Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF0W2FJ)

• DOT Name: Astrotactin-2 (ASTN2)
• Gene Name: ASTN2
• Related Disease:
  Cognitive impairment
  Alzheimer disease
  Autism
  Autosomal recessive limb-girdle muscular dystrophy type 2H
  Bardet biedl syndrome
  Bipolar disorder
  Breast carcinoma
  Chronic obstructive pulmonary disease
  Dementia
  Endometriosis
  Major depressive disorder
  Mental disorder
  Migraine disorder
  Neurodevelopmental disorder
  Pancreatic cancer
  Autism spectrum disorder
  Intellectual disability
• UniProt ID: ASTN2_HUMAN
• PDB ID: 5J67; 5J68; 5J69
• Pfam ID: PF18411 ; PF19743 ; PF19441 ; PF18577 ; PF01823
• Sequence:
  MAAAGARLSPGPGSGLRGRPRLCFHPGPPPLLPLLLLFLLLLPPPPLLAGATAAASREPD
  SPCRLKTVTVSTLPALRESDIGWSGARAGAGAGTGAGAAAAAASPGSPGSAGTAAESRLL
  LFVRNELPGRIAVQDDLDNTELPFFTLEMSGTAADISLVHWRQQWLENGTLYFHVSMSSS
  GQLAQATAPTLQEPSEIVEEQMHILHISVMGGLIALLLLLLVFTVALYAQRRWQKRRRIP
  QKSASTEATHEIHYIPSVLLGPQARESFRSSRLQTHNSVIGVPIRETPILDDYDCEEDEE
  PPRRANHVSREDEFGSQVTHTLDSLGHPGEEKVDFEKKAAAEATQETVESLMQKFKESFR
  ANTPIEIGQLQPPLRSTSAGKRKRRSKSRGGISFGRAKGTSGSEADDETQLTFYTEQYRS
  RRRSKGLLKSPVNKTALTLIAVSSCILAMVCGSQMSCPLTVKVTLHVPEHFIADGSSFVV
  SEGSYLDISDWLNPAKLSLYYQINATSPWVRDLCGQRTTDACEQLCDPETGECSCHEGYA
  PDPVHRHLCVRSDWGQSEGPWPYTTLERGYDLVTGEQAPEKILRSTFSLGQGLWLPVSKS
  FVVPPVELSINPLASCKTDVLVTEDPADVREEAMLSTYFETINDLLSSFGPVRDCSRNNG
  GCTRNFKCVSDRQVDSSGCVCPEELKPMKDGSGCYDHSKGIDCSDGFNGGCEQLCLQQTL
  PLPYDATSSTIFMFCGCVEEYKLAPDGKSCLMLSDVCEGPKCLKPDSKFNDTLFGEMLHG
  YNNRTQHVNQGQVFQMTFRENNFIKDFPQLADGLLVIPLPVEEQCRGVLSEPLPDLQLLT
  GDIRYDEAMGYPMVQQWRVRSNLYRVKLSTITLAAGFTNVLKILTKESSREELLSFIQHY
  GSHYIAEALYGSELTCIIHFPSKKVQQQLWLQYQKETTELGSKKELKSMPFITYLSGLLT
  AQMLSDDQLISGVEIRCEEKGRCPSTCHLCRRPGKEQLSPTPVLLEINRVVPLYTLIQDN
  GTKEAFKSALMSSYWCSGKGDVIDDWCRCDLSAFDANGLPNCSPLLQPVLRLSPTVEPSS
  TVVSLEWVDVQPAIGTKVSDYILQHKKVDEYTDTDLYTGEFLSFADDLLSGLGTSCVAAG
  RSHGEVPEVSIYSVIFKCLEPDGLYKFTLYAVDTRGRHSELSTVTLRTACPLVDDNKAEE
  IADKIYNLYNGYTSGKEQQMAYNTLMEVSASMLFRVQHHYNSHYEKFGDFVWRSEDELGP
  RKAHLILRRLERVSSHCSSLLRSAYIQSRVETVPYLFCRSEEVRPAGMVWYSILKDTKIT
  CEEKMVSMARNTYGESKGR
• Function: Mediates recycling of the neuronal cell adhesion molecule ASTN1 to the anterior pole of the cell membrane in migrating neurons. Promotes ASTN1 internalization and intracellular transport of endocytosed ASTN1. Selectively binds inositol-4,5-bisphosphate, inositol-3,4,5-trisphosphate and inositol-1,3,4,5-tetrakisphosphate, suggesting it is recruited to membranes that contain lipids with a phosphoinositide headgroup (Ref.6).

