Details of Drug Off-Target (DOT)

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

• DOT Name: Putative Polycomb group protein ASXL3 (ASXL3)
• Synonyms: Additional sex combs-like protein 3
• Gene Name: ASXL3
• Related Disease:
  Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome
  Syndromic intellectual disability
  Adult teratoma
  Epilepsy
  Intellectual disability
  Lung adenocarcinoma
  Megalencephaly
  Neurodevelopmental disorder
  Pontocerebellar hypoplasia type 1A
  Sleep disorder
  Small-cell lung cancer
  T-cell lymphoma
  Teratoma
  Advanced cancer
  Anxiety
  Asthma
  Breast cancer
  Breast carcinoma
  Congenital laryngomalacia
  Melanoma
  Neuroblastoma
  Autism spectrum disorder
• UniProt ID: ASXL3_HUMAN
• Pfam ID: PF13919 ; PF05066 ; PF13922
• Sequence:
  MKDKRKKKDRTWAEAARLALEKHPNSPMTAKQILEVIQKEGLKETSGTSPLACLNAMLHT
  NTRIGDGTFFKIPGKSGLYALKKEESSCPADGTLDLVCESELDGTDMAEANAHGEENGVC
  SKQVTDEASSTRDSSLTNTAVQSKLVSSFQQHTKKALKQALRQQQKRRNGVSMMVNKTVP
  RVVLTPLKVSDEQSDSPSGSESKNGEADSSDKEMKHGQKSPTGKQTSQHLKRLKKSGLGH
  LKWTKAEDIDIETPGSILVNTNLRALINKHTFASLPQHFQQYLLLLLPEVDRQMGSDGIL
  RLSTSALNNEFFAYAAQGWKQRLAEGEFTPEMQLRIRQEIEKEKKTEPWKEKFFERFYGE
  KLGMSREESVKLTTGPNNAGAQSSSSCGTSGLPVSAQTALAEQQPKSMKSPASPEPGFCA
  TLCPMVEIPPKDIMAELESEDILIPEESVIQEEIAEEVETSICECQDENHKTIPEFSEEA
  ESLTNSHEEPQIAPPEDNLESCVMMNDVLETLPHIEVKIEGKSESPQEEMTVVIDQLEVC
  DSLIPSTSSMTHVSDTEHKESETAVETSTPKIKTGSSSLEGQFPNEGIAIDMELQSDPEE
  QLSENACISETSFSSESPEGACTSLPSPGGETQSTSEESCTPASLETTFCSEVSSTENTD
  KYNQRNSTDENFHASLMSEISPISTSPEISEASLMSNLPLTSEASPVSNLPLTSETSPMS
  DLPLTSETSSVSSMLLTSETTFVSSLPLPSETSPISNSSINERMAHQQRKSPSVSEEPLS
  PQKDESSATAKPLGENLTSQQKNLSNTPEPIIMSSSSIAPEAFPSEDLHNKTLSQQTCKS
  HVDTEKPYPASIPELASTEMIKVKNHSVLQRTEKKVLPSPLELSVFSEGTDNKGNELPSA
  KLQDKQYISSVDKAPFSEGSRNKTHKQGSTQSRLETSHTSKSSEPSKSPDGIRNESRDSE
  ISKRKTAEQHSFGICKEKRARIEDDQSTRNISSSSPPEKEQPPREEPRVPPLKIQLSKIG
  PPFIIKSQPVSKPESRASTSTSVSGGRNTGARTLADIKARAQQARAQREAAAAAAVAAAA
  SIVSGAMGSPGEGGKTRTLAHIKEQTKAKLFAKHQARAHLFQTSKETRLPPPLSSKEGPP
  NLEVSSTPETKMEGSTGVIIVNPNCRSPSNKSAHLRETTTVLQQSLNPSKLPETATDLSV
  HSSDENIPVSHLSEKIVSSTSSENSSVPMLFNKNSVPVSVCSTAISGAIKEHPFVSSVDK
  SSVLMSVDSANTTISACNISMLKTIQGTDTPCIAIIPKCIESTPISATTEGSSISSSMDD
  KQLLISSSSASNLVSTQYTSVPTPSIGNNLPNLSTSSVLIPPMGINNRFPSEKIAIPGSE
  EQATVSMGTTVRAALSCSDSVAVTDSLVAHPTVAMFTGNMLTINSYDSPPKLSAESLDKN
  SGPRNRADNSGKPQQPPGGFAPAAINRSIPCKVIVDHSTTLTSSLSLTVSVESSEASLDL
  QGRPVRTEASVQPVACPQVSVISRPEPVANEGIDHSSTFIAASAAKQDSKTLPATCTSLR
  ELPLVPDKLNEPTAPSHNFAEQARGPAPFKSEADTTCSNQYNPSNRICWNDDGMRSTGQP
  LVTHSGSSKQKEYLEQSCPKAIKTEHANYLNVSELHPRNLVTNVALPVKSELHEADKGFR
  MDTEDFPGPELPPPAAEGASSVQQTQNMKASTSSPMEEAISLATDALKRVPGAGSSGCRL
