Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4Z9T8N)

• DOT Name: Myosin-7 (MYH7)
• Synonyms: Myosin heavy chain 7; Myosin heavy chain slow isoform; MyHC-slow; Myosin heavy chain, cardiac muscle beta isoform; MyHC-beta
• Gene Name: MYH7
• Related Disease:
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1S
  Hypertrophic cardiomyopathy
  Hypertrophic cardiomyopathy 1
  MYH7-related skeletal myopathy
  Myopathy, myosin storage, autosomal recessive
  Obsolete myopathy, myosin storage, autosomal dominant
  Congenital myopathy 7A, myosin storage, autosomal dominant
  Ebstein anomaly
  Hyaline body myopathy
  Left ventricular noncompaction
  Obsolete familial isolated dilated cardiomyopathy
  Arrhythmogenic right ventricular cardiomyopathy
  Congenital heart disease
• UniProt ID: MYH7_HUMAN
• PDB ID: 2FXM; 2FXO; 3DTP; 4DB1; 4P7H; 4PA0; 4XA1; 4XA3; 4XA4; 4XA6; 5CHX; 5CJ0; 5CJ1; 5CJ4; 5TBY; 5WJ7; 5WJB; 5WLQ; 5WLZ; 5WME; 6PF2; 6PFP; 8ACT; 8EFD; 8EFE; 8EFH; 8EFI; 8ENC; 8G4L
• Pfam ID: PF00063 ; PF02736 ; PF01576
• Sequence:
  MGDSEMAVFGAAAPYLRKSEKERLEAQTRPFDLKKDVFVPDDKQEFVKAKIVSREGGKVT
  AETEYGKTVTVKEDQVMQQNPPKFDKIEDMAMLTFLHEPAVLYNLKDRYGSWMIYTYSGL
  FCVTVNPYKWLPVYTPEVVAAYRGKKRSEAPPHIFSISDNAYQYMLTDRENQSILITGES
  GAGKTVNTKRVIQYFAVIAAIGDRSKKDQSPGKGTLEDQIIQANPALEAFGNAKTVRNDN
  SSRFGKFIRIHFGATGKLASADIETYLLEKSRVIFQLKAERDYHIFYQILSNKKPELLDM
  LLITNNPYDYAFISQGETTVASIDDAEELMATDNAFDVLGFTSEEKNSMYKLTGAIMHFG
  NMKFKLKQREEQAEPDGTEEADKSAYLMGLNSADLLKGLCHPRVKVGNEYVTKGQNVQQV
  IYATGALAKAVYERMFNWMVTRINATLETKQPRQYFIGVLDIAGFEIFDFNSFEQLCINF
  TNEKLQQFFNHHMFVLEQEEYKKEGIEWTFIDFGMDLQACIDLIEKPMGIMSILEEECMF
  PKATDMTFKAKLFDNHLGKSANFQKPRNIKGKPEAHFSLIHYAGIVDYNIIGWLQKNKDP
  LNETVVGLYQKSSLKLLSTLFANYAGADAPIEKGKGKAKKGSSFQTVSALHRENLNKLMT
  NLRSTHPHFVRCIIPNETKSPGVMDNPLVMHQLRCNGVLEGIRICRKGFPNRILYGDFRQ
  RYRILNPAAIPEGQFIDSRKGAEKLLSSLDIDHNQYKFGHTKVFFKAGLLGLLEEMRDER
  LSRIITRIQAQSRGVLARMEYKKLLERRDSLLVIQWNIRAFMGVKNWPWMKLYFKIKPLL
  KSAEREKEMASMKEEFTRLKEALEKSEARRKELEEKMVSLLQEKNDLQLQVQAEQDNLAD
  AEERCDQLIKNKIQLEAKVKEMNERLEDEEEMNAELTAKKRKLEDECSELKRDIDDLELT
  LAKVEKEKHATENKVKNLTEEMAGLDEIIAKLTKEKKALQEAHQQALDDLQAEEDKVNTL
  TKAKVKLEQQVDDLEGSLEQEKKVRMDLERAKRKLEGDLKLTQESIMDLENDKQQLDERL
  KKKDFELNALNARIEDEQALGSQLQKKLKELQARIEELEEELEAERTARAKVEKLRSDLS
  RELEEISERLEEAGGATSVQIEMNKKREAEFQKMRRDLEEATLQHEATAAALRKKHADSV
  AELGEQIDNLQRVKQKLEKEKSEFKLELDDVTSNMEQIIKAKANLEKMCRTLEDQMNEHR
  SKAEETQRSVNDLTSQRAKLQTENGELSRQLDEKEALISQLTRGKLTYTQQLEDLKRQLE
  EEVKAKNALAHALQSARHDCDLLREQYEEETEAKAELQRVLSKANSEVAQWRTKYETDAI
  QRTEELEEAKKKLAQRLQEAEEAVEAVNAKCSSLEKTKHRLQNEIEDLMVDVERSNAAAA
  ALDKKQRNFDKILAEWKQKYEESQSELESSQKEARSLSTELFKLKNAYEESLEHLETFKR
  ENKNLQEEISDLTEQLGSSGKTIHELEKVRKQLEAEKMELQSALEEAEASLEHEEGKILR
  AQLEFNQIKAEIERKLAEKDEEMEQAKRNHLRVVDSLQTSLDAETRSRNEALRVKKKMEG
  DLNEMEIQLSHANRMAAEAQKQVKSLQSLLKDTQIQLDDAVRANDDLKENIAIVERRNNL
  LQAELEELRAVVEQTERSRKLAEQELIETSERVQLLHSQNTSLINQKKKMDADLSQLQTE
  VEEAVQECRNAEEKAKKAITDAAMMAEELKKEQDTSAHLERMKKNMEQTIKDLQHRLDEA
  EQIALKGGKKQLQKLEARVRELENELEAEQKRNAESVKGMRKSERRIKELTYQTEEDRKN
  LLRLQDLVDKLQLKVKAYKRQAEEAEEQANTNLSKFRKVQHELDEAEERADIAESQVNKL
  RAKSRDIGTKGLNEE
• Function: Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction. Forms regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle.
• Tissue Specificity: Both wild type and variant Gln-403 are detected in skeletal muscle (at protein level).
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Motor proteins (hsa04814)
  Cytoskeleton in muscle cells (hsa04820)
  Thyroid hormone sig.ling pathway (hsa04919)
  Hypertrophic cardiomyopathy (hsa05410)
  Dilated cardiomyopathy (hsa05414)
  Viral myocarditis (hsa05416)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dilated cardiomyopathy	DISX608J	Definitive	Autosomal dominant	[1]
Dilated cardiomyopathy 1S	DISNNML2	Definitive	Autosomal dominant	[2]
Hypertrophic cardiomyopathy	DISQG2AI	Definitive	Autosomal dominant	[1]
Hypertrophic cardiomyopathy 1	DISFOPCJ	Definitive	Autosomal dominant	[3]
MYH7-related skeletal myopathy	DIS5EQO5	Definitive	Autosomal dominant	[1]
Myopathy, myosin storage, autosomal recessive	DISMK6ZJ	Strong	Autosomal recessive	[4]
Obsolete myopathy, myosin storage, autosomal dominant	DIS9MSP9	Moderate	Autosomal dominant	[3]
Congenital myopathy 7A, myosin storage, autosomal dominant	DISUV37B	Supportive	Autosomal dominant	[5]
Ebstein anomaly	DISO3NHV	Supportive	Autosomal dominant	[6]
Hyaline body myopathy	DIS0IGW9	Supportive	Autosomal dominant	[7]
Left ventricular noncompaction	DISJ4QEG	Supportive	Autosomal dominant	[8]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[9]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Limited	Autosomal dominant	[1]
Congenital heart disease	DISQBA23	Limited	Autosomal dominant	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Myosin-7 (MYH7) increases the abundance of Adenosine triphosphate.	[20]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nifedipine	DMSVOZT	Approved	Myosin-7 (MYH7) decreases the response to substance of Nifedipine.	[20]

