Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLJ59E7)

• DOT Name: Gap junction beta-3 protein (GJB3)
• Synonyms: Connexin-31; Cx31
• Gene Name: GJB3
• Related Disease:
  Erythrokeratodermia variabilis
  Erythrokeratodermia variabilis et progressiva 1
  Autosomal dominant nonsyndromic hearing loss 2B
  Autosomal dominant nonsyndromic hearing loss
  Hearing loss, autosomal recessive
  Neuropathy with hearing impairment
  Nonsyndromic genetic hearing loss
• UniProt ID: CXB3_HUMAN
• Pfam ID: PF00029
• Sequence:
  MDWKTLQALLSGVNKYSTAFGRIWLSVVFVFRVLVYVVAAERVWGDEQKDFDCNTKQPGC
  TNVCYDNYFPISNIRLWALQLIFVTCPSLLVILHVAYREERERRHRQKHGDQCAKLYDNA
  GKKHGGLWWTYLFSLIFKLIIEFLFLYLLHTLWHGFNMPRLVQCANVAPCPNIVDCYIAR
  PTEKKIFTYFMVGASAVCIVLTICELCYLICHRVLRGLHKDKPRGGCSPSSSASRASTCR
  CHHKLVEAGEVDPDPGNNKLQASAPNLTPI
• Function: One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
• Reactome Pathway: Gap junction assembly (R-HSA-190861)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Erythrokeratodermia variabilis	DIS4BMUQ	Definitive	Autosomal dominant	[1]
Erythrokeratodermia variabilis et progressiva 1	DISUI66N	Strong	Autosomal dominant	[2]
Autosomal dominant nonsyndromic hearing loss 2B	DISUNM3G	Moderate	Autosomal dominant	[3]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[4]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[5]
Neuropathy with hearing impairment	DIS3DLQQ	Supportive	Autosomal dominant	[6]
Nonsyndromic genetic hearing loss	DISZX61P	Disputed	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Gap junction beta-3 protein (GJB3) decreases the response to substance of Arsenic trioxide.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Gap junction beta-3 protein (GJB3).	[7]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Gap junction beta-3 protein (GJB3).	[9]

2 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 Gap junction beta-3 protein (GJB3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Gap junction beta-3 protein (GJB3).	[10]

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] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [4] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. 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.
• [5] Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss. Hum Mol Genet. 2000 Jan 1;9(1):63-7. doi: 10.1093/hmg/9.1.63.
• [6] Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. Hum Mol Genet. 2001 Apr 15;10(9):947-52. doi: 10.1093/hmg/10.9.947.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] 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.
• [9] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [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] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.