Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9FOLD7)

• DOT Name: Alpha-actinin-2 (ACTN2)
• Synonyms: Alpha-actinin skeletal muscle isoform 2; F-actin cross-linking protein
• Gene Name: ACTN2
• Related Disease:
  Intrinsic cardiomyopathy
  Atrial fibrillation
  Cardiomyopathy
  Dilated cardiomyopathy 1A
  Familial dilated cardiomyopathy
  Hypertrophic cardiomyopathy
  Myopathy, congenital, with structured cores and z-line abnormalities
  Paroxysmal familial ventricular fibrillation
  Polycythemia vera
  Rheumatic heart disease
  Trichomoniasis
  Ventricular tachycardia
  Dilated cardiomyopathy 1AA
  Limb-girdle muscular dystrophy
  Myopathy
  Obsolete familial isolated dilated cardiomyopathy
  Dilated cardiomyopathy
  Arrhythmia
  Dental caries
  Familial hypertrophic cardiomyopathy
  GNE myopathy
  Heart arrhythmia
  Myopathy, distal, 6, adult-onset, autosomal dominant
  Neoplasm
• UniProt ID: ACTN2_HUMAN
• PDB ID: 1H8B; 1HCI; 1QUU; 4D1E; 5A36; 5A37; 5A38; 5A4B; 6SWT; 6TS3; 7A8T; 7A8U; 7B55; 7B56; 7B57
• Pfam ID: PF00307 ; PF13499 ; PF08726 ; PF00435
• Sequence:
  MNQIEPGVQYNYVYDEDEYMIQEEEWDRDLLLDPAWEKQQRKTFTAWCNSHLRKAGTQIE
  NIEEDFRNGLKLMLLLEVISGERLPKPDRGKMRFHKIANVNKALDYIASKGVKLVSIGAE
  EIVDGNVKMTLGMIWTIILRFAIQDISVEETSAKEGLLLWCQRKTAPYRNVNIQNFHTSW
  KDGLGLCALIHRHRPDLIDYSKLNKDDPIGNINLAMEIAEKHLDIPKMLDAEDIVNTPKP
  DERAIMTYVSCFYHAFAGAEQAETAANRICKVLAVNQENERLMEEYERLASELLEWIRRT
  IPWLENRTPEKTMQAMQKKLEDFRDYRRKHKPPKVQEKCQLEINFNTLQTKLRISNRPAF
  MPSEGKMVSDIAGAWQRLEQAEKGYEEWLLNEIRRLERLEHLAEKFRQKASTHETWAYGK
  EQILLQKDYESASLTEVRALLRKHEAFESDLAAHQDRVEQIAAIAQELNELDYHDAVNVN
  DRCQKICDQWDRLGTLTQKRREALERMEKLLETIDQLHLEFAKRAAPFNNWMEGAMEDLQ
  DMFIVHSIEEIQSLITAHEQFKATLPEADGERQSIMAIQNEVEKVIQSYNIRISSSNPYS
  TVTMDELRTKWDKVKQLVPIRDQSLQEELARQHANERLRRQFAAQANAIGPWIQNKMEEI
  ARSSIQITGALEDQMNQLKQYEHNIINYKNNIDKLEGDHQLIQEALVFDNKHTNYTMEHI
  RVGWELLLTTIARTINEVETQILTRDAKGITQEQMNEFRASFNHFDRRKNGLMDHEDFRA
  CLISMGYDLGEAEFARIMTLVDPNGQGTVTFQSFIDFMTRETADTDTAEQVIASFRILAS
  DKPYILAEELRRELPPDQAQYCIKRMPAYSGPGSVPGALDYAAFSSALYGESDL
• Function: F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein.
• Tissue Specificity: Expressed in both skeletal and cardiac muscle.
• KEGG Pathway:
  Cytoskeleton in muscle cells (hsa04820)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
• Reactome Pathway:
  Nephrin family interactions (R-HSA-373753)
  Striated Muscle Contraction (R-HSA-390522)
  Unblocking of NMDA receptors, glutamate binding and activation (R-HSA-438066)
  Ras activation upon Ca2+ influx through NMDA receptor (R-HSA-442982)
  RAF/MAP kinase cascade (R-HSA-5673001)
  Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)
  Negative regulation of NMDA receptor-mediated neuronal transmission (R-HSA-9617324)
  Long-term potentiation (R-HSA-9620244)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intrinsic cardiomyopathy	DISYBB39	Definitive	Autosomal dominant	[1]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[2]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[3]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[4]
Familial dilated cardiomyopathy	DISBHDU9	Strong	GermlineCausalMutation	[5]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[2]
Myopathy, congenital, with structured cores and z-line abnormalities	DISQ210T	Strong	Autosomal dominant	[3]
Paroxysmal familial ventricular fibrillation	DISRM7IX	Strong	Genetic Variation	[5]
Polycythemia vera	DISB5FPO	Strong	Biomarker	[6]
Rheumatic heart disease	DISCI8JQ	Strong	Altered Expression	[7]
Trichomoniasis	DIS9HBNL	Strong	Biomarker	[8]
Ventricular tachycardia	DISIBXJ3	Strong	Genetic Variation	[9]
Dilated cardiomyopathy 1AA	DIS8K64W	Moderate	Autosomal dominant	[10]
Limb-girdle muscular dystrophy	DISI9Y1Z	moderate	Biomarker	[11]
Myopathy	DISOWG27	moderate	Genetic Variation	[3]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[12]
Dilated cardiomyopathy	DISX608J	Disputed	Genetic Variation	[9]
Arrhythmia	DISFF2NI	Limited	Genetic Variation	[13]
Dental caries	DISRBCMD	Limited	Biomarker	[14]
Familial hypertrophic cardiomyopathy	DISQ89HN	Limited	Genetic Variation	[13]
GNE myopathy	DIS73X4W	Limited	Genetic Variation	[15]
Heart arrhythmia	DISLKUNL	Limited	Autosomal dominant	[16]
Myopathy, distal, 6, adult-onset, autosomal dominant	DISVQZPM	Limited	Unknown	[17]
Neoplasm	DISZKGEW	Limited	Biomarker	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Alpha-actinin-2 (ACTN2).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alpha-actinin-2 (ACTN2).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alpha-actinin-2 (ACTN2).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Alpha-actinin-2 (ACTN2).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Alpha-actinin-2 (ACTN2).	[23]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Alpha-actinin-2 (ACTN2).	[24]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Alpha-actinin-2 (ACTN2).	[25]
Heroin diacetylmorphine	DMDBWHY	Approved	Heroin diacetylmorphine decreases the expression of Alpha-actinin-2 (ACTN2).	[26]
Ribavirin	DMEYLH9	Phase 1 Trial	Ribavirin decreases the expression of Alpha-actinin-2 (ACTN2).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Alpha-actinin-2 (ACTN2).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Alpha-actinin-2 (ACTN2).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alpha-actinin-2 (ACTN2).	[27]

