Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD9Y4UH)

• DOT Name: Guanine nucleotide-binding protein G(t) subunit alpha-2 (GNAT2)
• Synonyms: Transducin alpha-2 chain
• Gene Name: GNAT2
• Related Disease:
  Achromatopsia 4
  Cone-rod dystrophy
  Cone-rod dystrophy 2
  GNAT2-related retinopathy
  Usher syndrome type 1
  Cone-rod dystrophy 6
  Inherited retinal dystrophy
  Obesity
  Red color blindness
  Red-green color blindness
  Achromatopsia
  Cone dystrophy
  Blue cone monochromacy
  Leber congenital amaurosis 1
• UniProt ID: GNAT2_HUMAN
• PDB ID: 6N84; 6N85
• Pfam ID: PF00503
• Sequence:
  MGSGASAEDKELAKRSKELEKKLQEDADKEAKTVKLLLLGAGESGKSTIVKQMKIIHQDG
  YSPEECLEFKAIIYGNVLQSILAIIRAMTTLGIDYAEPSCADDGRQLNNLADSIEEGTMP
  PELVEVIRRLWKDGGVQACFERAAEYQLNDSASYYLNQLERITDPEYLPSEQDVLRSRVK
  TTGIIETKFSVKDLNFRMFDVGGQRSERKKWIHCFEGVTCIIFCAALSAYDMVLVEDDEV
  NRMHESLHLFNSICNHKFFAATSIVLFLNKKDLFEEKIKKVHLSICFPEYDGNNSYDDAG
  NYIKSQFLDLNMRKDVKEIYSHMTCATDTQNVKFVFDAVTDIIIKENLKDCGLF
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Transducin is an amplifier and one of the transducers of a visual impulse that performs the coupling between rhodopsin and cGMP-phosphodiesterase.
• Tissue Specificity: Retinal rod outer segment.
• KEGG Pathway: Phototransduction (hsa04744)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Ca2+ pathway (R-HSA-4086398)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Achromatopsia 4	DISIY8O9	Definitive	Autosomal recessive	[1]
Cone-rod dystrophy	DISY9RWN	Definitive	Genetic Variation	[2]
Cone-rod dystrophy 2	DISX2RWY	Definitive	Genetic Variation	[2]
GNAT2-related retinopathy	DISD8D6I	Definitive	Autosomal recessive	[3]
Usher syndrome type 1	DISR29E4	Definitive	Genetic Variation	[4]
Cone-rod dystrophy 6	DISNS9U8	Strong	Genetic Variation	[5]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[6]
Obesity	DIS47Y1K	Strong	Genetic Variation	[7]
Red color blindness	DISQHW4Z	Strong	Biomarker	[8]
Red-green color blindness	DISV3ZVU	Strong	Biomarker	[8]
Achromatopsia	DISKL51I	Supportive	Autosomal recessive	[8]
Cone dystrophy	DIS7SAZZ	Supportive	Autosomal dominant	[9]
Blue cone monochromacy	DISYV7KB	Limited	Genetic Variation	[10]
Leber congenital amaurosis 1	DISY2B33	Limited	Altered Expression	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Guanine nucleotide-binding protein G(t) subunit alpha-2 (GNAT2).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Guanine nucleotide-binding protein G(t) subunit alpha-2 (GNAT2).	[14]

1 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 increases the methylation of Guanine nucleotide-binding protein G(t) subunit alpha-2 (GNAT2).	[13]

References

• [1] Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene. Hum Mutat. 2019 Aug;40(8):1145-1155. doi: 10.1002/humu.23768. Epub 2019 May 6.
• [2] A three base pair deletion encoding the amino acid (lysine-270) in the alpha-cone transducin gene.Mol Vis. 2004 Apr 8;10:265-71.
• [3] 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.
• [4] Detection of cone alpha transducin mRNA in human fetal cochlea: negative mutation analysis in Usher syndrome.Hear Res. 1996 Sep 15;99(1-2):7-12. doi: 10.1016/s0378-5955(96)00073-1.
• [5] Transgenic zebrafish expressing mutant human RETGC-1 exhibit aberrant cone and rod morphology.Exp Eye Res. 2013 Mar;108:120-8. doi: 10.1016/j.exer.2013.01.003. Epub 2013 Jan 15.
• [6] Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the alpha subunit of cone transducin (GNAT2).J Med Genet. 2002 Sep;39(9):656-60. doi: 10.1136/jmg.39.9.656.
• [7] Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.Nat Genet. 2013 May;45(5):501-12. doi: 10.1038/ng.2606. Epub 2013 Apr 7.
• [8] Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet. 2002 Aug;71(2):422-5. doi: 10.1086/341835. Epub 2002 Jun 20.
• [9] Cone dystrophy phenotype associated with a frameshift mutation (M280fsX291) in the alpha-subunit of cone specific transducin (GNAT2). Br J Ophthalmol. 2003 Nov;87(11):1317-20. doi: 10.1136/bjo.87.11.1317.
• [10] Variant phenotypes of incomplete achromatopsia in two cousins with GNAT2 gene mutations.Invest Ophthalmol Vis Sci. 2004 Dec;45(12):4256-62. doi: 10.1167/iovs.04-0317.
• [11] Overexpression of Type 3 Iodothyronine Deiodinase Reduces Cone Death in the Leber Congenital Amaurosis Model Mice.Adv Exp Med Biol. 2018;1074:125-131. doi: 10.1007/978-3-319-75402-4_16.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.