Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL3YF1H)

• DOT Name: Ataxin-7 (ATXN7)
• Synonyms: Spinocerebellar ataxia type 7 protein
• Gene Name: ATXN7
• Related Disease:
  Autosomal dominant cerebellar ataxia type II
  Spinocerebellar ataxia type 3
  Age-related macular degeneration
  Attention deficit hyperactivity disorder
  Breast cancer
  Breast carcinoma
  Chorea-acanthocytosis
  Coloboma
  Colorectal carcinoma
  Colorectal neoplasm
  Cone-rod dystrophy
  Cone-rod dystrophy 2
  Congestive heart failure
  Depression
  Hepatocellular carcinoma
  Hereditary spastic paraplegia
  Huntington disease
  Macular degeneration
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Peripheral neuropathy
  Retinal degeneration
  Retinitis pigmentosa
  Schizophrenia
  Skin disease
  Spinocerebellar ataxia type 1
  Spinocerebellar ataxia type 2
  Spinocerebellar ataxia type 6
  Dystonia
  Movement disorder
  Obsolete spinocerebellar ataxia type 7
  Spinocerebellar ataxia type 17
  Spinocerebellar ataxia type 5
  Vision disorder
  Cardiac arrest
  Metastatic malignant neoplasm
  Amyloidosis
  Blindness
  Cerebellar disorder
  Kearns-Sayre syndrome
  Multiple sclerosis
  Parkinsonian disorder
  Pneumonia
  Spinocerebellar ataxia
• UniProt ID: ATX7_HUMAN
• PDB ID: 2KKR; 7KTR; 7KTS; 8H7G
• Pfam ID: PF08313
• Sequence:
  MSERAADDVRGEPRRAAAAAGGAAAAAARQQQQQQQQQQPPPPQPQRQQHPPPPPRRTRP
  EDGGPGAASTSAAAMATVGERRPLPSPEVMLGQSWNLWVEASKLPGKDGTELDESFKEFG
  KNREVMGLCREDMPIFGFCPAHDDFYLVVCNDCNQVVKPQAFQSHYERRHSSSSKPPLAV
  PPTSVFSFFPSLSKSKGGSASGSNRSSSGGVLSASSSSSKLLKSPKEKLQLRGNTRPMHP
  IQQSRVPHGRIMTPSVKVEKIHPKMDGTLLKSAVGPTCPATVSSLVKPGLNCPSIPKPTL
  PSPGQILNGKGLPAPPTLEKKPEDNSNNRKFLNKRLSEREFDPDIHCGVIDLDTKKPCTR
  SLTCKTHSLTQRRAVQGRRKRFDVLLAEHKNKTREKELIRHPDSQQPPQPLRDPHPAPPR
  TSQEPHQNPHGVIPSESKPFVASKPKPHTPSLPRPPGCPAQQGGSAPIDPPPVHESPHPP
  LPATEPASRLSSEEGEGDDKEESVEKLDCHYSGHHPQPASFCTFGSRQIGRGYYVFDSRW
  NRLRCALNLMVEKHLNAQLWKKIPPVPSTTSPISTRIPHRTNSVPTSQCGVSYLAAATVS
  TSPVLLSSTCISPNSKSVPAHGTTLNAQPAASGAMDPVCSMQSRQVSSSSSSPSTPSGLS
  SVPSSPMSRKPQKLKSSKSLRPKESSGNSTNCQNASSSTSGGSGKKRKNSSPLLVHSSSS
  SSSSSSSSHSMESFRKNCVAHSGPPYPSTVTSSHSIGLNCVTNKANAVNVRHDQSGRGPP
  TGSPAESIKRMSVMVNSSDSTLSLGPFIHQSNELPVNSHGSFSHSHTPLDKLIGKKRKCS
  PSSSSINNSSSKPTKVAKVPAVNNVHMKHTGTIPGAQGLMNSSLLHQPKARP
• Function: Acts as a component of the STAGA transcription coactivator-HAT complex. Mediates the interaction of STAGA complex with the CRX and is involved in CRX-dependent gene activation. Necessary for microtubule cytoskeleton stabilization.
• Tissue Specificity: .Isoform a is expressed in CNS, but is expressed predominantly in the peripherical tissues.; [Isoform b]: Isoform b is expressed in CNS . Also highly expressed in the frontal lobe, skeletal muscle and spinal cord and is expressed at a lower level in the lung, lymphoblast and intestine .
