Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT09MNQ8)

• DOT Name: Calsequestrin-2 (CASQ2)
• Synonyms: Calsequestrin, cardiac muscle isoform
• Gene Name: CASQ2
• Related Disease:
  Catecholaminergic polymorphic ventricular tachycardia
  Catecholaminergic polymorphic ventricular tachycardia 2
  Autoimmune disease
  Cardiac arrest
  Cardiac disease
  Cardiomyopathy
  Coronary atherosclerosis
  Coronary heart disease
  Disorder of orbital region
  High blood pressure
  Polymorphic ventricular tachycardia
  Ventricular tachycardia
  Ventricular tachycardia, familial
  Atrial fibrillation
  Cardiac failure
  Congestive heart failure
  Familial atrial fibrillation
  Supravalvular aortic stenosis
  Hypertrophic cardiomyopathy
  Arrhythmia
  Lateral meningocele syndrome
  Limb-mammary syndrome
• UniProt ID: CASQ2_HUMAN
• PDB ID: 2VAF; 6OWV; 6OWW; 7F05
• Pfam ID: PF01216
• Sequence:
  MKRTHLFIVGIYFLSSCRAEEGLNFPTYDGKDRVVSLSEKNFKQVLKKYDLLCLYYHEPV
  SSDKVTQKQFQLKEIVLELVAQVLEHKAIGFVMVDAKKEAKLAKKLGFDEEGSLYILKGD
  RTIEFDGEFAADVLVEFLLDLIEDPVEIISSKLEVQAFERIEDYIKLIGFFKSEDSEYYK
  AFEEAAEHFQPYIKFFATFDKGVAKKLSLKMNEVDFYEPFMDEPIAIPNKPYTEEELVEF
  VKEHQRPTLRRLRPEEMFETWEDDLNGIHIVAFAEKSDPDGYEFLEILKQVARDNTDNPD
  LSILWIDPDDFPLLVAYWEKTFKIDLFRPQIGVVNVTDADSVWMEIPDDDDLPTAEELED
  WIEDVLSGKINTEDDDEDDDDDDNSDEEDNDDSDDDDDE
• Function: Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle. Calcium ions are bound by clusters of acidic residues at the protein surface, especially at the interface between subunits. Can bind around 60 Ca(2+) ions. Regulates the release of lumenal Ca(2+) via the calcium release channel RYR2; this plays an important role in triggering muscle contraction. Plays a role in excitation-contraction coupling in the heart and in regulating the rate of heart beats.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Cardiac muscle contraction (hsa04260)
• Reactome Pathway:
  Ion homeostasis (R-HSA-5578775)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Catecholaminergic polymorphic ventricular tachycardia	DISSAS1A	Definitive	Autosomal recessive	[1]
Catecholaminergic polymorphic ventricular tachycardia 2	DIS9AWAE	Definitive	Autosomal recessive	[2]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[3]
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[4]
Cardiac disease	DISVO1I5	Strong	Biomarker	[5]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[6]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[7]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[7]
Disorder of orbital region	DISH0ECJ	Strong	Altered Expression	[3]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[4]
Polymorphic ventricular tachycardia	DISCPO8T	Strong	Genetic Variation	[8]
Ventricular tachycardia	DISIBXJ3	Strong	Altered Expression	[9]
Ventricular tachycardia, familial	DISYG7IE	Strong	Biomarker	[10]
Atrial fibrillation	DIS15W6U	moderate	Genetic Variation	[11]
Cardiac failure	DISDC067	moderate	Genetic Variation	[7]
Congestive heart failure	DIS32MEA	moderate	Genetic Variation	[7]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[12]
Supravalvular aortic stenosis	DIS8FSJD	moderate	ModifyingMutation	[13]
Hypertrophic cardiomyopathy	DISQG2AI	Disputed	Autosomal dominant	[1]
Arrhythmia	DISFF2NI	Limited	Altered Expression	[9]
Lateral meningocele syndrome	DISG74RP	Limited	Biomarker	[14]
Limb-mammary syndrome	DIS7H4FP	Limited	Biomarker	[14]

