Details of Drug Off-Target (DOT)

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

• DOT Name: Troponin I, fast skeletal muscle (TNNI2)
• Synonyms: Troponin I, fast-twitch isoform
• Gene Name: TNNI2
• Related Disease:
  Spondylocarpotarsal synostosis syndrome
  Arthrogryposis
  Arthrogryposis, distal, type 1A
  Distal arthrogryposis
  Distal arthrogryposis type 2B1
  Myocardial infarction
  Arthrogryposis, distal, type 1B
  Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome
  Congenital contractural arachnodactyly
  Distal arthrogryposis type 5D
  Gordon syndrome
  Myopathy
  Trismus-pseudocamptodactyly syndrome
  Digitotalar dysmorphism
  Sheldon-hall syndrome
  Freeman-Sheldon syndrome
  Gastric cancer
  Stomach cancer
• UniProt ID: TNNI2_HUMAN
• PDB ID: 2MKP; 7KAA
• Pfam ID: PF00992
• Sequence:
  MGDEEKRNRAITARRQHLKSVMLQIAATELEKEESRREAEKQNYLAEHCPPLHIPGSMSE
  VQELCKQLHAKIDAAEEEKYDMEVRVQKTSKELEDMNQKLFDLRGKFKRPPLRRVRMSAD
  AMLKALLGSKHKVCMDLRANLKQVKKEDTEKERDLRDVGDWRKNIEEKSGMEGRKKMFES
  ES
• Function: Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
• KEGG Pathway:
  Motor proteins (hsa04814)
  Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway: Striated Muscle Contraction (R-HSA-390522)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spondylocarpotarsal synostosis syndrome	DISF9VP3	Definitive	Genetic Variation	[1]
Arthrogryposis	DISC81CM	Strong	Biomarker	[2]
Arthrogryposis, distal, type 1A	DISD8IKM	Strong	Genetic Variation	[3]
Distal arthrogryposis	DIS3QIEL	Strong	Genetic Variation	[4]
Distal arthrogryposis type 2B1	DIS6VMTJ	Strong	Autosomal dominant	[5]
Myocardial infarction	DIS655KI	Strong	Biomarker	[6]
Arthrogryposis, distal, type 1B	DISHXTV4	moderate	Biomarker	[7]
Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome	DISBCS1Y	moderate	Biomarker	[7]
Congenital contractural arachnodactyly	DISOM1K7	moderate	Biomarker	[7]
Distal arthrogryposis type 5D	DISYDVKR	moderate	Biomarker	[7]
Gordon syndrome	DISVMP0Y	moderate	Biomarker	[7]
Myopathy	DISOWG27	moderate	Biomarker	[8]
Trismus-pseudocamptodactyly syndrome	DISZ2Y71	moderate	Biomarker	[7]
Digitotalar dysmorphism	DISOW5Q1	Supportive	Autosomal dominant	[9]
Sheldon-hall syndrome	DISOCVMC	Supportive	Autosomal dominant	[9]
Freeman-Sheldon syndrome	DIS7V9PS	Limited	Biomarker	[7]
Gastric cancer	DISXGOUK	Limited	Biomarker	[10]
Stomach cancer	DISKIJSX	Limited	Biomarker	[10]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Troponin I, fast skeletal muscle (TNNI2) increases the Cardiotoxicity ADR of Doxorubicin.	[23]
Cyclophosphamide	DM4O2Z7	Approved	Troponin I, fast skeletal muscle (TNNI2) increases the Cardiotoxicity ADR of Cyclophosphamide.	[23]

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 Troponin I, fast skeletal muscle (TNNI2).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Troponin I, fast skeletal muscle (TNNI2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Troponin I, fast skeletal muscle (TNNI2).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Troponin I, fast skeletal muscle (TNNI2).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Troponin I, fast skeletal muscle (TNNI2).	[14]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Troponin I, fast skeletal muscle (TNNI2).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Troponin I, fast skeletal muscle (TNNI2).	[17]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Troponin I, fast skeletal muscle (TNNI2).	[18]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Troponin I, fast skeletal muscle (TNNI2).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Troponin I, fast skeletal muscle (TNNI2).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Troponin I, fast skeletal muscle (TNNI2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Troponin I, fast skeletal muscle (TNNI2).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Troponin I, fast skeletal muscle (TNNI2).	[22]

References

• [1] Protein-altering MYH3 variants are associated with a spectrum of phenotypes extending to spondylocarpotarsal synostosis syndrome. Eur J Hum Genet. 2016 Dec;24(12):1746-1751. doi: 10.1038/ejhg.2016.84. Epub 2016 Jul 6.
• [2] A novel TNNI2 mutation causes Freeman-Sheldon syndrome in a Chinese family with an affected adult with only facial contractures.Gene. 2013 Sep 25;527(2):630-5. doi: 10.1016/j.gene.2013.06.082. Epub 2013 Jul 11.
• [3] A novel missense mutation of TNNI2 in a Chinese family cause distal arthrogryposis type 1.Am J Med Genet A. 2016 Jan;170A(1):135-41. doi: 10.1002/ajmg.a.37391. Epub 2015 Sep 16.
• [4] Identification of a novel pathogenic mutation of the MYH3 gene in a family with distal arthrogryposis type 2B.Mol Med Rep. 2020 Jan;21(1):438-444. doi: 10.3892/mmr.2019.10820. Epub 2019 Nov 15.
• [5] Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Am J Hum Genet. 2003 Mar;72(3):681-90. doi: 10.1086/368294.
• [6] The Troponin-I fast skeletal muscle is reliable marker for the determination of vitality in the suicide hanging.Forensic Sci Int. 2019 Aug;301:284-288. doi: 10.1016/j.forsciint.2019.05.055. Epub 2019 Jun 4.
• [7] A gain-of-function mutation in Tnni2 impeded bone development through increasing Hif3a expression in DA2B mice.PLoS Genet. 2014 Oct 23;10(10):e1004589. doi: 10.1371/journal.pgen.1004589. eCollection 2014 Oct.
• [8] Biomarkers of drug-induced skeletal muscle injury in the rat: troponin I and myoglobin.Toxicol Sci. 2009 Oct;111(2):402-12. doi: 10.1093/toxsci/kfp166. Epub 2009 Jul 23.
• [9] Spectrum of mutations that cause distal arthrogryposis types 1 and 2B. Am J Med Genet A. 2013 Mar;161A(3):550-5. doi: 10.1002/ajmg.a.35809. Epub 2013 Feb 7.
• [10] Troponin I2 as a Specific Biomarker for Prediction of Peritoneal Metastasis in Gastric Cancer.Ann Surg Oncol. 2018 Jul;25(7):2083-2090. doi: 10.1245/s10434-018-6480-z. Epub 2018 Apr 16.
• [11] 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.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] 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.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [18] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [19] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.