Details of Drug Off-Target (DOT)

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

• DOT Name: Gap junction beta-2 protein (GJB2)
• Synonyms: Connexin-26; Cx26
• Gene Name: GJB2
• Related Disease:
  Autosomal recessive nonsyndromic hearing loss 1A
  Bart-Pumphrey syndrome
  Hearing loss, autosomal recessive
  Ichthyosis, hystrix-like, with hearing loss
  Keratoderma hereditarium mutilans
  Palmoplantar keratoderma-deafness syndrome
  Autosomal dominant keratitis-ichthyosis-hearing loss syndrome
  Autosomal dominant nonsyndromic hearing loss 3A
  Autosomal dominant nonsyndromic hearing loss
  KID syndrome
• UniProt ID: CXB2_HUMAN
• PDB ID: 2ZW3; 3IZ1; 3IZ2; 5ER7; 5ERA; 5KJ3; 5KJG; 6UVR; 6UVS; 6UVT; 7QEO; 7QEQ; 7QER; 7QES; 7QET; 7QEU; 7QEV; 7QEW; 7QEY
• Pfam ID: PF00029
• Sequence:
  MDWGTLQTILGGVNKHSTSIGKIWLTVLFIFRIMILVVAAKEVWGDEQADFVCNTLQPGC
  KNVCYDHYFPISHIRLWALQLIFVSTPALLVAMHVAYRRHEKKRKFIKGEIKSEFKDIEE
  IKTQKVRIEGSLWWTYTSSIFFRVIFEAAFMYVFYVMYDGFSMQRLVKCNAWPCPNTVDC
  FVSRPTEKTVFTVFMIAVSGICILLNVTELCYLLIRYCSGKSKKPV
• Function: Structural component of 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:
  Transport of connexins along the secretory pathway (R-HSA-190827)
  Gap junction assembly (R-HSA-190861)
  Transport of connexons to the plasma membrane (R-HSA-190872)
  Oligomerization of connexins into connexons (R-HSA-190704)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive nonsyndromic hearing loss 1A	DISB4SRG	Definitive	Autosomal recessive	[1]
Bart-Pumphrey syndrome	DISRAGDE	Definitive	Autosomal dominant	[2]
Hearing loss, autosomal recessive	DIS8G9R9	Definitive	Autosomal recessive	[3]
Ichthyosis, hystrix-like, with hearing loss	DISHW55J	Definitive	Autosomal dominant	[4]
Keratoderma hereditarium mutilans	DIS8KG10	Definitive	Autosomal dominant	[5]
Palmoplantar keratoderma-deafness syndrome	DISL46K2	Definitive	Autosomal dominant	[4]
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome	DISXOU3H	Strong	Autosomal dominant	[1]
Autosomal dominant nonsyndromic hearing loss 3A	DISZWPLU	Strong	Autosomal dominant	[6]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[7]
KID syndrome	DISRBJLW	Supportive	Autosomal dominant	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Gap junction beta-2 protein (GJB2).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Gap junction beta-2 protein (GJB2).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gap junction beta-2 protein (GJB2).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Gap junction beta-2 protein (GJB2).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Gap junction beta-2 protein (GJB2).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Gap junction beta-2 protein (GJB2).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Gap junction beta-2 protein (GJB2).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Gap junction beta-2 protein (GJB2).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Gap junction beta-2 protein (GJB2).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Gap junction beta-2 protein (GJB2).	[18]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Gap junction beta-2 protein (GJB2).	[19]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Gap junction beta-2 protein (GJB2).	[20]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Gap junction beta-2 protein (GJB2).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Gap junction beta-2 protein (GJB2).	[22]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Gap junction beta-2 protein (GJB2).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Gap junction beta-2 protein (GJB2).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Gap junction beta-2 protein (GJB2).	[27]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Gap junction beta-2 protein (GJB2).	[28]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Gap junction beta-2 protein (GJB2).	[29]

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 increases the methylation of Gap junction beta-2 protein (GJB2).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Gap junction beta-2 protein (GJB2).	[26]

References

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• [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] A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350). J Med Genet. 2000 Jan;37(1):50-1. doi: 10.1136/jmg.37.1.50.
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