Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCEW5XW)

DOT Name Myotilin (MYOT)
Synonyms 57 kDa cytoskeletal protein; Myofibrillar titin-like Ig domains protein; Titin immunoglobulin domain protein
Gene Name MYOT
Related Disease
Muscular dystrophy ( )
Cardiomyopathy ( )
Distal myopathy ( )
Limb-girdle muscular dystrophy ( )
Mitochondrial disease ( )
Myofibrillar myopathy ( )
Myofibrillar myopathy 3 ( )
Neuromuscular disease ( )
Peripheral neuropathy ( )
Atrial fibrillation ( )
Distal myopathy with vocal cord weakness ( )
Familial atrial fibrillation ( )
Respiratory failure ( )
Obsolete spheroid body myopathy ( )
Acute myelogenous leukaemia ( )
Central core myopathy ( )
GNE myopathy ( )
Idiopathic cardiomyopathy ( )
Myopathy ( )
Nemaline myopathy ( )
Neoplasm ( )
UniProt ID
MYOTI_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
2KDG; 2KKQ
Pfam ID
PF07679
Sequence
MFNYERPKHFIQSQNPCGSRLQPPGPETSSFSSQTKQSSIIIQPRQCTEQRFSASSTLSS
HITMSSSAFPASPKQHAGSNPGQRVTTTYNQSPASFLSSILPSQPDYNSSKIPSAMDSNY
QQSSAGQPINAKPSQTANAKPIPRTPDHEIQGSKEALIQDLERKLKCKDTLLHNGNQRLT
YEEKMARRLLGPQNAAAVFQAQDDSGAQDSQQHNSEHARLQVPTSQVRSRSTSRGDVNDQ
DAIQEKFYPPRFIQVPENMSIDEGRFCRMDFKVSGLPAPDVSWYLNGRTVQSDDLHKMIV
SEKGLHSLIFEVVRASDAGAYACVAKNRAGEATFTVQLDVLAKEHKRAPMFIYKPQSKKV
LEGDSVKLECQISAIPPPKLFWKRNNEMVQFNTDRISLYQDNTGRVTLLIKDVNKKDAGW
YTVSAVNEAGVTTCNTRLDVTARPNQTLPAPKQLRVRPTFSKYLALNGKGLNVKQAFNPE
GEFQRLAAQSGLYESEEL
Function Component of a complex of multiple actin cross-linking proteins. Involved in the control of myofibril assembly and stability at the Z lines in muscle cells.
Tissue Specificity Expressed in skeletal muscle (at protein level). Expressed in skeletal muscle, heart, bone marrow and thyroid gland.
KEGG Pathway
Cytoskeleton in muscle cells (hsa04820 )

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Muscular dystrophy DISJD6P7 Definitive Genetic Variation [1]
Cardiomyopathy DISUPZRG Strong Genetic Variation [2]
Distal myopathy DIS7F5R0 Strong Genetic Variation [3]
Limb-girdle muscular dystrophy DISI9Y1Z Strong Biomarker [4]
Mitochondrial disease DISKAHA3 Strong Biomarker [5]
Myofibrillar myopathy DISF24LW Strong Genetic Variation [6]
Myofibrillar myopathy 3 DISENXUL Strong Autosomal dominant [7]
Neuromuscular disease DISQTIJZ Strong Genetic Variation [8]
Peripheral neuropathy DIS7KN5G Strong Genetic Variation [2]
Atrial fibrillation DIS15W6U moderate Biomarker [9]
Distal myopathy with vocal cord weakness DISIA80W moderate Genetic Variation [10]
Familial atrial fibrillation DISL4AGF moderate Biomarker [9]
Respiratory failure DISVMYJO moderate Genetic Variation [11]
Obsolete spheroid body myopathy DIS3D6EB Supportive Autosomal dominant [12]
Acute myelogenous leukaemia DISCSPTN Limited Biomarker [13]
Central core myopathy DIS18AZZ Limited Biomarker [14]
GNE myopathy DIS73X4W Limited Genetic Variation [15]
Idiopathic cardiomyopathy DISUGBZL Limited Biomarker [2]
Myopathy DISOWG27 Limited Biomarker [16]
Nemaline myopathy DIS5IYLY Limited Biomarker [14]
Neoplasm DISZKGEW Limited Biomarker [17]
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⏷ Show the Full List of 21 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
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 Myotilin (MYOT). [18]
Etoposide DMNH3PG Approved Etoposide increases the expression of Myotilin (MYOT). [19]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of Myotilin (MYOT). [20]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Myotilin (MYOT). [21]
Torcetrapib DMDHYM7 Discontinued in Phase 2 Torcetrapib increases the expression of Myotilin (MYOT). [22]
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References

