Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6NDC1M)

• DOT Name: Optic atrophy 3 protein (OPA3)
• Gene Name: OPA3
• Related Disease:
  3-methylglutaconic aciduria type 3
  3-methylglutaconic aciduria
  3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
  Angle-closure glaucoma
  Autosomal dominant optic atrophy
  Autosomal dominant optic atrophy, classic form
  Barth syndrome
  Cataract
  Leber hereditary optic neuropathy
  Optic atrophy 3
  Primary angle-closure glaucoma
  Alcohol dependence
  Cerebellar ataxia
  Dilated cardiomyopathy
  Hereditary optic atrophy
  Movement disorder
  Nervous system disease
  Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy
  Optic nerve disorder
  Squamous cell carcinoma
• UniProt ID: OPA3_HUMAN
• Pfam ID: PF07047
• Sequence:
  MVVGAFPMAKLLYLGIRQVSKPLANRIKEAARRSEFFKTYICLPPAQLYHWVEMRTKMRI
  MGFRGTVIKPLNEEAAAELGAELLGEATIFIVGGGCLVLEYWRHQAQQRHKEEEQRAAWN
  ALRDEVGHLALALEALQAQVQAAPPQGALEELRTELQEVRAQLCNPGRSASHAVPASKK
• Function: May play some role in mitochondrial processes.
• Tissue Specificity: Ubiquitous. Most prominent expression in skeletal muscle and kidney.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-methylglutaconic aciduria type 3	DISDQMDY	Definitive	Autosomal recessive	[1]
3-methylglutaconic aciduria	DIS8G1WP	Strong	Biomarker	[2]
3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome	DISKAAPW	Strong	Genetic Variation	[3]
Angle-closure glaucoma	DISZ95KY	Strong	Biomarker	[4]
Autosomal dominant optic atrophy	DISOCR1N	Strong	Genetic Variation	[5]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Biomarker	[6]
Barth syndrome	DISDI4KU	Strong	Genetic Variation	[3]
Cataract	DISUD7SL	Strong	Biomarker	[6]
Leber hereditary optic neuropathy	DIS7Y2EE	Strong	Genetic Variation	[7]
Optic atrophy 3	DISTOAI0	Strong	Autosomal dominant	[8]
Primary angle-closure glaucoma	DISX8UKZ	Strong	Biomarker	[4]
Alcohol dependence	DIS4ZSCO	moderate	Biomarker	[9]
Cerebellar ataxia	DIS9IRAV	moderate	Genetic Variation	[2]
Dilated cardiomyopathy	DISX608J	Limited	Genetic Variation	[10]
Hereditary optic atrophy	DISCV4E4	Limited	Genetic Variation	[11]
Movement disorder	DISOJJ2D	Limited	Genetic Variation	[12]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[13]
Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy	DISBN7PA	Limited	Genetic Variation	[14]
Optic nerve disorder	DISSOQM8	Limited	Genetic Variation	[7]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[15]

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 Optic atrophy 3 protein (OPA3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Optic atrophy 3 protein (OPA3).	[21]

5 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 Optic atrophy 3 protein (OPA3).	[17]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Optic atrophy 3 protein (OPA3).	[18]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Optic atrophy 3 protein (OPA3).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Optic atrophy 3 protein (OPA3).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Optic atrophy 3 protein (OPA3).	[22]

References

• [1] 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.
• [2] Atypical presentation of Costeff syndrome-severe psychomotor involvement and electrical status epilepticus during slow wave sleep.Eur J Paediatr Neurol. 2015 Nov;19(6):733-6. doi: 10.1016/j.ejpn.2015.06.006. Epub 2015 Jul 9.
• [3] Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature.J Inherit Metab Dis. 2013 Nov;36(6):923-8. doi: 10.1007/s10545-012-9580-0. Epub 2013 Jan 8.
• [4] Nuclear and mitochondrial analysis of patients with primary angle-closure glaucoma.Invest Ophthalmol Vis Sci. 2007 Dec;48(12):5591-6. doi: 10.1167/iovs.07-0780.
• [5] A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network.J Med Genet. 2013 Dec;50(12):848-58. doi: 10.1136/jmedgenet-2013-101774. Epub 2013 Oct 17.
• [6] Clinical and molecular genetic findings in autosomal dominant OPA3-related optic neuropathy.Neurogenetics. 2015 Jan;16(1):69-75. doi: 10.1007/s10048-014-0416-y. Epub 2014 Aug 27.
• [7] Genetic and Clinical Analyses of DOA and LHON in 304 Chinese Patients with Suspected Childhood-Onset Hereditary Optic Neuropathy.PLoS One. 2017 Jan 12;12(1):e0170090. doi: 10.1371/journal.pone.0170090. eCollection 2017.
• [8] OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet. 2004 Sep;41(9):e110. doi: 10.1136/jmg.2003.016576.
• [9] Genome-wide association discoveries of alcohol dependence.Am J Addict. 2014 Nov-Dec;23(6):526-39. doi: 10.1111/j.1521-0391.2014.12147.x.
• [10] A missense mutation in the murine Opa3 gene models human Costeff syndrome.Brain. 2008 Feb;131(Pt 2):368-80. doi: 10.1093/brain/awm333.
• [11] Mutation screening of mitochondrial DNA as well as OPA1 and OPA3 in a Chinese cohort with suspected hereditary optic atrophy.Invest Ophthalmol Vis Sci. 2014 Sep 9;55(10):6987-95. doi: 10.1167/iovs.14-14953.
• [12] Behr syndrome with homozygous C19ORF12 mutation.J Neurol Sci. 2015 Oct 15;357(1-2):115-8. doi: 10.1016/j.jns.2015.07.009. Epub 2015 Jul 9.
• [13] A novel OPA3 mutation revealed by exome sequencing: an example of reverse phenotyping.JAMA Neurol. 2013 Jun;70(6):783-7. doi: 10.1001/jamaneurol.2013.1174.
• [14] First cases of dominant optic atrophy in Saudi Arabia: report of two novel OPA1 mutations.J Neuroophthalmol. 2013 Dec;33(4):349-53. doi: 10.1097/WNO.0b013e31829ffb9a.
• [15] Putative biomarkers of malignant transformation of sinonasal inverted papilloma into squamous cell carcinoma.J Int Med Res. 2019 Jun;47(6):2371-2380. doi: 10.1177/0300060519838385. Epub 2019 Apr 16.
• [16] 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.
• [17] 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.
• [18] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [19] 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.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] 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.