Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLF9WW4)

• DOT Name: Gap junction gamma-2 protein (GJC2)
• Synonyms: Connexin-46.6; Cx46.6; Connexin-47; Cx47; Gap junction alpha-12 protein
• Gene Name: GJC2
• Related Disease:
  Hereditary spastic paraplegia 44
  Hypomyelinating leukodystrophy 2
  Lymphatic malformation 3
  Lymphatic malformation
• UniProt ID: CXG2_HUMAN
• Pfam ID: PF00029
• Sequence:
  MTNMSWSFLTRLLEEIHNHSTFVGKVWLTVLVVFRIVLTAVGGEAIYSDEQAKFTCNTRQ
  PGCDNVCYDAFAPLSHVRFWVFQIVVISTPSVMYLGYAVHRLARASEQERRRALRRRPGP
  RRAPRAHLPPPHAGWPEPADLGEEEPMLGLGEEEEEEETGAAEGAGEEAEEAGAEEACTK
  AVGADGKAAGTPGPTGQHDGRRRIQREGLMRVYVAQLVARAAFEVAFLVGQYLLYGFEVR
  PFFPCSRQPCPHVVDCFVSRPTEKTVFLLVMYVVSCLCLLLNLCEMAHLGLGSAQDAVRG
  RRGPPASAPAPAPRPPPCAFPAAAAGLACPPDYSLVVRAAERARAHDQNLANLALQALRD
  GAAAGDRDRDSSPCVGLPAASRGPPRAGAPASRTGSATSAGTVGEQGRPGTHERPGAKPR
  AGSEKGSASSRDGKTTVWI
• 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. May play a role in myelination in central and peripheral nervous systems.
• Tissue Specificity: Expressed in central nervous system, in sciatic nerve and sural nerve. Also detected in skeletal muscles.
• 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
Hereditary spastic paraplegia 44	DISOCU0D	Definitive	Autosomal dominant	[1]
Hypomyelinating leukodystrophy 2	DISINIV9	Definitive	Autosomal recessive	[2]
Lymphatic malformation 3	DISFFVUQ	Strong	Autosomal dominant	[3]
Lymphatic malformation	DIS4D8VL	Supportive	Autosomal dominant	[3]

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 gamma-2 protein (GJC2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Gap junction gamma-2 protein (GJC2).	[7]

3 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 Gap junction gamma-2 protein (GJC2).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Gap junction gamma-2 protein (GJC2).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Gap junction gamma-2 protein (GJC2).	[8]

References

• [1] Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain. 2009 Feb;132(Pt 2):426-38. doi: 10.1093/brain/awn328. Epub 2008 Dec 4.
• [2] GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease. Neurology. 2008 Mar 4;70(10):748-54. doi: 10.1212/01.wnl.0000284828.84464.35. Epub 2007 Dec 19.
• [3] GJC2 missense mutations cause human lymphedema. Am J Hum Genet. 2010 Jun 11;86(6):943-8. doi: 10.1016/j.ajhg.2010.04.010. Epub 2010 May 27.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.
• [8] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.