Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRPN93S)

• DOT Name: Myosin-binding protein C, slow-type (MYBPC1)
• Synonyms: Slow MyBP-C; C-protein, skeletal muscle slow isoform
• Gene Name: MYBPC1
• Related Disease:
  Neoplasm
  Arthrogryposis
  Arthrogryposis, distal, type 1A
  Arthrogryposis, distal, type 1B
  Congenital stationary night blindness 2A
  Distal arthrogryposis
  Freeman-Sheldon syndrome
  Hypertrophic cardiomyopathy
  Hypophosphatasia
  Lethal congenital contracture syndrome 4
  Myopathy
  Myopathy, congenital, with tremor
  Skeletal muscle disorder
  Digitotalar dysmorphism
  Lethal congenital contracture syndrome 3
  Dilated cardiomyopathy
• UniProt ID: MYPC1_HUMAN
• PDB ID: 1X44; 2DAV; 2YUV; 2YUW; 2YUX; 2YUZ; 2YXM
• Pfam ID: PF00041 ; PF07679 ; PF18362
• Sequence:
  MPEPTKKEENEVPAPAPPPEEPSKEKEAGTTPAKDWTLVETPPGEEQAKQNANSQLSILF
  IEKPQGGTVKVGEDITFIAKVKAEDLLRKPTIKWFKGKWMDLASKAGKHLQLKETFERHS
  RVYTFEMQIIKAKDNFAGNYRCEVTYKDKFDSCSFDLEVHESTGTTPNIDIRSAFKRSGE
  GQEDAGELDFSGLLKRREVKQQEEEPQVDVWELLKNAKPSEYEKIAFQYGITDLRGMLKR
  LKRMRREEKKSAAFAKILDPAYQVDKGGRVRFVVELADPKLEVKWYKNGQEIRPSTKYIF
  EHKGCQRILFINNCQMTDDSEYYVTAGDEKCSTELFVREPPIMVTKQLEDTTAYCGERVE
  LECEVSEDDANVKWFKNGEEIIPGPKSRYRIRVEGKKHILIIEGATKADAAEYSVMTTGG
  QSSAKLSVDLKPLKILTPLTDQTVNLGKEICLKCEISENIPGKWTKNGLPVQESDRLKVV
  HKGRIHKLVIANALTEDEGDYVFAPDAYNVTLPAKVHVIDPPKIILDGLDADNTVTVIAG
  NKLRLEIPISGEPPPKAMWSRGDKAIMEGSGRIRTESYPDSSTLVIDIAERDDSGVYHIN
  LKNEAGEAHASIKVKVVDFPDPPVAPTVTEVGDDWCIMNWEPPAYDGGSPILGYFIERKK
  KQSSRWMRLNFDLCKETTFEPKKMIEGVAYEVRIFAVNAIGISKPSMPSRPFVPLAVTSP
  PTLLTVDSVTDTTVTMRWRPPDHIGAAGLDGYVLEYCFEGSTSAKQSDENGEAAYDLPAE
  DWIVANKDLIDKTKFTITGLPTDAKIFVRVKAVNAAGASEPKYYSQPILVKEIIEPPKIR
  IPRHLKQTYIRRVGEAVNLVIPFQGKPRPELTWKKDGAEIDKNQINIRNSETDTIIFIRK
  AERSHSGKYDLQVKVDKFVETASIDIQIIDRPGPPQIVKIEDVWGENVALTWTPPKDDGN
  AAITGYTIQKADKKSMEWFTVIEHYHRTSATITELVIGNEYYFRVFSENMCGLSEDATMT
  KESAVIARDGKIYKNPVYEDFDFSEAPMFTQPLVNTYAIAGYNATLNCSVRGNPKPKITW
  MKNKVAIVDDPRYRMFSNQGVCTLEIRKPSPYDGGTYCCKAVNDLGTVEIECKLEVKVIA
  Q
• Function: Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands. Slow skeletal protein that binds to both myosin and actin. In vitro, binds to native thin filaments and modifies the activity of actin-activated myosin ATPase. May modulate muscle contraction or may play a more structural role.
• KEGG Pathway: 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
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Arthrogryposis	DISC81CM	Strong	Genetic Variation	[2]
Arthrogryposis, distal, type 1A	DISD8IKM	Strong	Biomarker	[3]
Arthrogryposis, distal, type 1B	DISHXTV4	Strong	Autosomal dominant	[4]
Congenital stationary night blindness 2A	DISA57KI	Strong	Genetic Variation	[5]
Distal arthrogryposis	DIS3QIEL	Strong	Genetic Variation	[6]
Freeman-Sheldon syndrome	DIS7V9PS	Strong	Genetic Variation	[3]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[4]
Hypophosphatasia	DISCQ0O2	Strong	Genetic Variation	[5]
Lethal congenital contracture syndrome 4	DISHK3DO	Strong	Autosomal recessive	[7]
Myopathy	DISOWG27	Strong	Genetic Variation	[8]
Myopathy, congenital, with tremor	DISIDZC7	Strong	Autosomal dominant	[4]
Skeletal muscle disorder	DISR9DGU	Strong	Genetic Variation	[8]
Digitotalar dysmorphism	DISOW5Q1	Supportive	Autosomal dominant	[4]
Lethal congenital contracture syndrome 3	DISU931I	Supportive	Autosomal recessive	[7]
Dilated cardiomyopathy	DISX608J	Limited	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Myosin-binding protein C, slow-type (MYBPC1).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Myosin-binding protein C, slow-type (MYBPC1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Myosin-binding protein C, slow-type (MYBPC1).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Myosin-binding protein C, slow-type (MYBPC1).	[13]
ACYLINE	DM9GRTK	Phase 2	ACYLINE decreases the expression of Myosin-binding protein C, slow-type (MYBPC1).	[14]

