Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4C498E)

• DOT Name: Troponin T, fast skeletal muscle (TNNT3)
• Synonyms: TnTf; Beta-TnTF; Fast skeletal muscle troponin T; fTnT
• Gene Name: TNNT3
• Related Disease:
  Arthrogryposis
  Distal arthrogryposis
  Oculopharyngeal muscular dystrophy
  Arthrogryposis, distal, type 1A
  Breast cancer
  Breast carcinoma
  Clubfoot
  Disorder of orbital region
  Distal arthrogryposis type 2B1
  Glaucoma/ocular hypertension
  Arthrogryposis, distal, type 2B2
  Nemaline myopathy
  Digitotalar dysmorphism
  Sheldon-hall syndrome
  Congenital vertical talus
  Freeman-Sheldon syndrome
• UniProt ID: TNNT3_HUMAN
• Pfam ID: PF00992
• Sequence:
  MSDEEVEQVEEQYEEEEEAQEEAAEVHEEVHEPEEVQEDTAEEDAEEEKPRPKLTAPKIP
  EGEKVDFDDIQKKRQNKDLMELQALIDSHFEARKKEEEELVALKERIEKRRAERAEQQRI
  RAEKERERQNRLAEEKARREEEDAKRRAEDDLKKKKALSSMGANYSSYLAKADQKRGKKQ
  TAREMKKKILAERRKPLNIDHLGEDKLRDKAKELWETLHQLEIDKFEFGEKLKRQKYDIT
  TLRSRIDQAQKHSKKAGTPAKGKVGGRWK
• Function: Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
• Tissue Specificity: In fetal and adult fast skeletal muscles, with a higher level expression in fetal than in adult muscle.
• 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

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthrogryposis	DISC81CM	Definitive	Biomarker	[1]
Distal arthrogryposis	DIS3QIEL	Definitive	Genetic Variation	[2]
Oculopharyngeal muscular dystrophy	DISF4G07	Definitive	Biomarker	[3]
Arthrogryposis, distal, type 1A	DISD8IKM	Strong	GermlineCausalMutation	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Clubfoot	DISLXT4S	Strong	Genetic Variation	[1]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[6]
Distal arthrogryposis type 2B1	DIS6VMTJ	Strong	Autosomal dominant	[7]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Biomarker	[6]
Arthrogryposis, distal, type 2B2	DIS9G47C	Moderate	Autosomal dominant	[8]
Nemaline myopathy	DIS5IYLY	Moderate	Autosomal recessive	[8]
Digitotalar dysmorphism	DISOW5Q1	Supportive	Autosomal dominant	[4]
Sheldon-hall syndrome	DISOCVMC	Supportive	Autosomal dominant	[4]
Congenital vertical talus	DISZF3HD	Limited	Genetic Variation	[9]
Freeman-Sheldon syndrome	DIS7V9PS	Limited	Biomarker	[10]

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 T, fast skeletal muscle (TNNT3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Troponin T, fast skeletal muscle (TNNT3).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Troponin T, fast skeletal muscle (TNNT3).	[12]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Troponin T, fast skeletal muscle (TNNT3).	[13]

References

• [1] Skeletal muscle contractile gene (TNNT3, MYH3, TPM2) mutations not found in vertical talus or clubfoot.Clin Orthop Relat Res. 2009 May;467(5):1195-200. doi: 10.1007/s11999-008-0694-5. Epub 2009 Jan 14.
• [2] Nemaline myopathy and distal arthrogryposis associated with an autosomal recessiveTNNT3splice variant.Hum Mutat. 2018 Mar;39(3):383-388. doi: 10.1002/humu.23385. Epub 2018 Jan 13.
• [3] Nuclear poly(A)-binding protein aggregates misplace a pre-mRNA outside of SC35 speckle causing its abnormal splicing.Nucleic Acids Res. 2016 Dec 15;44(22):10929-10945. doi: 10.1093/nar/gkw703. Epub 2016 Aug 9.
• [4] 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.
• [5] Genome-wide association study identifies five new breast cancer susceptibility loci.Nat Genet. 2010 Jun;42(6):504-7. doi: 10.1038/ng.586. Epub 2010 May 9.
• [6] An examination of the regulatory mechanism of Pxdn mutation-induced eye disorders using microarray analysis.Int J Mol Med. 2016 Jun;37(6):1449-56. doi: 10.3892/ijmm.2016.2572. Epub 2016 Apr 20.
• [7] Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B. Am J Hum Genet. 2003 Jul;73(1):212-4. doi: 10.1086/376418.
• [8] 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.
• [9] A novel mutation in TNNT3 associated with Sheldon-Hall syndrome in a Chinese family with vertical talus.Eur J Med Genet. 2011 May-Jun;54(3):351-3. doi: 10.1016/j.ejmg.2011.03.002. Epub 2011 Mar 12.
• [10] 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.
• [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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] 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.
• [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.