV8; 8EV9; 8EVA; 8EVB; 8EVC
• Pfam ID: PF00027 ; PF00520
• Sequence:
  MFKSLTKVNKVKPIGENNENEQSSRRNEEGSHPSNQSQQTTAQEENKGEEKSLKTKSTPV
  TSEEPHTNIQDKLSKKNSSGDLTTNPDPQNAAEPTGTVPEQKEMDPGKEGPNSPQNKPPA
  APVINEYADAQLHNLVKRMRQRTALYKKKLVEGDLSSPEASPQTAKPTAVPPVKESDDKP
  TEHYYRLLWFKVKKMPLTEYLKRIKLPNSIDSYTDRLYLLWLLLVTLAYNWNCCFIPLRL
  VFPYQTADNIHYWLIADIICDIIYLYDMLFIQPRLQFVRGGDIIVDSNELRKHYRTSTKF
  QLDVASIIPFDICYLFFGFNPMFRANRMLKYTSFFEFNHHLESIMDKAYIYRVIRTTGYL
  LFILHINACVYYWASNYEGIGTTRWVYDGEGNEYLRCYYWAVRTLITIGGLPEPQTLFEI
  VFQLLNFFSGVFVFSSLIGQMRDVIGAATANQNYFRACMDDTIAYMNNYSIPKLVQKRVR
  TWYEYTWDSQRMLDESDLLKTLPTTVQLALAIDVNFSIISKVDLFKGCDTQMIYDMLLRL
  KSVLYLPGDFVCKKGEIGKEMYIIKHGEVQVLGGPDGTKVLVTLKAGSVFGEISLLAAGG
  GNRRTANVVAHGFANLLTLDKKTLQEILVHYPDSERILMKKARVLLKQKAKTAEATPPRK
  DLALLFPPKEETPKLFKTLLGGTGKASLARLLKLKREQAAQKKENSEGGEEEGKENEDKQ
  KENEDKQKENEDKGKENEDKDKGREPEEKPLDRPECTASPIAVEEEPHSVRRTVLPRGTS
  RQSLIISMAPSAEGGEEVLTIEVKEKAKQ
• Function: Visual signal transduction is mediated by a G-protein coupled cascade using cGMP as second messenger. This protein can be activated by cGMP which leads to an opening of the cation channel and thereby causing a depolarization of rod 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 efficiency of the channel when coexpressed with CNGA3. Essential for the generation of light-evoked electrical responses in the red-, green- and blue sensitive cones.
• Tissue Specificity: Expressed specifically in the retina.
• KEGG Pathway: cAMP sig.ling pathway (hsa04024)

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 3	DISR4EMI	Definitive	Autosomal recessive	[1]
CNGB3-related retinopathy	DISFFREC	Definitive	Autosomal recessive	[2]
Achromatopsia	DISKL51I	Supportive	Autosomal recessive	[3]
Cone dystrophy	DIS7SAZZ	Supportive	Autosomal dominant	[4]
Severe early-childhood-onset retinal dystrophy	DISFDRFO	Limited	Autosomal recessive	[5]

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 Cyclic nucleotide-gated cation channel beta-3 (CNGB3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cyclic nucleotide-gated cation channel beta-3 (CNGB3).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cyclic nucleotide-gated cation channel beta-3 (CNGB3).	[8]

References

• [1] A frameshift insertion in the cone cyclic nucleotide gated cation channel causes complete achromatopsia in a consanguineous family from a rural isolate. Eur J Hum Genet. 2002 Oct;10(10):638-42. doi: 10.1038/sj.ejhg.5200856.
• [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] Progressive cone dystrophy associated with mutation in CNGB3. Invest Ophthalmol Vis Sci. 2004 Jun;45(6):1975-82. doi: 10.1167/iovs.03-0898.
• [5] Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases. Hum Mutat. 2005 Mar;25(3):248-58. doi: 10.1002/humu.20142.
• [6] 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.
• [7] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [8] 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.