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Autosomal recessive limb-girdle muscular dystrophy type 2H	DISZ100M	Strong	CausalMutation	[4]
Bardet biedl syndrome	DISTBNZW	Strong	CausalMutation	[5]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[7]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[8]
Dementia	DISXL1WY	Strong	Biomarker	[9]
Endometriosis	DISX1AG8	Strong	Genetic Variation	[10]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[11]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[12]
Migraine disorder	DISFCQTG	Strong	Biomarker	[13]
Neurodevelopmental disorder	DIS372XH	moderate	Altered Expression	[14]
Pancreatic cancer	DISJC981	moderate	Genetic Variation	[15]
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[16]
Intellectual disability	DISMBNXP	Limited	Autosomal dominant	[16]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Astrotactin-2 (ASTN2) affects the response to substance of Methamphetamine.	[37]

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 Astrotactin-2 (ASTN2).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Astrotactin-2 (ASTN2).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Astrotactin-2 (ASTN2).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Astrotactin-2 (ASTN2).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Astrotactin-2 (ASTN2).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Astrotactin-2 (ASTN2).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Astrotactin-2 (ASTN2).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Astrotactin-2 (ASTN2).	[23]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Astrotactin-2 (ASTN2).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Astrotactin-2 (ASTN2).	[26]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Astrotactin-2 (ASTN2).	[27]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Astrotactin-2 (ASTN2).	[28]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Astrotactin-2 (ASTN2).	[29]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Astrotactin-2 (ASTN2).	[30]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Astrotactin-2 (ASTN2).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Astrotactin-2 (ASTN2).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Astrotactin-2 (ASTN2).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Astrotactin-2 (ASTN2).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Astrotactin-2 (ASTN2).	[35]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Astrotactin-2 (ASTN2).	[36]

References

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• [2] Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer's Disease.Mol Neurobiol. 2019 May;56(5):3235-3243. doi: 10.1007/s12035-018-1298-z. Epub 2018 Aug 15.
• [3] Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.Nature. 2009 May 28;459(7246):569-73. doi: 10.1038/nature07953. Epub 2009 Apr 28.
• [4] The common missense mutation D489N in TRIM32 causing limb girdle muscular dystrophy 2H leads to loss of the mutated protein in knock-in mice resulting in a Trim32-null phenotype.Hum Mol Genet. 2011 Oct 15;20(20):3925-32. doi: 10.1093/hmg/ddr311. Epub 2011 Jul 20.
• [5] Scapuloperoneal muscular dystrophy phenotype due to TRIM32-sarcotubular myopathy in South Dakota Hutterite.Neuromuscul Disord. 2013 Feb;23(2):133-8. doi: 10.1016/j.nmd.2012.09.010. Epub 2012 Nov 9.
• [6] A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder.Schizophr Res. 2010 Dec;124(1-3):192-9. doi: 10.1016/j.schres.2010.09.002.
• [7] 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.
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• [9] Common variants at 12q14 and 12q24 are associated with hippocampal volume.Nat Genet. 2012 Apr 15;44(5):545-51. doi: 10.1038/ng.2237.
• [10] Endometriosis is associated with rare copy number variants.PLoS One. 2014 Aug 1;9(8):e103968. doi: 10.1371/journal.pone.0103968. eCollection 2014.
• [11] Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
• [12] Induced pluripotent stem cells derived from a schizophrenia patient with ASTN2 deletion.Stem Cell Res. 2018 Jul;30:81-84. doi: 10.1016/j.scr.2018.05.013. Epub 2018 May 19.
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• [14] Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes.Hum Mol Genet. 2014 May 15;23(10):2752-68. doi: 10.1093/hmg/ddt669. Epub 2013 Dec 30.
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• [19] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [20] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
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• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
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• [30] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
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• [32] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [33] 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.
• [34] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [35] 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.
• [36] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [37] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.