Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA5DE38)

• DOT Name: Cyclic nucleotide-gated cation channel beta-1 (CNGB1)
• Synonyms: Cyclic nucleotide-gated cation channel 4; CNG channel 4; CNG-4; CNG4; Cyclic nucleotide-gated cation channel gamma; Cyclic nucleotide-gated cation channel modulatory subunit; Cyclic nucleotide-gated channel beta-1; CNG channel beta-1; Glutamic acid-rich protein; GARP
• Gene Name: CNGB1
• Related Disease:
  CNGB1-related retinopathy
  Primary biliary cholangitis
  Retinitis pigmentosa 45
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Food allergy
  Neoplasm
  Osteoarthritis
  Relapsing-remitting multiple sclerosis
  Thyroid gland papillary carcinoma
  Retinitis pigmentosa
  Lung cancer
  Lung carcinoma
  Advanced cancer
  Asthma
  Atopic dermatitis
  Colorectal carcinoma
  Melanoma
• UniProt ID: CNGB1_HUMAN
• PDB ID: 7RH9; 7RHG; 7RHH; 7RHI; 7RHJ; 7RHK; 7RHL; 8DGH; 8DGK
• Pfam ID: PF00027
• Sequence:
  MLGWVQRVLPQPPGTPRKTKMQEEEEVEPEPEMEAEVEPEPNPEEAETESESMPPEESFK
  EEEVAVADPSPQETKEAALTSTISLRAQGAEISEMNSPSRRVLTWLMKGVEKVIPQPVHS
  ITEDPAQILGHGSTGDTGCTDEPNEALEAQDTRPGLRLLLWLEQNLERVLPQPPKSSEVW
  RDEPAVATGAASDPAPPGRPQEMGPKLQARETPSLPTPIPLQPKEEPKEAPAPEPQPGSQ
  AQTSSLPPTRDPARLVAWVLHRLEMALPQPVLHGKIGEQEPDSPGICDVQTISILPGGQV
  EPDLVLEEVEPPWEDAHQDVSTSPQGTEVVPAYEEENKAVEKMPRELSRIEEEKEDEEEE
  EEEEEEEEEEEVTEVLLDSCVVSQVGVGQSEEDGTRPQSTSDQKLWEEVGEEAKKEAEEK
  AKEEAEEVAEEEAEKEPQDWAETKEEPEAEAEAASSGVPATKQHPEVQVEDTDADSCPLM
  AEENPPSTVLPPPSPAKSDTLIVPSSASGTHRKKLPSEDDEAEELKALSPAESPVVAWSD
  PTTPKDTDGQDRAASTASTNSAIINDRLQELVKLFKERTEKVKEKLIDPDVTSDEESPKP
  SPAKKAPEPAPDTKPAEAEPVEEEHYCDMLCCKFKHRPWKKYQFPQSIDPLTNLMYVLWL
  FFVVMAWNWNCWLIPVRWAFPYQTPDNIHHWLLMDYLCDLIYFLDITVFQTRLQFVRGGD
  IITDKKDMRNNYLKSRRFKMDLLSLLPLDFLYLKVGVNPLLRLPRCLKYMAFFEFNSRLE
  SILSKAYVYRVIRTTAYLLYSLHLNSCLYYWASAYQGLGSTHWVYDGVGNSYIRCYYFAV
  KTLITIGGLPDPKTLFEIVFQLLNYFTGVFAFSVMIGQMRDVVGAATAGQTYYRSCMDST
  VKYMNFYKIPKSVQNRVKTWYEYTWHSQGMLDESELMVQLPDKMRLDLAIDVNYNIVSKV
  ALFQGCDRQMIFDMLKRLRSVVYLPNDYVCKKGEIGREMYIIQAGQVQVLGGPDGKSVLV
  TLKAGSVFGEISLLAVGGGNRRTANVVAHGFTNLFILDKKDLNEILVHYPESQKLLRKKA
  RRMLRSNNKPKEEKSVLILPPRAGTPKLFNAALAMTGKMGGKGAKGGKLAHLRARLKELA
  ALEAAAKQQELVEQAKSSQDVKGEEGSAAPDQHTHPKEAATDPPAPRTPPEPPGSPPSSP
  PPASLGRPEGEEEGPAEPEEHSVRICMSPGPEPGEQILSVKMPEEREEKAE
• Function: Subunit of cyclic nucleotide-gated (CNG) channels, nonselective cation channels, which play important roles in both visual and olfactory signal transduction. When associated with CNGA1, it is involved in the regulation of ion flow into the rod photoreceptor outer segment (ROS), in response to light-induced alteration of the levels of intracellular cGMP.; Isoform GARP2 is a high affinity rod photoreceptor phosphodiesterase (PDE6)-binding protein that modulates its catalytic properties: it is a regulator of spontaneous activation of rod PDE6, thereby serving to lower rod photoreceptor 'dark noise' and allowing these sensory cells to operate at the single photon detection limit.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Olfactory transduction (hsa04740)
  Phototransduction (hsa04744)
• Reactome Pathway:
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  VxPx cargo-targeting to cilium (R-HSA-5620916)
  Activation of the phototransduction cascade (R-HSA-2485179)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
CNGB1-related retinopathy	DISC2X5N	Definitive	Autosomal recessive	[1]
Primary biliary cholangitis	DIS43E0O	Definitive	Biomarker	[2]
Retinitis pigmentosa 45	DISTLR67	Definitive	Autosomal recessive	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Food allergy	DISMQ1BP	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Osteoarthritis	DIS05URM	Strong	Biomarker	[8]
Relapsing-remitting multiple sclerosis	DISSXFCF	Strong	Altered Expression	[9]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[10]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[11]
Lung cancer	DISCM4YA	Disputed	Altered Expression	[12]
Lung carcinoma	DISTR26C	Disputed	Altered Expression	[12]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[13]
Asthma	DISW9QNS	Limited	Genetic Variation	[14]
Atopic dermatitis	DISTCP41	Limited	Biomarker	[15]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[16]
