Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQQMJ94)

• DOT Name: Telethonin (TCAP)
• Synonyms: Titin cap protein
• Gene Name: TCAP
• Related Disease:
  Autosomal recessive limb-girdle muscular dystrophy
  Autosomal recessive limb-girdle muscular dystrophy type 2B
  Autosomal recessive limb-girdle muscular dystrophy type 2E
  Autosomal recessive limb-girdle muscular dystrophy type 2F
  Autosomal recessive limb-girdle muscular dystrophy type 2G
  Breast cancer
  Breast carcinoma
  Cardiomyopathy
  Dilated cardiomyopathy 1A
  Familial dilated cardiomyopathy
  Gastric cancer
  Hermansky-Pudlak syndrome
  Hypertrophic cardiomyopathy 25
  Limb-girdle muscular dystrophy
  Neuromuscular disease
  Stomach cancer
  Obsolete familial isolated dilated cardiomyopathy
  Hypertrophic cardiomyopathy
  Dilated cardiomyopathy
  Inflammatory bowel disease
  Muscular dystrophy
  Myopathy
• UniProt ID: TELT_HUMAN
• PDB ID: 1YA5; 2F8V
• Pfam ID: PF09470
• Sequence:
  MATSELSCEVSEENCERREAFWAEWKDLTLSTRPEEGCSLHEEDTQRHETYHQQGQCQVL
  VQRSPWLMMRMGILGRGLQEYQLPYQRVLPLPIFTPAKMGATKEEREDTPIQLQELLALE
  TALGGQCVDRQEVAEITKQLPPVVPVSKPGALRRSLSRSMSQEAQRG
• Function: Muscle assembly regulating factor. Mediates the antiparallel assembly of titin (TTN) molecules at the sarcomeric Z-disk.
• Tissue Specificity: Heart and skeletal muscle.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway: Striated Muscle Contraction (R-HSA-390522)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive limb-girdle muscular dystrophy	DISWPGLM	Definitive	Autosomal recessive	[1]
Autosomal recessive limb-girdle muscular dystrophy type 2B	DISWWCL7	Strong	Genetic Variation	[2]
Autosomal recessive limb-girdle muscular dystrophy type 2E	DISQH5PB	Strong	Biomarker	[3]
Autosomal recessive limb-girdle muscular dystrophy type 2F	DISXFDEG	Strong	Genetic Variation	[3]
Autosomal recessive limb-girdle muscular dystrophy type 2G	DISCTJYI	Strong	Autosomal recessive	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[6]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[7]
Familial dilated cardiomyopathy	DISBHDU9	Strong	GermlineCausalMutation	[8]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Hermansky-Pudlak syndrome	DISCY0HQ	Strong	Biomarker	[9]
Hypertrophic cardiomyopathy 25	DISAJ57O	Strong	Autosomal dominant	[10]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Biomarker	[9]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[11]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[6]
Hypertrophic cardiomyopathy	DISQG2AI	Disputed	Autosomal dominant	[1]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[1]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[12]
Muscular dystrophy	DISJD6P7	Limited	Biomarker	[13]
Myopathy	DISOWG27	Limited	Biomarker	[14]

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 Telethonin (TCAP).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Telethonin (TCAP).	[22]

8 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 Telethonin (TCAP).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Telethonin (TCAP).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Telethonin (TCAP).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Telethonin (TCAP).	[16]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Telethonin (TCAP).	[19]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Telethonin (TCAP).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Telethonin (TCAP).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Telethonin (TCAP).	[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] Dysferlin protein analysis in limb-girdle muscular dystrophies.J Mol Neurosci. 2001 Aug;17(1):71-80. doi: 10.1385/JMN:17:1:71.
• [3] Seven autosomal recessive limb-girdle muscular dystrophies in the Brazilian population: from LGMD2A to LGMD2G.Am J Med Genet. 1999 Feb 19;82(5):392-8. doi: 10.1002/(sici)1096-8628(19990219)82:5<392::aid-ajmg7>3.0.co;2-0.
• [4] 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.
• [5] Evolutionary recombination hotspot around GSDML-GSDM locus is closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon.Int J Oncol. 2004 Apr;24(4):757-63.
• [6] Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol. 2004 Dec 7;44(11):2192-201. doi: 10.1016/j.jacc.2004.08.058.
• [7] Common susceptibility variants examined for association with dilated cardiomyopathy.Ann Hum Genet. 2010 Mar;74(2):110-6. doi: 10.1111/j.1469-1809.2010.00566.x. Epub 2010 Feb 18.
• [8] Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy.Clin Transl Sci. 2008 May;1(1):21-6. doi: 10.1111/j.1752-8062.2008.00017.x.
• [9] Precise therapeutic gene correction by a simple nuclease-induced double-stranded break.Nature. 2019 Apr;568(7753):561-565. doi: 10.1038/s41586-019-1076-8. Epub 2019 Apr 3.
• [10] The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell. 2002 Dec 27;111(7):943-55. doi: 10.1016/s0092-8674(02)01226-6.
• [11] Novel mutation in TCAP manifesting with asymmetric calves and early-onset joint retractions.Neuromuscul Disord. 2016 Nov;26(11):749-753. doi: 10.1016/j.nmd.2016.07.003. Epub 2016 Jul 16.
• [12] Effect of TELEmedicine for Inflammatory Bowel Disease on Patient Activation and Self-Efficacy.Dig Dis Sci. 2020 Jan;65(1):96-103. doi: 10.1007/s10620-018-5433-5. Epub 2019 Jan 2.
• [13] A study of FHL1, BAG3, MATR3, PTRF and TCAP in Australian muscular dystrophy patients.Neuromuscul Disord. 2011 Nov;21(11):776-81. doi: 10.1016/j.nmd.2011.05.007. Epub 2011 Jun 17.
• [14] Rare diagnosis of telethoninopathy (LGMD2G) in a Turkish patient.Neuromuscul Disord. 2017 Sep;27(9):856-860. doi: 10.1016/j.nmd.2017.05.017. Epub 2017 Jun 1.
• [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] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] 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.
• [20] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] 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.
• [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.