• Reactome Pathway:
  Ub-specific processing proteases (R-HSA-5689880)
  HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Definitive	Autosomal dominant	[1]
Spinocerebellar ataxia type 3	DISQBQID	Definitive	Biomarker	[2]
Age-related macular degeneration	DIS0XS2C	Strong	Altered Expression	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Chorea-acanthocytosis	DISW1V6N	Strong	Biomarker	[7]
Coloboma	DISP39N5	Strong	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[5]
Cone-rod dystrophy	DISY9RWN	Strong	Genetic Variation	[9]
Cone-rod dystrophy 2	DISX2RWY	Strong	Genetic Variation	[9]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[10]
Depression	DIS3XJ69	Strong	Genetic Variation	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[13]
Huntington disease	DISQPLA4	Strong	Biomarker	[9]
Macular degeneration	DISLKKHD	Strong	Altered Expression	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[14]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[15]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[16]
Retinal degeneration	DISM1JHQ	Strong	Altered Expression	[17]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[16]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[18]
Skin disease	DISDW8R6	Strong	Biomarker	[19]
Spinocerebellar ataxia type 1	DISF7BO2	Strong	Biomarker	[20]
Spinocerebellar ataxia type 2	DISF7WDI	Strong	Biomarker	[2]
Spinocerebellar ataxia type 6	DISH7224	Strong	Biomarker	[20]
Dystonia	DISJLFGW	moderate	Biomarker	[21]
Movement disorder	DISOJJ2D	moderate	Biomarker	[20]
Obsolete spinocerebellar ataxia type 7	DISO7W75	Moderate	Autosomal dominant	[22]
Spinocerebellar ataxia type 17	DISJXO7P	moderate	Biomarker	[23]
Spinocerebellar ataxia type 5	DISPYXJ0	moderate	Biomarker	[20]
Vision disorder	DIS8R6NJ	moderate	Biomarker	[20]
Cardiac arrest	DIS9DIA4	Disputed	Biomarker	[24]
Metastatic malignant neoplasm	DIS86UK6	Disputed	Biomarker	[25]
Amyloidosis	DISHTAI2	Limited	Biomarker	[26]
Blindness	DISTIM10	Limited	Genetic Variation	[9]
Cerebellar disorder	DIS2O7WM	Limited	Genetic Variation	[27]
Kearns-Sayre syndrome	DIS9UK5R	Limited	Biomarker	[28]
Multiple sclerosis	DISB2WZI	Limited	Genetic Variation	[29]
Parkinsonian disorder	DISHGY45	Limited	Genetic Variation	[30]
Pneumonia	DIS8EF3M	Limited	Biomarker	[31]
Spinocerebellar ataxia	DISYMHUK	Limited	Genetic Variation	[32]

10 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 Ataxin-7 (ATXN7).	[33]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ataxin-7 (ATXN7).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ataxin-7 (ATXN7).	[35]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Ataxin-7 (ATXN7).	[19]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Ataxin-7 (ATXN7).	[37]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Ataxin-7 (ATXN7).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ataxin-7 (ATXN7).	[39]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Ataxin-7 (ATXN7).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ataxin-7 (ATXN7).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ataxin-7 (ATXN7).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Ataxin-7 (ATXN7).	[38]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ataxin-7 (ATXN7).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ataxin-7 (ATXN7).	[38]

References

• [1] Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature. 1995 Nov 23;378(6555):403-6. doi: 10.1038/378403a0.
• [2] Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes.Brain. 2014 Sep;137(Pt 9):2444-55. doi: 10.1093/brain/awu174. Epub 2014 Jun 26.
• [3] Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia.Hum Mol Genet. 2011 Feb 1;20(3):510-27. doi: 10.1093/hmg/ddq496. Epub 2010 Nov 15.
• [4] The Atxn7-overexpressing mice showed hyperactivity and impulsivity which were ameliorated by atomoxetine treatment: A possible animal model of the hyperactive-impulsive phenotype of ADHD.Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jan 10;88:311-319. doi: 10.1016/j.pnpbp.2018.08.012. Epub 2018 Aug 17.
• [5] Rad51C-ATXN7 fusion gene expression in colorectal tumors.Mol Cancer. 2016 Jun 13;15(1):47. doi: 10.1186/s12943-016-0527-1.
• [6] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [7] Clinical and genetic analysis of 29 Brazilian patients with Huntington's disease-like phenotype.Arq Neuropsiquiatr. 2011 Jun;69(3):419-23. doi: 10.1590/s0004-282x2011000400002.
• [8] Loss of zebrafish Ataxin-7, a SAGA subunit responsible for SCA7 retinopathy, causes ocular coloboma and malformation of photoreceptors.Hum Mol Genet. 2019 Mar 15;28(6):912-927. doi: 10.1093/hmg/ddy401.
• [9] Molecular Mechanisms and Therapeutic Strategies in Spinocerebellar Ataxia Type 7.Adv Exp Med Biol. 2018;1049:197-218. doi: 10.1007/978-3-319-71779-1_9.
• [10] Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype.Neurology. 1998 Oct;51(4):1081-6. doi: 10.1212/wnl.51.4.1081.
