Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGQL1AM)

• DOT Name: LIM domain-binding protein 3 (LDB3)
• Synonyms: Protein cypher; Z-band alternatively spliced PDZ-motif protein
• Gene Name: LDB3
• Related Disease:
  Hypertrophic cardiomyopathy
  Barth syndrome
  Becker muscular dystrophy
  Cardiac disease
  Cardiomyopathy
  Dilated cardiomyopathy 1A
  Distal myopathy
  Familial dilated cardiomyopathy
  Mitochondrial disease
  Myofibrillar myopathy
  Myofibrillar myopathy 4
  Myotonic dystrophy
  Neuromuscular disease
  Muscular dystrophy
  Myofibrillar myopathy 1
  Obsolete familial isolated dilated cardiomyopathy
  Arrhythmogenic right ventricular cardiomyopathy
  Acute myelogenous leukaemia
  Dilated cardiomyopathy
  Left ventricular noncompaction
  Myeloproliferative neoplasm
  Myopathy
  Myotonic dystrophy type 1
• UniProt ID: LDB3_HUMAN
• PDB ID: 1RGW; 4YDP
• Pfam ID: PF15936 ; PF00412 ; PF00595
• Sequence:
  MSYSVTLTGPGPWGFRLQGGKDFNMPLTISRITPGSKAAQSQLSQGDLVVAIDGVNTDTM
  THLEAQNKIKSASYNLSLTLQKSKRPIPISTTAPPVQTPLPVIPHQKDPALDTNGSLVAP
  SPSPEARASPGTPGTPELRPTFSPAFSRPSAFSSLAEASDPGPPRASLRAKTSPEGARDL
  LGPKALPGSSQPRQYNNPIGLYSAETLREMAQMYQMSLRGKASGVGLPGGSLPIKDLAVD
  SASPVYQAVIKSQNKPEDEADEWARRSSNLQSRSFRILAQMTGTEFMQDPDEEALRRSST
  PIEHAPVCTSQATTPLLPASAQPPAAASPSAASPPLATAAAHTAIASASTTAPASSPADS
  PRPQASSYSPAVAASSAPATHTSYSEGPAAPAPKPRVVTTASIRPSVYQPVPASTYSPSP
  GANYSPTPYTPSPAPAYTPSPAPAYTPSPVPTYTPSPAPAYTPSPAPNYNPAPSVAYSGG
  PAEPASRPPWVTDDSFSQKFAPGKSTTSISKQTLPRGGPAYTPAGPQVPPLARGTVQRAE
  RFPASSRTPLCGHCNNVIRGPFLVAMGRSWHPEEFTCAYCKTSLADVCFVEEQNNVYCER
  CYEQFFAPLCAKCNTKIMGEVMHALRQTWHTTCFVCAACKKPFGNSLFHMEDGEPYCEKD
  YINLFSTKCHGCDFPVEAGDKFIEALGHTWHDTCFICAVCHVNLEGQPFYSKKDRPLCKK
  HAHTINL
• Function: May function as an adapter in striated muscle to couple protein kinase C-mediated signaling via its LIM domains to the cytoskeleton.
• Tissue Specificity: Expressed primarily in skeletal muscle and to a lesser extent in heart. Also detected in brain and placenta.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypertrophic cardiomyopathy	DISQG2AI	Definitive	Genetic Variation	[1]
Barth syndrome	DISDI4KU	Strong	Genetic Variation	[2]
Becker muscular dystrophy	DIS5IYHL	Strong	Genetic Variation	[2]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[3]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[3]
Distal myopathy	DIS7F5R0	Strong	Genetic Variation	[4]
Familial dilated cardiomyopathy	DISBHDU9	Strong	GermlineCausalMutation	[5]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[6]
Myofibrillar myopathy	DISF24LW	Strong	Genetic Variation	[7]
Myofibrillar myopathy 4	DISS9ZCY	Strong	Autosomal dominant	[8]
Myotonic dystrophy	DISNBEMX	Strong	Biomarker	[9]
Neuromuscular disease	DISQTIJZ	Strong	CausalMutation	[10]
Muscular dystrophy	DISJD6P7	moderate	Biomarker	[11]
Myofibrillar myopathy 1	DIS99A51	moderate	Biomarker	[11]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[12]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Disputed	Autosomal dominant	[13]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[14]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[13]
Left ventricular noncompaction	DISJ4QEG	Limited	Genetic Variation	[15]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Biomarker	[14]
Myopathy	DISOWG27	Limited	Altered Expression	[16]
Myotonic dystrophy type 1	DISJC0OX	Limited	Genetic Variation	[17]

