Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXVE9SF)

• DOT Name: Triadin (TRDN)
• Gene Name: TRDN
• Related Disease:
  Catecholaminergic polymorphic ventricular tachycardia
  Catecholaminergic polymorphic ventricular tachycardia 5
  Arrhythmia
  Cardiac arrest
  Catecholaminergic polymorphic ventricular tachycardia 1
  Congenital multicore myopathy with external ophthalmoplegia
  Congenital myopathy
  Congestive heart failure
  Diabetic kidney disease
  Familial long QT syndrome
  Long QT syndrome
  Multiminicore myopathy
  Neuropathy, congenital hypomyelinating, 2
  Non-insulin dependent diabetes
  Type-1 diabetes
  Ventricular septal defect
• UniProt ID: TRDN_HUMAN
• Pfam ID: PF05279
• Sequence:
  MTEITAEGNASTTTTVIDSKNGSVPKSPGKVLKRTVTEDIVTTFSSPAAWLLVIALIITW
  SAVAIVMFDLVDYKNFSASSIAKIGSDPLKLVRDAMEETTDWIYGFFSLLSDIISSEDEE
  DDDGDEDTDKGEIDEPPLRKKEIHKDKTEKQEKPERKIQTKVTHKEKEKGKEKVREKEKP
  EKKATHKEKIEKKEKPETKTLAKEQKKAKTAEKSEEKTKKEVKGGKQEKVKQTAAKVKEV
  QKTPSKPKEKEDKEKAAVSKHEQKDQYAFCRYMIDIFVHGDLKPGQSPAIPPPLPTEQAS
  RPTPASPALEEKEGEKKKAEKKVTSETKKKEKEDIKKKSEKETAIDVEKKEPGKASETKQ
  GTVKIAAQAAAKKDEKKEDSKKTKKPAEVEQPKGKKQEKKEKHVEPAKSPKKEHSVPSDK
  QVKAKTERAKEEIGAVSIKKAVPGKKEEKTTKTVEQEIRKEKSGKTSSILKDKEPIKGKE
  EKVPASLKEKEPETKKDEKMSKAGKEVKPKPPQLQGKKEEKPEPQIKKEAKPAISEKVQI
  HKQDIVKPEKTVSHGKPEEKVLKQVKAVTIEKTAKPKPTKKAEHREREPPSIKTDKPKPT
  PKGTSEVTESGKKKTEISEKESKEKADMKHLREEKVSTRKESLQLHNVTKAEKPARVSKD
  VEDVPASKKAKEGTEDVSPTKQKSPISFFQCVYLDGYNGYGFQFPFTPADRPGESSGQAN
  SPGQKQQGQ
• Function: Contributes to the regulation of lumenal Ca2+ release via the sarcoplasmic reticulum calcium release channels RYR1 and RYR2, a key step in triggering skeletal and heart muscle contraction. Required for normal organization of the triad junction, where T-tubules and the sarcoplasmic reticulum terminal cisternae are in close contact. Required for normal skeletal muscle strength. 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

16 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 5	DISO0CXA	Definitive	Autosomal recessive	[2]
Arrhythmia	DISFF2NI	Strong	Genetic Variation	[3]
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[4]
Catecholaminergic polymorphic ventricular tachycardia 1	DISKGB3F	Strong	Genetic Variation	[5]
Congenital multicore myopathy with external ophthalmoplegia	DIS39ELI	Strong	Biomarker	[6]
Congenital myopathy	DISLSK9G	Strong	Biomarker	[7]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[8]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[9]
Familial long QT syndrome	DISRNNCY	Strong	Autosomal recessive	[4]
Long QT syndrome	DISMKWS3	Strong	Autosomal recessive	[1]
Multiminicore myopathy	DISE6VYN	Strong	Biomarker	[6]
Neuropathy, congenital hypomyelinating, 2	DISRN8BK	Strong	Genetic Variation	[10]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[10]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[10]
Ventricular septal defect	DISICO41	Strong	Biomarker	[11]

3 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 Triadin (TRDN).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Triadin (TRDN).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Triadin (TRDN).	[15]

1 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 decreases the methylation of Triadin (TRDN).	[14]

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] Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest: Elucidation of the Triadin Knockout Syndrome. Circulation. 2015 Jun 9;131(23):2051-60. doi: 10.1161/CIRCULATIONAHA.115.015397. Epub 2015 Apr 28.
• [3] A novel homozygous mutation in the TRDN gene causes a severe form of pediatric malignant ventricular arrhythmia.Heart Rhythm. 2020 Feb;17(2):296-304. doi: 10.1016/j.hrthm.2019.08.018. Epub 2019 Aug 19.
• [4] International Triadin Knockout Syndrome Registry. Circ Genom Precis Med. 2019 Feb;12(2):e002419. doi: 10.1161/CIRCGEN.118.002419.
• [5] Interplay between Triadin and Calsequestrin in the Pathogenesis of CPVT in the Mouse.Mol Ther. 2020 Jan 8;28(1):171-179. doi: 10.1016/j.ymthe.2019.09.012. Epub 2019 Sep 13.
• [6] Abnormal distribution of calcium-handling proteins: a novel distinctive marker in core myopathies.J Neuropathol Exp Neurol. 2007 Jan;66(1):57-65. doi: 10.1097/NEN.0b013e31802d47ce.
• [7] Congenital myopathy associated with the triadin knockout syndrome.Neurology. 2017 Mar 21;88(12):1153-1156. doi: 10.1212/WNL.0000000000003745. Epub 2017 Feb 15.
• [8] 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.
• [9] Co-inheritance of specific genotypes of HSPG and ApoE gene increases risk of type 2 diabetic nephropathy.Mol Cell Biochem. 2003 Dec;254(1-2):353-8. doi: 10.1023/a:1027364121738.
• [10] A genome-wide association study suggests that MAPK14 is associated with diabetic foot ulcers.Br J Dermatol. 2017 Dec;177(6):1664-1670. doi: 10.1111/bjd.15787. Epub 2017 Nov 27.
• [11] Efficient Mining of Variants From Trios for Ventricular Septal Defect Association Study.Front Genet. 2019 Aug 8;10:670. doi: 10.3389/fgene.2019.00670. eCollection 2019.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] 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.
• [15] 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.