References

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• [2] Disease modeling of a mutation in -actinin 2 guides clinical therapy in hypertrophic cardiomyopathy.EMBO Mol Med. 2019 Dec;11(12):e11115. doi: 10.15252/emmm.201911115. Epub 2019 Nov 3.
• [3] ACTN2 mutations cause "Multiple structured Core Disease" (MsCD). Acta Neuropathol. 2019 Mar;137(3):501-519. doi: 10.1007/s00401-019-01963-8. Epub 2019 Jan 30.
• [4] Whole exome sequencing identifies a novel mutation (c.333??T?C) of TNNI3K in a Chinese family with dilated cardiomyopathy and cardiac conduction disease.Gene. 2018 Mar 30;648:63-67. doi: 10.1016/j.gene.2018.01.055. Epub 2018 Jan 20.
• [5] Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.BMC Med Genet. 2014 Sep 16;15:99. doi: 10.1186/s12881-014-0099-0.
• [6] An unconventional antigen translated by a novel internal ribosome entry site elicits antitumor humoral immune reactions.J Immunol. 2006 Oct 1;177(7):4907-16. doi: 10.4049/jimmunol.177.7.4907.
• [7] Increased -Actinin-2 Expression in the Atrial Myocardium of Patients with Atrial Fibrillation Related to Rheumatic Heart Disease.Cardiology. 2016;135(3):151-159. doi: 10.1159/000446362. Epub 2016 Jun 25.
• [8] Role of -Actinin 2 in Cytoadherence and Cytotoxicity of Trichomonas vaginalis.J Microbiol Biotechnol. 2017 Oct 28;27(10):1844-1854. doi: 10.4014/jmb.1706.06050.
• [9] Whole-Exome Sequencing Identifies a Novel Mutation (p.L320R) of Alpha-Actinin 2 in a Chinese Family with Dilated Cardiomyopathy and Ventricular Tachycardia.Cytogenet Genome Res. 2019;157(3):148-152. doi: 10.1159/000496077. Epub 2019 Jan 11.
• [10] Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes. Circ Genom Precis Med. 2019 Feb;12(2):e002460. doi: 10.1161/CIRCGEN.119.002460.
• [11] Telethonin and other new proteins of the Z-disc of skeletal muscle.IUBMB Life. 2001 May;51(5):275-82. doi: 10.1080/152165401317190761.
• [12] Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. Mol Genet Metab. 2003 Sep-Oct;80(1-2):207-15. doi: 10.1016/s1096-7192(03)00142-2.
• [13] Novel -actinin 2 variant associated with familial hypertrophic cardiomyopathy and juvenile atrial arrhythmias: a massively parallel sequencing study.Circ Cardiovasc Genet. 2014 Dec;7(6):741-50. doi: 10.1161/CIRCGENETICS.113.000486. Epub 2014 Aug 30.
• [14] Genetic Association of MPPED2 and ACTN2 with Dental Caries.J Dent Res. 2014 Jul;93(7):626-32. doi: 10.1177/0022034514534688. Epub 2014 May 8.
• [15] The Interaction of UDP-N-Acetylglucosamine 2-Epimerase/N-Acetylmannosamine Kinase (GNE) and Alpha-Actinin 2 Is Altered in GNE Myopathy M743T Mutant.Mol Neurobiol. 2017 May;54(4):2928-2938. doi: 10.1007/s12035-016-9862-x. Epub 2016 Mar 29.
• [16] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [17] Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations. Ann Neurol. 2019 Jun;85(6):899-906. doi: 10.1002/ana.25470. Epub 2019 Apr 3.
• [18] Gene profiling reveals specific oncogenic mechanisms and signaling pathways in oncocytic and papillary thyroid carcinoma.Oncogene. 2005 Jun 9;24(25):4155-61. doi: 10.1038/sj.onc.1208578.
• [19] 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.
• [20] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [21] 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.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [25] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [26] Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology. 2006 Oct;31(10):2304-12. doi: 10.1038/sj.npp.1301089. Epub 2006 May 3.
• [27] 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.
• [28] Inhibition of cardiomyocyte differentiation of human induced pluripotent stem cells by Ribavirin: Implication for its cardiac developmental toxicity. Toxicology. 2020 Apr 15;435:152422. doi: 10.1016/j.tox.2020.152422. Epub 2020 Feb 26.
• [29] 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.
• [30] 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.