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 LIM domain-binding protein 3 (LDB3).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of LIM domain-binding protein 3 (LDB3).	[24]

10 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 LIM domain-binding protein 3 (LDB3).	[19]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of LIM domain-binding protein 3 (LDB3).	[20]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of LIM domain-binding protein 3 (LDB3).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of LIM domain-binding protein 3 (LDB3).	[22]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of LIM domain-binding protein 3 (LDB3).	[23]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of LIM domain-binding protein 3 (LDB3).	[19]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of LIM domain-binding protein 3 (LDB3).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of LIM domain-binding protein 3 (LDB3).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of LIM domain-binding protein 3 (LDB3).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of LIM domain-binding protein 3 (LDB3).	[27]

References

• [1] Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy. Biochem Biophys Res Commun. 2006 Dec 29;351(4):896-902. doi: 10.1016/j.bbrc.2006.10.119. Epub 2006 Nov 9.
• [2] Genetic heterogeneity of left-ventricular noncompaction cardiomyopathy.Clin Cardiol. 2008 May;31(5):201-4. doi: 10.1002/clc.20202.
• [3] Impact of LDB3 gene polymorphisms on clinical presentation and implantable cardioverter defibrillator (ICD) implantation in Chinese patients with idiopathic dilated cardiomyopathy.J Zhejiang Univ Sci B. 2019 Sept.;20(9):766-775. doi: 10.1631/jzus.B1900017.
• [4] A novel mutation in the PDZ-like motif of ZASP causes distal ZASP-related myofibrillar myopathy.Neuropathology. 2017 Feb;37(1):45-51. doi: 10.1111/neup.12328. Epub 2016 Aug 21.
• [5] A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C.J Biol Chem. 2004 Feb 20;279(8):6746-52. doi: 10.1074/jbc.M311849200. Epub 2003 Dec 3.
• [6] Cardiogenetics, neurogenetics, and pathogenetics of left ventricular hypertrabeculation/noncompaction.Pediatr Cardiol. 2009 Jul;30(5):659-81. doi: 10.1007/s00246-008-9359-0. Epub 2009 Jan 29.
• [7] Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes.BMC Genomics. 2013 Apr 15;14:248. doi: 10.1186/1471-2164-14-248.
• [8] Mutations in ZASP define a novel form of muscular dystrophy in humans. Ann Neurol. 2005 Feb;57(2):269-76. doi: 10.1002/ana.20376.
• [9] LDB3 splicing abnormalities are specific to skeletal muscles of patients with myotonic dystrophy type 1 and alter its PKC binding affinity.Neurobiol Dis. 2014 Sep;69:200-5. doi: 10.1016/j.nbd.2014.05.026. Epub 2014 May 27.
• [10] Expression and Purification of ZASP Subdomains and Clinically Important Isoforms: High-Affinity Binding to G-Actin.Biochemistry. 2017 Apr 11;56(14):2061-2070. doi: 10.1021/acs.biochem.7b00067. Epub 2017 Apr 3.
• [11] Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy.J Cell Biol. 2001 Nov 12;155(4):605-12. doi: 10.1083/jcb.200107092. Epub 2001 Nov 5.
• [12] Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J Am Coll Cardiol. 2003 Dec 3;42(11):2014-27. doi: 10.1016/j.jacc.2003.10.021.
• [13] 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.
• [14] Epigenetic inactivation of suppressors of cytokine signalling in Philadelphia-negative chronic myeloproliferative disorders.Br J Haematol. 2008 May;141(4):504-11. doi: 10.1111/j.1365-2141.2008.07072.x. Epub 2008 Mar 3.
• [15] Loss of function of hNav1.5 by a ZASP1 mutation associated with intraventricular conduction disturbances in left ventricular noncompaction.Circ Arrhythm Electrophysiol. 2012 Oct;5(5):1017-26. doi: 10.1161/CIRCEP.111.969220. Epub 2012 Aug 28.
• [16] Flies deficient in Muscleblind protein model features of myotonic dystrophy with altered splice forms of Z-band associated transcripts.Hum Genet. 2006 Nov;120(4):487-99. doi: 10.1007/s00439-006-0228-8. Epub 2006 Aug 23.
• [17] RNA sequencing reveals abnormal LDB3 splicing in sudden cardiac death.Forensic Sci Int. 2019 Sep;302:109906. doi: 10.1016/j.forsciint.2019.109906. Epub 2019 Jul 26.
• [18] 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.
• [19] 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.
• [20] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [23] 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.
• [24] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [25] 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.
• [26] 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.
• [27] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.