Details of Drug Off-Target (DOT)

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

• DOT Name: Myopalladin (MYPN)
• Synonyms: 145 kDa sarcomeric protein
• Gene Name: MYPN
• Related Disease:
  Dilated cardiomyopathy 1A
  MYPN-related myopathy
  Cardiomyopathy, familial restrictive, 1
  Cholelithiasis
  Epithelial ovarian cancer
  Familial restrictive cardiomyopathy
  Nemaline myopathy
  Ovarian cancer
  Ovarian neoplasm
  Restrictive cardiomyopathy
  Short QT syndrome
  Atrial fibrillation
  Cardiomyopathy
  Familial atrial fibrillation
  Myopathy
  Cap myopathy
  Childhood-onset nemaline myopathy
  Obsolete familial isolated dilated cardiomyopathy
  Obsolete familial isolated restrictive cardiomyopathy
  Hypertrophic cardiomyopathy
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1KK
  Familial dilated cardiomyopathy
  Psoriasis
• UniProt ID: MYPN_HUMAN
• Pfam ID: PF07679
• Sequence:
  MQDDSIEASTSISQLLRESYLAETRHRGNNERSRAEPSSNPCHFGSPSGAAEGGGGQDDL
  PDLSAFLSQEELDESVNLARLAINYDPLEKADETQARKRLSPDQMKHSPNLSFEPNFCQD
  NPRSPTSSKESPQEAKRPQYCSETQSKKVFLNKAADFIEELSSLFKSHSSKRIRPRACKN
  HKSKLESQNKVMQENSSSFSDLSERRERSSVPIPIPADTRDNEVNHALEQQEAKRREAEQ
  AASEAAGGDTTPGSSPSSLYYEEPLGQPPRFTQKLRSREVPEGTRVQLDCIVVGIPPPQV
  RWYCEGKELENSPDIHIVQAGNLHSLTIAEAFEEDTGRYSCFASNIYGTDSTSAEIYIEG
  VSSSDSEGDPNKEEMNRIQKPNEVSSPPTTSAVIPPAVPQAQHLVAQPRVATIQQCQSPT
  NYLQGLDGKPIIAAPVFTKMLQNLSASEGQLVVFECRVKGAPSPKVEWYREGTLIEDSPD
  FRILQKKPRSMAEPEEICTLVIAEVFAEDSGCFTCTASNKYGTVSSIAQLHVRGNEDLSN
  NGSLHSANSTTNLAAIEPQPSPPHSEPPSVEQPPKPKLEGVLVNHNEPRSSSRIGLRVHF
  NLPEDDKGSEASSEAGVVTTRQTRPDSFQERFNGQATKTPEPSSPVKEPPPVLAKPKLDS
  TQLQQLHNQVLLEQHQLQNPPPSSPKEFPFSMTVLNSNAPPAVTTSSKQVKAPSSQTFSL
  ARPKYFFPSTNTTAATVAPSSSPVFTLSSTPQTIQRTVSKESLLVSHPSVQTKSPGGLSI
  QNEPLPPGPTEPTPPPFTFSIPSGNQFQPRCVSPIPVSPTSRIQNPVAFLSSVLPSLPAI
  PPTNAMGLPRSAPSMPSQGLAKKNTKSPQPVNDDNIRETKNAVIRDLGKKITFSDVRPNQ
  QEYKISSFEQRLMNEIEFRLERTPVDESDDEIQHDEIPTGKCIAPIFDKRLKHFRVTEGS
  PVTFTCKIVGIPVPKVYWFKDGKQISKRNEHCKMRREGDGTCSLHIESTTSDDDGNYTIM
  AANPQGRISCSGHLMVQSLPIRSRLTSAGQSHRGRSRVQERDKEPLQERFFRPHFLQAPG
  DMVAHEGRLCRLDCKVSGLPPPELTWLLNGQPVLPDASHKMLVRETGVHSLLIDPLTQRD
  AGTYKCIATNKTGQNSFSLELSVVAKEVKKAPVILEKLQNCGVPEGHPVRLECRVIGMPP
  PVFYWKKDNETIPCTRERISMHQDTTGYACLLIQPAKKSDAGWYTLSAKNEAGIVSCTAR
  LDIYAQWHHQIPPPMSVRPSGSRYGSLTSKGLDIFSAFSSMESTMVYSCSSRSVVESDEL
• Function: Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines.
• Tissue Specificity: Expressed in adult skeletal muscle and fetal heart.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dilated cardiomyopathy 1A	DIS0RK9Z	Definitive	Genetic Variation	[1]
MYPN-related myopathy	DISTPE0P	Definitive	Autosomal recessive	[2]
Cardiomyopathy, familial restrictive, 1	DIS4AJ17	Strong	Genetic Variation	[3]
Cholelithiasis	DISERLZB	Strong	Genetic Variation	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[5]
Familial restrictive cardiomyopathy	DISL4MMU	Strong	Genetic Variation	[6]
Nemaline myopathy	DIS5IYLY	Strong	Genetic Variation	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[5]
Restrictive cardiomyopathy	DISFAF31	Strong	Genetic Variation	[8]
Short QT syndrome	DISOI9X1	Strong	Genetic Variation	[9]
Atrial fibrillation	DIS15W6U	moderate	Biomarker	[10]
Cardiomyopathy	DISUPZRG	moderate	Genetic Variation	[11]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[10]
Myopathy	DISOWG27	moderate	Genetic Variation	[12]
Cap myopathy	DIS4S4WQ	Supportive	Autosomal dominant	[12]
Childhood-onset nemaline myopathy	DIST7MSL	Supportive	Autosomal dominant	[7]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[13]
Obsolete familial isolated restrictive cardiomyopathy	DIS51KNV	Supportive	Autosomal dominant	[3]
Hypertrophic cardiomyopathy	DISQG2AI	Disputed	Autosomal dominant	[2]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[2]
Dilated cardiomyopathy 1KK	DISJPZLJ	Limited	Autosomal dominant	[14]
Familial dilated cardiomyopathy	DISBHDU9	Limited	GermlineCausalMutation	[15]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Myopalladin (MYPN).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Myopalladin (MYPN).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Myopalladin (MYPN).	[25]