3 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 Calsequestrin-2 (CASQ2).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Calsequestrin-2 (CASQ2).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Calsequestrin-2 (CASQ2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calsequestrin-2 (CASQ2).	[17]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Calsequestrin-2 (CASQ2).	[19]
Dexamethasone	DMMWZET	Approved	Dexamethasone affects the expression of Calsequestrin-2 (CASQ2).	[20]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Calsequestrin-2 (CASQ2).	[21]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Calsequestrin-2 (CASQ2).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Calsequestrin-2 (CASQ2).	[23]

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] Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2006 Sep 5;114(10):1012-9. doi: 10.1161/CIRCULATIONAHA.106.623793. Epub 2006 Aug 14.
• [3] The cardiac calsequestrin gene (CASQ2) is up-regulated in the thyroid in patients with Graves' ophthalmopathy--support for a role of autoimmunity against calsequestrin as the triggering event.Clin Endocrinol (Oxf). 2010 Oct;73(4):522-8. doi: 10.1111/j.1365-2265.2009.03753.x.
• [4] Association of CASQ2 polymorphisms with sudden cardiac arrest and heart failure in patients with coronary artery disease.Heart Rhythm. 2014 Apr;11(4):646-52. doi: 10.1016/j.hrthm.2014.01.015. Epub 2014 Jan 17.
• [5] Calsequestrin 2 and arrhythmias.Am J Physiol Heart Circ Physiol. 2012 Mar 15;302(6):H1250-60. doi: 10.1152/ajpheart.00779.2011. Epub 2011 Dec 23.
• [6] Targeted next-generation sequencing (NGS) of nine candidate genes with custom AmpliSeq in patients and a cardiomyopathy risk group.Clin Chim Acta. 2015 Jun 15;446:132-40. doi: 10.1016/j.cca.2015.04.014. Epub 2015 Apr 17.
• [7] Common Variants in TRDN and CALM1 Are Associated with Risk of Sudden Cardiac Death in Chronic Heart Failure Patients in Chinese Han Population.PLoS One. 2015 Jul 21;10(7):e0132459. doi: 10.1371/journal.pone.0132459. eCollection 2015.
• [8] Molecular genetics of exercise-induced polymorphic ventricular tachycardia: identification of three novel cardiac ryanodine receptor mutations and two common calsequestrin 2 amino-acid polymorphisms.Eur J Hum Genet. 2003 Nov;11(11):888-91. doi: 10.1038/sj.ejhg.5201061.
• [9] Viral delivered gene therapy to treat catecholaminergic polymorphic ventricular tachycardia (CPVT2) in mouse models.Heart Rhythm. 2017 Jul;14(7):1053-1060. doi: 10.1016/j.hrthm.2017.03.025. Epub 2017 Mar 20.
• [10] Active cascade screening in primary inherited arrhythmia syndromes: does it lead to prophylactic treatment?.J Am Coll Cardiol. 2010 Jun 8;55(23):2570-6. doi: 10.1016/j.jacc.2009.12.063.
• [11] Calcium-Mediated Oscillation in Membrane Potentials and Atrial-Triggered Activity in Atrial Cells of Casq2(R33Q/R33Q) Mutation Mice.Front Physiol. 2018 Nov 2;9:1447. doi: 10.3389/fphys.2018.01447. eCollection 2018.
• [12] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [13] Age-related differences in the expression of proto-oncogene and contractile protein genes in response to pressure overload in the rat myocardium.J Clin Invest. 1992 Mar;89(3):939-46. doi: 10.1172/JCI115675.
• [14] Expression of subtype-specific group 1 leiomyosarcoma markers in a wide variety of sarcomas by gene expression analysis and immunohistochemistry.Am J Surg Pathol. 2011 Apr;35(4):583-9. doi: 10.1097/PAS.0b013e318211abd6.
• [15] 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.
• [16] 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.
• [17] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [18] 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.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [21] Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol. 2018 Apr;92(4):1507-1524.
• [22] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [23] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.