• [11] Large normal-range TBP and ATXN7 CAG repeat lengths are associated with increased lifetime risk of depression.Transl Psychiatry. 2017 Jun 6;7(6):e1143. doi: 10.1038/tp.2017.116.
• [12] ATXN7 Gene Variants and Expression Predict Post-Operative Clinical Outcomes in Hepatitis B Virus-Related Hepatocellular Carcinoma.Cell Physiol Biochem. 2016;39(6):2427-2438. doi: 10.1159/000452511. Epub 2016 Nov 11.
• [13] Factors influencing disease progression in autosomal dominant cerebellar ataxia and spastic paraplegia.Arch Neurol. 2012 Apr;69(4):500-8. doi: 10.1001/archneurol.2011.2713.
• [14] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [15] Circular RNA ATXN7 is upregulated in non-small cell lung cancer and promotes disease progression.Oncol Lett. 2019 Jun;17(6):4803-4810. doi: 10.3892/ol.2019.10168. Epub 2019 Mar 19.
• [16] The wide spectrum of spinocerebellar ataxias (SCAs).Cerebellum. 2005;4(1):2-6. doi: 10.1080/14734220510007914.
• [17] Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration.Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8472-7. doi: 10.1073/pnas.0503505102. Epub 2005 Jun 2.
• [18] Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study.JAMA Psychiatry. 2019 Oct 1;76(10):1026-1034. doi: 10.1001/jamapsychiatry.2019.1335.
• [19] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [20] Clinical and molecular effect on offspring of a marriage of consanguineous spinocerebellar ataxia type 7 mutation carriers: a family case report.Int J Clin Exp Med. 2014 Dec 15;7(12):5896-903. eCollection 2014.
• [21] Facial grimacing and clinical correlates in spinocerebellar ataxia type 3.J Neurol Sci. 2019 Feb 15;397:138-140. doi: 10.1016/j.jns.2019.01.001. Epub 2019 Jan 2.
• [22] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [23] Friedreich's ataxia and other hereditary ataxias in Greece: an 18-year perspective.J Neurol Sci. 2014 Jan 15;336(1-2):87-92. doi: 10.1016/j.jns.2013.10.012. Epub 2013 Oct 16.
• [24] Spinocerebellar ataxia type 7: a neurodegenerative disorder with peripheral neuropathy.Eur Neurol. 2015;73(3-4):173-8. doi: 10.1159/000370239. Epub 2015 Jan 20.
• [25] Prospective Immunophenotyping of CD8(+) T Cells and Associated Clinical Outcomes of Patients With Oligometastatic Prostate Cancer Treated With Metastasis-Directed SBRT.Int J Radiat Oncol Biol Phys. 2019 Jan 1;103(1):229-240. doi: 10.1016/j.ijrobp.2018.09.001. Epub 2018 Sep 8.
• [26] Amyloid precursor-like protein 2 cleavage contributes to neuronal intranuclear inclusions and cytotoxicity in spinocerebellar ataxia-7 (SCA7).Neurobiol Dis. 2011 Jan;41(1):33-42. doi: 10.1016/j.nbd.2010.08.016. Epub 2010 Aug 20.
• [27] Spinocerebellar ataxia type 7 cerebellar disease requires the coordinated action of mutant ataxin-7 in neurons and glia, and displays non-cell-autonomous bergmann glia degeneration.J Neurosci. 2011 Nov 9;31(45):16269-78. doi: 10.1523/JNEUROSCI.4000-11.2011.
• [28] Spinocerebellar ataxia type 7 mimicking Kearns-Sayre syndrome: a clinical diagnosis is desirable.J Neurol Sci. 2008 Jan 15;264(1-2):173-6. doi: 10.1016/j.jns.2007.07.023. Epub 2007 Aug 27.
• [29] Interferon induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice.Brain. 2013 Jun;136(Pt 6):1732-45. doi: 10.1093/brain/awt061. Epub 2013 Mar 21.
• [30] Autosomal dominant cerebellar ataxias: a systematic review of clinical features.Eur J Neurol. 2014 Apr;21(4):607-15. doi: 10.1111/ene.12350. Epub 2014 Feb 12.
• [31] Zinc uptake by Streptococcus pneumoniae depends on both AdcA and AdcAII and is essential for normal bacterial morphology and virulence.Mol Microbiol. 2011 Nov;82(4):904-16. doi: 10.1111/j.1365-2958.2011.07862.x. Epub 2011 Oct 24.
• [32] Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal.Eur J Neurol. 2010 Jan;17(1):124-8. doi: 10.1111/j.1468-1331.2009.02757.x. Epub 2009 Jul 29.
• [33] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [34] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [35] 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.
• [36] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [37] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [38] 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.
• [39] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [40] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [41] 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.
• [42] 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.
• [43] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.