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 Myosin-7 (MYH7).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Myosin-7 (MYH7).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Myosin-7 (MYH7).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myosin-7 (MYH7).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Myosin-7 (MYH7).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Myosin-7 (MYH7).	[14]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Myosin-7 (MYH7).	[14]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Myosin-7 (MYH7).	[15]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Myosin-7 (MYH7).	[12]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Myosin-7 (MYH7).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Myosin-7 (MYH7).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Myosin-7 (MYH7).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Myosin-7 (MYH7).	[19]

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] Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes. Sci Rep. 2017 Nov 1;7(1):14829. doi: 10.1038/s41598-017-13675-8.
• [3] 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.
• [4] Homozygous mutation in MYH7 in myosin storage myopathy and cardiomyopathy. Neurology. 2007 Mar 20;68(12):962. doi: 10.1212/01.wnl.0000257131.13438.2c.
• [5] MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy. Neuromuscul Disord. 2007 Apr;17(4):321-9. doi: 10.1016/j.nmd.2007.01.010. Epub 2007 Mar 2.
• [6] Familial ebstein anomaly, left ventricular hypertrabeculation, and ventricular septal defect associated with a MYH7 mutation. Am J Med Genet A. 2013 Dec;161A(12):3187-90. doi: 10.1002/ajmg.a.36182. Epub 2013 Aug 16.
• [7] Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy. Neurology. 2004 May 11;62(9):1518-21. doi: 10.1212/01.wnl.0000123255.92062.37.
• [8] Novel mutation in exon 14 of the sarcomere gene MYH7 in familial left ventricular noncompaction with bicuspid aortic valve. Circ Heart Fail. 2014 Nov;7(6):1059-62. doi: 10.1161/CIRCHEARTFAILURE.114.001666.
• [9] Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med. 2000 Dec 7;343(23):1688-96. doi: 10.1056/NEJM200012073432304.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.
• [19] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [20] CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy. Eur Heart J. 2018 Nov 14;39(43):3879-3892. doi: 10.1093/eurheartj/ehy249.