Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9DZ7JQ)

• DOT Name: Alpha-actinin-3 (ACTN3)
• Synonyms: Alpha-actinin skeletal muscle isoform 3; F-actin cross-linking protein
• Gene Name: ACTN3
• Related Disease:
  Cone-rod dystrophy 2
  Campomelic dysplasia
  Congestive heart failure
  Craniometaphyseal dysplasia, autosomal dominant
  Dermatomyositis
  Duchenne muscular dystrophy
  Glycogen storage disease type II
  Idiopathic inflammatory myopathy
  Muscular dystrophy
  Myopathy
  Myositis disease
  Polymyositis
  Glycogen storage disease V
  Amyotrophic lateral sclerosis
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: ACTN3_HUMAN
• PDB ID: 1TJT; 1WKU; 3LUE
• Pfam ID: PF00307 ; PF08726 ; PF00435
• Sequence:
  MMMVMQPEGLGAGEGRFAGGGGGGEYMEQEEDWDRDLLLDPAWEKQQRKTFTAWCNSHLR
  KAGTQIENIEEDFRNGLKLMLLLEVISGERLPRPDKGKMRFHKIANVNKALDFIASKGVK
  LVSIGAEEIVDGNLKMTLGMIWTIILRFAIQDISVEETSAKEGLLLWCQRKTAPYRNVNV
  QNFHTSWKDGLALCALIHRHRPDLIDYAKLRKDDPIGNLNTAFEVAEKYLDIPKMLDAED
  IVNTPKPDEKAIMTYVSCFYHAFAGAEQAETAANRICKVLAVNQENEKLMEEYEKLASEL
  LEWIRRTVPWLENRVGEPSMSAMQRKLEDFRDYRRLHKPPRIQEKCQLEINFNTLQTKLR
  LSHRPAFMPSEGKLVSDIANAWRGLEQVEKGYEDWLLSEIRRLQRLQHLAEKFRQKASLH
  EAWTRGKEEMLSQRDYDSALLQEVRALLRRHEAFESDLAAHQDRVEHIAALAQELNELDY
  HEAASVNSRCQAICDQWDNLGTLTQKRRDALERMEKLLETIDRLQLEFARRAAPFNNWLD
  GAVEDLQDVWLVHSVEETQSLLTAHDQFKATLPEADRERGAIMGIQGEIQKICQTYGLRP
  CSTNPYITLSPQDINTKWDMVRKLVPSCDQTLQEELARQQVNERLRRQFAAQANAIGPWI
  QAKVEEVGRLAAGLAGSLEEQMAGLRQQEQNIINYKTNIDRLEGDHQLLQESLVFDNKHT
  VYSMEHIRVGWEQLLTSIARTINEVENQVLTRDAKGLSQEQLNEFRASFNHFDRKQNGMM
  EPDDFRACLISMGYDLGEVEFARIMTMVDPNAAGVVTFQAFIDFMTRETAETDTTEQVVA
  SFKILAGDKNYITPEELRRELPAKQAEYCIRRMVPYKGSGAPAGALDYVAFSSALYGESD
  L
• 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 only in a subset of type 2 skeletal muscle fibers.
• KEGG Pathway:
  Cytoskeleton in muscle cells (hsa04820)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
• Reactome Pathway:
  Striated Muscle Contraction (R-HSA-390522)
  Nephrin family interactions (R-HSA-373753)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy 2	DISX2RWY	Definitive	Biomarker	[1]
Campomelic dysplasia	DISVTW53	Strong	Altered Expression	[2]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[3]
Craniometaphyseal dysplasia, autosomal dominant	DISU12OO	Strong	Altered Expression	[2]
Dermatomyositis	DIS50C5O	Strong	Biomarker	[4]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Genetic Variation	[5]
Glycogen storage disease type II	DISXZPBC	Strong	Genetic Variation	[6]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Genetic Variation	[4]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[2]
Myopathy	DISOWG27	Strong	Genetic Variation	[7]
Myositis disease	DISCIXF0	Strong	Genetic Variation	[4]
Polymyositis	DIS5DHFP	Strong	Biomarker	[4]
Glycogen storage disease V	DISJNC0O	moderate	Genetic Variation	[8]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[9]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[10]
Ovarian cancer	DISZJHAP	Limited	Genetic Variation	[10]
Ovarian neoplasm	DISEAFTY	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Alpha-actinin-3 (ACTN3).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alpha-actinin-3 (ACTN3).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-actinin-3 (ACTN3).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Alpha-actinin-3 (ACTN3).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Alpha-actinin-3 (ACTN3).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Alpha-actinin-3 (ACTN3).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Alpha-actinin-3 (ACTN3).	[19]

2 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 decreases the methylation of Alpha-actinin-3 (ACTN3).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Alpha-actinin-3 (ACTN3).	[18]

References

• [1] Role of alpha-actinin-3 in contractile properties of human single muscle fibers: a case series study in paraplegics.PLoS One. 2012;7(11):e49281. doi: 10.1371/journal.pone.0049281. Epub 2012 Nov 8.
• [2] Deficiency of alpha-actinin-3 (ACTN3) occurs in different forms of muscular dystrophy.Neuropediatrics. 1997 Aug;28(4):223-8. doi: 10.1055/s-2007-973704.
• [3] ACTN3 R577X polymorphism and long-term survival in patients with chronic heart failure.BMC Cardiovasc Disord. 2014 Jul 24;14:90. doi: 10.1186/1471-2261-14-90.
• [4] The ACTN3 R577X polymorphism is associated with inflammatory myopathies in a Mexican population.Scand J Rheumatol. 2012 Oct;41(5):396-400. doi: 10.3109/03009742.2012.669495. Epub 2012 May 29.
• [5] Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy.Nat Commun. 2017 Jan 31;8:14143. doi: 10.1038/ncomms14143.
• [6] Genotype-phenotype correlation in Pompe disease, a step forward. Orphanet J Rare Dis. 2014 Aug 8;9:102. doi: 10.1186/s13023-014-0102-z.
• [7] ACTN3 R577X Polymorphism Is Associated With the Incidence and Severity of Injuries in Professional Football Players.Clin J Sport Med. 2019 Jan;29(1):57-61. doi: 10.1097/JSM.0000000000000487.
• [8] Is evolutionary loss our gain? The role of ACTN3 p.Arg577Ter (R577X) genotype in athletic performance, ageing, and disease.Hum Mutat. 2018 Dec;39(12):1774-1787. doi: 10.1002/humu.23663. Epub 2018 Nov 8.
• [9] Differential gene expression in patients with amyotrophic lateral sclerosis.Amyotroph Lateral Scler. 2011 Jul;12(4):250-6. doi: 10.3109/17482968.2011.560946. Epub 2011 Mar 4.
• [10] Frequent translocations of 11q13.2 and 19p13.2 in ovarian cancer.Genes Chromosomes Cancer. 2014 Jun;53(6):447-53. doi: 10.1002/gcc.22152. Epub 2014 Feb 24.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [14] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.