3 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-binding protein C, slow-type (MYBPC1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Myosin-binding protein C, slow-type (MYBPC1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Myosin-binding protein C, slow-type (MYBPC1).	[16]

References

• [1] RANKL expression in normal and malignant breast tissue responds to progesterone and is up-regulated during the luteal phase.Breast Cancer Res Treat. 2014 Aug;146(3):515-23. doi: 10.1007/s10549-014-3049-9. Epub 2014 Jul 10.
• [2] Heterozygous variants in MYBPC1 are associated with an expanded neuromuscular phenotype beyond arthrogryposis.Hum Mutat. 2019 Aug;40(8):1115-1126. doi: 10.1002/humu.23760. Epub 2019 May 5.
• [3] 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.
• [4] Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1. Hum Mol Genet. 2010 Apr 1;19(7):1165-73. doi: 10.1093/hmg/ddp587. Epub 2010 Jan 2.
• [5] Unique disease heritage of the Dutch-German Mennonite population.Am J Med Genet A. 2008 Apr 15;146A(8):1072-87. doi: 10.1002/ajmg.a.32061.
• [6] Two novel mutations in myosin binding protein C slow causing distal arthrogryposis type 2 in two large Han Chinese families may suggest important functional role of immunoglobulin domain C2.PLoS One. 2015 Feb 13;10(2):e0117158. doi: 10.1371/journal.pone.0117158. eCollection 2015.
• [7] Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a mutation in MYBPC1. Hum Mutat. 2012 Oct;33(10):1435-8. doi: 10.1002/humu.22122. Epub 2012 Jun 7.
• [8] Novel mutations in MYBPC1 are associated with myogenic tremor and mild myopathy.Ann Neurol. 2019 Jul;86(1):129-142. doi: 10.1002/ana.25494. Epub 2019 May 17.
• [9] A novel missense mutation in the myosin binding protein-C gene is responsible for hypertrophic cardiomyopathy with left ventricular dysfunction and dilation in elderly patients.J Am Coll Cardiol. 2003 Mar 5;41(5):781-6. doi: 10.1016/s0735-1097(02)02957-1.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [14] Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41.
• [15] 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.
• [16] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.