Melanoma	DIS1RRCY	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cyclic nucleotide-gated cation channel beta-1 (CNGB1).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cyclic nucleotide-gated cation channel beta-1 (CNGB1).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Cyclic nucleotide-gated cation channel beta-1 (CNGB1).	[19]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Cyclic nucleotide-gated cation channel beta-1 (CNGB1).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Cyclic nucleotide-gated cation channel beta-1 (CNGB1).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cyclic nucleotide-gated cation channel beta-1 (CNGB1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cyclic nucleotide-gated cation channel beta-1 (CNGB1).	[25]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Cyclic nucleotide-gated cation channel beta-1 (CNGB1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cyclic nucleotide-gated cation channel beta-1 (CNGB1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cyclic nucleotide-gated cation channel beta-1 (CNGB1).	[24]

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] Novel biomarkers for primary biliary cholangitis to improve diagnosis and understand underlying regulatory mechanisms.Liver Int. 2019 Nov;39(11):2124-2135. doi: 10.1111/liv.14128. Epub 2019 May 15.
• [3] Olfactory Dysfunction in Patients With CNGB1-Associated Retinitis Pigmentosa. JAMA Ophthalmol. 2018 Jul 1;136(7):761-769. doi: 10.1001/jamaophthalmol.2018.1621.
• [4] B lymphocytes confer immune tolerance via cell surface GARP-TGF- complex.JCI Insight. 2018 Apr 5;3(7):e99863. doi: 10.1172/jci.insight.99863. eCollection 2018 Apr 5.
• [5] IGHG, IGKC, and FCGR genes and endogenous antibody responses to GARP in patients with breast cancer and matched controls.Hum Immunol. 2018 Aug;79(8):632-637. doi: 10.1016/j.humimm.2018.06.001. Epub 2018 Jun 4.
• [6] Glycoprotein A (GARP) in children who outgrow food allergy.Allergol Immunopathol (Madr). 2020 Jan-Feb;48(1):67-72. doi: 10.1016/j.aller.2019.06.008. Epub 2019 Aug 30.
• [7] Deletion of GARP on mouse regulatory T cells is not sufficient to inhibit the growth of transplanted tumors.Cell Immunol. 2018 Oct;332:129-133. doi: 10.1016/j.cellimm.2018.07.011. Epub 2018 Jul 30.
• [8] A genome-wide linkage scan reveals CD53 as an important regulator of innate TNF-alpha levels.Eur J Hum Genet. 2010 Aug;18(8):953-9. doi: 10.1038/ejhg.2010.52. Epub 2010 Apr 21.
• [9] Promising effect of rapamycin on multiple sclerosis.Mult Scler Relat Disord. 2018 Nov;26:40-45. doi: 10.1016/j.msard.2018.08.009. Epub 2018 Aug 10.
• [10] Increased Expression of GARP in Papillary Thyroid Carcinoma.Endocr Pathol. 2019 Mar;30(1):1-7. doi: 10.1007/s12022-018-9557-0.
• [11] 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.
• [12] Expression of GARP Is Increased in Tumor-Infiltrating Regulatory T Cells and Is Correlated to Clinicopathology of Lung Cancer Patients.Front Immunol. 2017 Feb 14;8:138. doi: 10.3389/fimmu.2017.00138. eCollection 2017.
• [13] GARP Dampens Cancer Immunity by Sustaining Function and Accumulation of Regulatory T Cells in the Colon.Cancer Res. 2019 Mar 15;79(6):1178-1190. doi: 10.1158/0008-5472.CAN-18-2623. Epub 2019 Jan 23.
• [14] Identification of IL6R and chromosome 11q13.5 as risk loci for asthma.Lancet. 2011 Sep 10;378(9795):1006-14. doi: 10.1016/S0140-6736(11)60874-X.
• [15] Atopic Dermatitis According to GARP: New Mechanistic Insights in Disease Pathogenesis.J Invest Dermatol. 2016 Dec;136(12):2340-2341. doi: 10.1016/j.jid.2016.08.020.
• [16] Array CGH identifies distinct DNA copy number profiles of oncogenes and tumor suppressor genes in chromosomal- and microsatellite-unstable sporadic colorectal carcinomas.J Mol Med (Berl). 2007 Mar;85(3):293-304. doi: 10.1007/s00109-006-0126-5. Epub 2006 Dec 2.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [19] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [20] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [21] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [22] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [23] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [24] 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.
• [25] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [26] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.