Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTETEMM0)

• DOT Name: Voltage-dependent calcium channel gamma-2 subunit (CACNG2)
• Synonyms: Neuronal voltage-gated calcium channel gamma-2 subunit; Transmembrane AMPAR regulatory protein gamma-2; TARP gamma-2
• Gene Name: CACNG2
• Related Disease:
  Autosomal dominant non-syndromic intellectual disability
  Complex neurodevelopmental disorder
  Intellectual disability, autosomal dominant 10
• UniProt ID: CCG2_HUMAN
• PDB ID: 6DLZ; 6DM0; 6DM1; 6O9G; 6TNO
• Pfam ID: PF00822
• Sequence:
  MGLFDRGVQMLLTTVGAFAAFSLMTIAVGTDYWLYSRGVCKTKSVSENETSKKNEEVMTH
  SGLWRTCCLEGNFKGLCKQIDHFPEDADYEADTAEYFLRAVRASSIFPILSVILLFMGGL
  CIAASEFYKTRHNIILSAGIFFVSAGLSNIIGIIVYISANAGDPSKSDSKKNSYSYGWSF
  YFGALSFIIAEMVGVLAVHMFIDRHKQLRATARATDYLQASAITRIPSYRYRYQRRSRSS
  SRSTEPSHSRDASPVGIKGFNTLPSTEISMYTLSRDPLKAATTPTATYNSDRDNSFLQVH
  NCIQKENKDSLHSNTANRRTTPV
• Function: Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits. Thought to stabilize the calcium channel in an inactivated (closed) state.
• Tissue Specificity: Brain.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Oxytocin sig.ling pathway (hsa04921)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  Trafficking of AMPA receptors (R-HSA-399719)
  LGI-ADAM interactions (R-HSA-5682910)
  Presynaptic depolarization and calcium channel opening (R-HSA-112308)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[1]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[2]
Intellectual disability, autosomal dominant 10	DISZM91M	Limited	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Voltage-dependent calcium channel gamma-2 subunit (CACNG2).	[4]

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 Voltage-dependent calcium channel gamma-2 subunit (CACNG2).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Voltage-dependent calcium channel gamma-2 subunit (CACNG2).	[6]

References

• [1] Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet. 2011 Mar 11;88(3):306-16. doi: 10.1016/j.ajhg.2011.02.001. Epub 2011 Mar 3.
• [2] 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.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [5] 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.
• [6] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.