Details of Drug Off-Target (DOT)

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

• DOT Name: Myosin-3 (MYH3)
• Synonyms: Muscle embryonic myosin heavy chain; Myosin heavy chain 3; Myosin heavy chain, fast skeletal muscle, embryonic; SMHCE
• Gene Name: MYH3
• Related Disease:
  Distal arthrogryposis
  Freeman-Sheldon syndrome
  Arthrogryposis
  Autosomal dominant prognathism
  Contractures, pterygia, and variable skeletal fusions syndrome 1B
  Distal arthrogryposis type 2B1
  Myopathy
  Scott syndrome
  Autosomal recessive multiple pterygium syndrome
  Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A
  Digitotalar dysmorphism
  Sheldon-hall syndrome
  Spondylocarpotarsal synostosis syndrome
  Arthrogryposis, distal, type 1A
• UniProt ID: MYH3_HUMAN
• Pfam ID: PF00063 ; PF02736 ; PF01576
• Sequence:
  MSSDTEMEVFGIAAPFLRKSEKERIEAQNQPFDAKTYCFVVDSKEEYAKGKIKSSQDGKV
  TVETEDNRTLVVKPEDVYAMNPPKFDRIEDMAMLTHLNEPAVLYNLKDRYTSWMIYTYSG
  LFCVTVNPYKWLPVYNPEVVEGYRGKKRQEAPPHIFSISDNAYQFMLTDRENQSILITGE
  SGAGKTVNTKRVIQYFATIAATGDLAKKKDSKMKGTLEDQIISANPLLEAFGNAKTVRND
  NSSRFGKFIRIHFGTTGKLASADIETYLLEKSRVTFQLKAERSYHIFYQILSNKKPELIE
  LLLITTNPYDYPFISQGEILVASIDDAEELLATDSAIDILGFTPEEKSGLYKLTGAVMHY
  GNMKFKQKQREEQAEPDGTEVADKTAYLMGLNSSDLLKALCFPRVKVGNEYVTKGQTVDQ
  VHHAVNALSKSVYEKLFLWMVTRINQQLDTKLPRQHFIGVLDIAGFEIFEYNSLEQLCIN
  FTNEKLQQFFNHHMFVLEQEEYKKEGIEWTFIDFGMDLAACIELIEKPMGIFSILEEECM
  FPKATDTSFKNKLYDQHLGKSNNFQKPKVVKGRAEAHFSLIHYAGTVDYSVSGWLEKNKD
  PLNETVVGLYQKSSNRLLAHLYATFATADADSGKKKVAKKKGSSFQTVSALFRENLNKLM
  SNLRTTHPHFVRCIIPNETKTPGAMEHSLVLHQLRCNGVLEGIRICRKGFPNRILYGDFK
  QRYRVLNASAIPEGQFIDSKKACEKLLASIDIDHTQYKFGHTKVFFKAGLLGTLEEMRDD
  RLAKLITRTQAVCRGFLMRVEFQKMVQRRESIFCIQYNIRSFMNVKHWPWMKLFFKIKPL
  LKSAETEKEMATMKEEFQKTKDELAKSEAKRKELEEKLVTLVQEKNDLQLQVQAESENLL
  DAEERCDQLIKAKFQLEAKIKEVTERAEDEEEINAELTAKKRKLEDECSELKKDIDDLEL
  TLAKVEKEKHATENKVKNLTEELSGLDETIAKLTREKKALQEAHQQALDDLQAEEDKVNS
  LNKTKSKLEQQVEDLESSLEQEKKLRVDLERNKRKLEGDLKLAQESILDLENDKQQLDER
  LKKKDFEYCQLQSKVEDEQTLGLQFQKKIKELQARIEELEEEIEAERATRAKTEKQRSDY
  ARELEELSERLEEAGGVTSTQIELNKKREAEFLKLRRDLEEATLQHEAMVAALRKKHADS
  VAELGEQIDNLQRVKQKLEKEKSEFKLEIDDLSSSMESVSKSKANLEKICRTLEDQLSEA
  RGKNEEIQRSLSELTTQKSRLQTEAGELSRQLEEKESIVSQLSRSKQAFTQQTEELKRQL
  EEENKAKNALAHALQSSRHDCDLLREQYEEEQEGKAELQRALSKANSEVAQWRTKYETDA
  IQRTEELEEAKKKLAQRLQDSEEQVEAVNAKCASLEKTKQRLQGEVEDLMVDVERANSLA
  AALDKKQRNFDKVLAEWKTKCEESQAELEASLKESRSLSTELFKLKNAYEEALDQLETVK
  RENKNLEQEIADLTEQIAENGKTIHELEKSRKQIELEKADIQLALEEAEAALEHEEAKIL
  RIQLELTQVKSEIDRKIAEKDEEIEQLKRNYQRTVETMQSALDAEVRSRNEAIRLKKKME
  GDLNEIEIQLSHANRQAAETLKHLRSVQGQLKDTQLHLDDALRGQEDLKEQLAIVERRAN
  LLQAEVEELRATLEQTERARKLAEQELLDSNERVQLLHTQNTSLIHTKKKLETDLMQLQS
  EVEDASRDARNAEEKAKKAITDAAMMAEELKKEQDTSAHLERMKKNLEQTVKDLQHRLDE
  AEQLALKGGKKQIQKLETRIRELEFELEGEQKKNTESVKGLRKYERRVKELTYQSEEDRK
  NVLRLQDLVDKLQVKVKSYKRQAEEADEQANAHLTKFRKAQHELEEAEERADIAESQVNK
  LRAKTRDFTSSRMVVHESEE
• Function: Muscle contraction.
• Tissue Specificity: Expressed in fetal bone, thymus, placenta, heart, brain, and liver.
• 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

