Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAY8WOO)

• DOT Name: Calsequestrin-1 (CASQ1)
• Synonyms: Calmitine; Calsequestrin, skeletal muscle isoform
• Gene Name: CASQ1
• Related Disease:
  Autoimmune disease
  Disease of orbital part of eye adnexa
  Duchenne muscular dystrophy
  Malignant hyperthermia of anesthesia
  Migraine with aura
  Myopathy
  Myopathy due to calsequestrin and SERCA1 protein overload
  Myopathy, tubular aggregate, 1
  Myositis disease
  Stroke
  X-linked myopathy with excessive autophagy
  Stormorken syndrome
  Tubular aggregate myopathy
  Non-insulin dependent diabetes
• UniProt ID: CASQ1_HUMAN
• PDB ID: 3UOM; 5CRD; 5CRE; 5CRG; 5CRH
• Pfam ID: PF01216
• Sequence:
  MSATDRMGPRAVPGLRLALLLLLVLGTPKSGVQGQEGLDFPEYDGVDRVINVNAKNYKNV
  FKKYEVLALLYHEPPEDDKASQRQFEMEELILELAAQVLEDKGVGFGLVDSEKDAAVAKK
  LGLTEVDSMYVFKGDEVIEYDGEFSADTIVEFLLDVLEDPVELIEGERELQAFENIEDEI
  KLIGYFKSKDSEHYKAFEDAAEEFHPYIPFFATFDSKVAKKLTLKLNEIDFYEAFMEEPV
  TIPDKPNSEEEIVNFVEEHRRSTLRKLKPESMYETWEDDMDGIHIVAFAEEADPDGFEFL
  ETLKAVAQDNTENPDLSIIWIDPDDFPLLVPYWEKTFDIDLSAPQIGVVNVTDADSVWME
  MDDEEDLPSAEELEDWLEDVLEGEINTEDDDDDDDD
• 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, often at the interface between subunits. Can bind around 80 Ca(2+) ions. Regulates the release of lumenal Ca(2+) via the calcium release channel RYR1; this plays an important role in triggering muscle contraction. Negatively regulates store-operated Ca(2+) entry (SOCE) activity.
• Tissue Specificity: Expressed in myoblasts (at protein level).
• KEGG Pathway: Calcium sig.ling pathway (hsa04020)
• Reactome Pathway:
  Ion homeostasis (R-HSA-5578775)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Biomarker	[1]
Disease of orbital part of eye adnexa	DISGWPWX	Strong	Biomarker	[1]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Biomarker	[2]
Malignant hyperthermia of anesthesia	DISYC9XI	Strong	Biomarker	[3]
Migraine with aura	DISDM7I8	Strong	Biomarker	[4]
Myopathy	DISOWG27	Strong	Genetic Variation	[5]
Myopathy due to calsequestrin and SERCA1 protein overload	DIS43MK2	Strong	Autosomal dominant	[6]
Myopathy, tubular aggregate, 1	DISLKMBA	Strong	Genetic Variation	[7]
Myositis disease	DISCIXF0	Strong	Biomarker	[1]
Stroke	DISX6UHX	Strong	Genetic Variation	[8]
X-linked myopathy with excessive autophagy	DIS1AFQH	Strong	Genetic Variation	[9]
Stormorken syndrome	DIS9US3H	moderate	Biomarker	[10]
Tubular aggregate myopathy	DISC11WH	Supportive	Autosomal dominant	[7]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[11]

5 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-1 (CASQ1).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Calsequestrin-1 (CASQ1).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Calsequestrin-1 (CASQ1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Calsequestrin-1 (CASQ1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Calsequestrin-1 (CASQ1).	[16]

References

• [1] Pathogenesis of thyroid eye disease--does autoimmunity against the TSH receptor explain all cases?.Endokrynol Pol. 2010 Mar-Apr;61(2):222-7.
• [2] Role of the mitochondrial DNA and calmitine in myopathies.Biochim Biophys Acta. 1995 May 24;1271(1):159-63. doi: 10.1016/0925-4439(95)00023-w.
• [3] Estrogens Protect Calsequestrin-1 Knockout Mice from Lethal Hyperthermic Episodes by Reducing Oxidative Stress in Muscle.Oxid Med Cell Longev. 2017;2017:6936897. doi: 10.1155/2017/6936897. Epub 2017 Sep 10.
• [4] Association analysis of chromosome 1 migraine candidate genes.BMC Med Genet. 2007 Aug 29;8:57. doi: 10.1186/1471-2350-8-57.
• [5] A Calsequestrin-1 Mutation Associated with a Skeletal Muscle Disease Alters Sarcoplasmic Ca2+ Release.PLoS One. 2016 May 19;11(5):e0155516. doi: 10.1371/journal.pone.0155516. eCollection 2016.
• [6] Anesthetic- and heat-induced sudden death in calsequestrin-1-knockout mice. FASEB J. 2009 Jun;23(6):1710-20. doi: 10.1096/fj.08-121335. Epub 2009 Feb 23.
• [7] Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy. Hum Mutat. 2017 Dec;38(12):1761-1773. doi: 10.1002/humu.23338. Epub 2017 Sep 26.
• [8] An association study of CASQ1 gene polymorphisms and heat stroke.Genomics Proteomics Bioinformatics. 2014 Jun;12(3):127-32. doi: 10.1016/j.gpb.2014.03.004. Epub 2014 Jun 2.
• [9] A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates. Hum Mutat. 2014 Oct;35(10):1163-70. doi: 10.1002/humu.22631. Epub 2014 Sep 10.
• [10] Gain-of-function mutations in STIM1 and ORAI1 causing tubular aggregate myopathy and Stormorken syndrome.Cell Calcium. 2018 Dec;76:1-9. doi: 10.1016/j.ceca.2018.07.008. Epub 2018 Sep 3.
• [11] Studies of association of the CASQ1 rs2275703 polymorphism in relation to type 2 diabetes and related quantitative metabolic traits among 7,088 Danish whites.Mol Genet Metab. 2007 Nov;92(3):278-82. doi: 10.1016/j.ymgme.2007.06.011. Epub 2007 Aug 2.
• [12] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [13] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [16] 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.