Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXV6ETF)

• DOT Name: Gap junction alpha-3 protein (GJA3)
• Synonyms: Connexin-46; Cx46
• Gene Name: GJA3
• Related Disease:
  Cataract 14 multiple types
  Early-onset nuclear cataract
  Early-onset posterior polar cataract
  Pulverulent cataract
• UniProt ID: CXA3_HUMAN
• Pfam ID: PF00029
• Sequence:
  MGDWSFLGRLLENAQEHSTVIGKVWLTVLFIFRILVLGAAAEDVWGDEQSDFTCNTQQPG
  CENVCYDRAFPISHIRFWALQIIFVSTPTLIYLGHVLHIVRMEEKKKEREEEEQLKRESP
  SPKEPPQDNPSSRDDRGRVRMAGALLRTYVFNIIFKTLFEVGFIAGQYFLYGFELKPLYR
  CDRWPCPNTVDCFISRPTEKTIFIIFMLAVACASLLLNMLEIYHLGWKKLKQGVTSRLGP
  DASEAPLGTADPPPLPPSSRPPAVAIGFPPYYAHTAAPLGQARAVGYPGAPPPAADFKLL
  ALTEARGKGQSAKLYNGHHHLLMTEQNWANQAAERQPPALKAYPAASTPAAPSPVGSSSP
  PLAHEAEAGAAPLLLDGSGSSLEGSALAGTPEEEEQAVTTAAQMHQPPLPLGDPGRASKA
  SRASSGRARPEDLAI
• Function: Structural component of lens fiber gap junctions. Gap junctions are dodecameric channels that connect the cytoplasm of adjoining cells. They are formed by the docking of two hexameric hemichannels, one from each cell membrane. Small molecules and ions diffuse from one cell to a neighboring cell via the central pore.
• Reactome Pathway: Gap junction assembly (R-HSA-190861)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract 14 multiple types	DISVRJYC	Definitive	Autosomal dominant	[1]
Early-onset nuclear cataract	DISGIHUY	Supportive	Autosomal dominant	[2]
Early-onset posterior polar cataract	DISJFK9W	Supportive	Autosomal dominant	[3]
Pulverulent cataract	DISMJ2AH	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Gap junction alpha-3 protein (GJA3).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Gap junction alpha-3 protein (GJA3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Gap junction alpha-3 protein (GJA3).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gap junction alpha-3 protein (GJA3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Gap junction alpha-3 protein (GJA3).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Gap junction alpha-3 protein (GJA3).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Gap junction alpha-3 protein (GJA3).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Gap junction alpha-3 protein (GJA3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Gap junction alpha-3 protein (GJA3).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Gap junction alpha-3 protein (GJA3).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Gap junction alpha-3 protein (GJA3).	[14]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Gap junction alpha-3 protein (GJA3).	[15]

References

• [1] Further evidence of autosomal dominant congenital zonular pulverulent cataracts linked to 13q11 (CZP3) and a novel mutation in connexin 46 (GJA3). Hum Genet. 2000 Feb;106(2):206-9. doi: 10.1007/s004390051029.
• [2] Two novel mutations of connexin genes in Chinese families with autosomal dominant congenital nuclear cataract. Br J Ophthalmol. 2005 Nov;89(11):1535-7. doi: 10.1136/bjo.2005.075184.
• [3] Molecular analysis of cataract families in India: new mutations in the CRYBB2 and GJA3 genes and rare polymorphisms. Mol Vis. 2010 Sep 10;16:1837-47.
• [4] A novel mutation in GJA3 associated with congenital Coppock-like cataract in a large Chinese family. Mol Vis. 2012;18:2114-8. Epub 2012 Jul 26.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [13] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.