1 Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM.Hum Mol Genet. 2006 Aug 1;15(15):2348-62. doi: 10.1093/hmg/ddl160. Epub 2006 Jun 26.
2 Mutations in myotilin cause myofibrillar myopathy.Neurology. 2004 Apr 27;62(8):1363-71. doi: 10.1212/01.wnl.0000123576.74801.75.
3 Generalized muscle pseudo-hypertrophy and stiffness associated with the myotilin Ser55Phe mutation: a novel myotilinopathy phenotype?.J Neurol Sci. 2009 Feb 15;277(1-2):167-71. doi: 10.1016/j.jns.2008.10.019. Epub 2008 Nov 22.
4 Impact of next-generation sequencing panels in the evaluation of limb-girdle muscular dystrophies.Ann Hum Genet. 2019 Sep;83(5):331-347. doi: 10.1111/ahg.12319. Epub 2019 May 7.
5 Mitochondrial abnormalities in myofibrillar myopathies.Clin Neuropathol. 2014 Mar-Apr;33(2):134-42. doi: 10.5414/NP300693.
6 Novel recessive myotilin mutation causes severe myofibrillar myopathy.Neurogenetics. 2014 Aug;15(3):151-6. doi: 10.1007/s10048-014-0410-4. Epub 2014 Jun 14.
7 Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet. 2000 Sep 1;9(14):2141-7. doi: 10.1093/hmg/9.14.2141.
8 Maintenance of muscle mass, fiber size, and contractile function in mice lacking the Z-disc protein myotilin.Ups J Med Sci. 2009;114(4):235-41. doi: 10.3109/03009730903276399.
9 Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.Nat Genet. 2018 Sep;50(9):1234-1239. doi: 10.1038/s41588-018-0171-3. Epub 2018 Jul 30.
10 Myotilin is not the causative gene for vocal cord and pharyngeal weakness with distal myopathy (VCPDM).Ann Hum Genet. 2006 May;70(Pt 3):414-6. doi: 10.1111/j.1529-8817.2005.00252.x.
11 A novel mutation in the myotilin gene (MYOT) causes a severe form of limb girdle muscular dystrophy 1A (LGMD1A).J Neurol. 2011 Aug;258(8):1437-44. doi: 10.1007/s00415-011-5953-9. Epub 2011 Feb 20.
12 A mutation in myotilin causes spheroid body myopathy. Neurology. 2005 Dec 27;65(12):1936-40. doi: 10.1212/01.wnl.0000188872.28149.9a.
13 A radiation hybrid breakpoint map of the acute myeloid leukemia (AML) and limb-girdle muscular dystrophy 1A (LGMD1A) regions of chromosome 5q31 localizing 122 expressed sequences.Genomics. 1999 Apr 1;57(1):24-35. doi: 10.1006/geno.1999.5765.
14 Beyond LGMD1A: myotilin is a component of central core lesions and nemaline rods.Neuromuscul Disord. 2003 Aug;13(6):451-5. doi: 10.1016/s0960-8966(03)00064-6.
15 Myopathies resulting from mutations in sarcomeric proteins.Curr Opin Neurol. 2004 Oct;17(5):529-37. doi: 10.1097/00019052-200410000-00003.
16 New insights into the protein aggregation pathology in myotilinopathy by combined proteomic and immunolocalization analyses.Acta Neuropathol Commun. 2016 Feb 3;4:8. doi: 10.1186/s40478-016-0280-0.
17 TTID: A novel gene at 5q31 encoding a protein with titin-like features.Genomics. 1999 Sep 1;60(2):226-33. doi: 10.1006/geno.1999.5912.
18 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.
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 Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
21 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.
22 Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.