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Distal arthrogryposis	DIS3QIEL	Definitive	Genetic Variation	[1]
Freeman-Sheldon syndrome	DIS7V9PS	Definitive	Autosomal dominant	[2]
Arthrogryposis	DISC81CM	Strong	Genetic Variation	[3]
Autosomal dominant prognathism	DIS2G3FF	Strong	Altered Expression	[4]
Contractures, pterygia, and variable skeletal fusions syndrome 1B	DISX1F8T	Strong	Autosomal recessive	[5]
Distal arthrogryposis type 2B1	DIS6VMTJ	Strong	Autosomal dominant	[6]
Myopathy	DISOWG27	Strong	Genetic Variation	[7]
Scott syndrome	DIS4N4IB	Strong	Genetic Variation	[5]
Autosomal recessive multiple pterygium syndrome	DISVK1D4	Supportive	Autosomal recessive	[5]
Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A	DISBVI4Y	Supportive	Autosomal dominant	[8]
Digitotalar dysmorphism	DISOW5Q1	Supportive	Autosomal dominant	[9]
Sheldon-hall syndrome	DISOCVMC	Supportive	Autosomal dominant	[9]
Spondylocarpotarsal synostosis syndrome	DISF9VP3	Supportive	Autosomal recessive	[10]
Arthrogryposis, distal, type 1A	DISD8IKM	Limited	GermlineCausalMutation	[9]

10 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 Myosin-3 (MYH3).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Myosin-3 (MYH3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Myosin-3 (MYH3).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Myosin-3 (MYH3).	[15]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Myosin-3 (MYH3).	[16]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Myosin-3 (MYH3).	[15]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Myosin-3 (MYH3).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Myosin-3 (MYH3).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Myosin-3 (MYH3).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Myosin-3 (MYH3).	[19]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Myosin-3 (MYH3).	[13]

References

• [1] 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.
• [2] Embryonic myosin heavy-chain mutations cause distal arthrogryposis and developmental myosin myopathy that persists postnatally. Arch Neurol. 2008 Aug;65(8):1083-90. doi: 10.1001/archneur.65.8.1083.
• [3] De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. Am J Hum Genet. 2015 Mar 5;96(3):462-73. doi: 10.1016/j.ajhg.2015.01.003. Epub 2015 Feb 12.
• [4] Developmental myosin heavy chain mRNA in masseter after orthognathic surgery: a preliminary study.J Craniomaxillofac Surg. 2011 Sep;39(6):401-6. doi: 10.1016/j.jcms.2010.06.001. Epub 2010 Jul 29.
• [5] Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound Heterozygosity for Variants in MYH3. Am J Hum Genet. 2018 Jun 7;102(6):1115-1125. doi: 10.1016/j.ajhg.2018.04.008. Epub 2018 May 24.
• [6] Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet. 2006 May;38(5):561-5. doi: 10.1038/ng1775. Epub 2006 Apr 16.
• [7] Developmental MYH3 Myopathy Associated with Expression of Mutant Protein and Reduced Expression Levels of Embryonic MyHC.PLoS One. 2015 Nov 6;10(11):e0142094. doi: 10.1371/journal.pone.0142094. eCollection 2015.
• [8] Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3. Am J Hum Genet. 2015 May 7;96(5):841-9. doi: 10.1016/j.ajhg.2015.04.004.
• [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] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.