7 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 Myopalladin (MYPN).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Myopalladin (MYPN).	[19]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Myopalladin (MYPN).	[20]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Myopalladin (MYPN).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Myopalladin (MYPN).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Myopalladin (MYPN).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Myopalladin (MYPN).	[26]

References

• [1] Targeted next-generation sequencing of candidate genes reveals novel mutations in patients with dilated cardiomyopathy.Int J Mol Med. 2015 Dec;36(6):1479-86. doi: 10.3892/ijmm.2015.2361. Epub 2015 Oct 7.
• [2] 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.
• [3] Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations. Hum Mol Genet. 2012 May 1;21(9):2039-53. doi: 10.1093/hmg/dds022. Epub 2012 Jan 27.
• [4] A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.Nat Genet. 2007 Aug;39(8):995-9. doi: 10.1038/ng2101. Epub 2007 Jul 15.
• [5] Cloning and expression of functional cDNA genes of a mouse/human chimeric antibody rcM4.Tumori. 1994 Dec 31;80(6):473-9. doi: 10.1177/030089169408000613.
• [6] Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy.J Am Coll Cardiol. 2014 Dec 30;64(25):2765-76. doi: 10.1016/j.jacc.2014.09.071.
• [7] Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy. Am J Hum Genet. 2017 Jan 5;100(1):169-178. doi: 10.1016/j.ajhg.2016.11.017. Epub 2016 Dec 22.
• [8] Myopalladin promotes muscle growth through modulation of the serum response factor pathway.J Cachexia Sarcopenia Muscle. 2020 Feb;11(1):169-194. doi: 10.1002/jcsm.12486. Epub 2019 Oct 24.
• [9] Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome.J Transl Med. 2017 Apr 20;15(1):78. doi: 10.1186/s12967-017-1180-1.
• [10] 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.
• [11] Congenital myopathy with hanging big toe due to homozygous myopalladin (MYPN) mutation.Skelet Muscle. 2019 May 27;9(1):14. doi: 10.1186/s13395-019-0199-9.
• [12] Recessive MYPN mutations cause cap myopathy with occasional nemaline rods. Ann Neurol. 2017 Mar;81(3):467-473. doi: 10.1002/ana.24900. Epub 2017 Mar 20.
• [13] Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy. Cardiovasc Res. 2008 Jan;77(1):118-25. doi: 10.1093/cvr/cvm015. Epub 2007 Sep 19.
• [14] Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes. Circ Genom Precis Med. 2019 Feb;12(2):e002460. doi: 10.1161/CIRCGEN.119.002460.
• [15] Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy.Eur J Hum Genet. 2013 Mar;21(3):294-300. doi: 10.1038/ejhg.2012.173. Epub 2012 Aug 15.
• [16] Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis.Nat Commun. 2015 Apr 9;6:6793. doi: 10.1038/ncomms7793.
• [17] 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.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [21] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [22] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [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.
• [24] 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.
• [25] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [26] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.