  SSVEANNPLVTQLLQGNLPLEKVLPQPRLGAKLEINRLPLPLQTTSVGKTAPERNVEIPP
  SSPNPDGKGYLAGTLAPLQMRKRENHPKKRVARTVGEHTQVKCEPGKLLVEPDVKGVPCV
  ISSGISQLGHSQPFKQEWLNKHSMQNRIVHSPEVKQQKRLLPSCSFQQNLFHVDKNGGFH
  TDAGTSHRQQFYQMPVAARGPIPTAALLQASSKTPVGCNAFAFNRHLEQKGLGEVSLSSA
  PHQLRLANMLSPNMPMKEGDEVGGTAHTMPNKALVHPPPPPPPPPPPPLALPPPPPPPPP
  LPPPLPNAEVPSDQKQPPVTMETTKRLSWPQSTGICSNIKSEPLSFEEGLSSSCELGMKQ
  VSYDQNEMKEQLKAFALKSADFSSYLLSEPQKPFTQLAAQKMQVQQQQQLCGNYPTIHFG
  STSFKRAASAIEKSIGILGSGSNPATGLSGQNAQMPVQNFADSSNADELELKCSCRLKAM
  IVCKGCGAFCHDDCIGPSKLCVACLVVR
• Function: Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. PcG proteins are not required to initiate repression, but to maintain it during later stages of development. They probably act via methylation of histones, rendering chromatin heritably changed in its expressibility.
• Tissue Specificity: Expressed in pancreatic islets, testis, neuroblastoma, head and neck tumor.
• KEGG Pathway: Polycomb repressive complex (hsa03083)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome	DISI930V	Definitive	Autosomal dominant	[1]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[2]
Adult teratoma	DISBY81U	Strong	Biomarker	[3]
Epilepsy	DISBB28L	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[6]
Megalencephaly	DISYW5SV	Strong	Biomarker	[7]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[4]
Pontocerebellar hypoplasia type 1A	DIS7X0VS	Strong	Genetic Variation	[8]
Sleep disorder	DIS3JP1U	Strong	Genetic Variation	[9]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[3]
T-cell lymphoma	DISSXRTQ	Strong	Biomarker	[10]
Teratoma	DIS6ICY4	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[3]
Anxiety	DISIJDBA	moderate	CausalMutation	[9]
Asthma	DISW9QNS	moderate	CausalMutation	[9]
Breast cancer	DIS7DPX1	moderate	Biomarker	[11]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[11]
Congenital laryngomalacia	DISWQG9L	moderate	CausalMutation	[9]
Melanoma	DIS1RRCY	moderate	Biomarker	[11]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[12]
Autism spectrum disorder	DISXK8NV	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Putative Polycomb group protein ASXL3 (ASXL3).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Putative Polycomb group protein ASXL3 (ASXL3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Putative Polycomb group protein ASXL3 (ASXL3).	[19]

4 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 Putative Polycomb group protein ASXL3 (ASXL3).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Putative Polycomb group protein ASXL3 (ASXL3).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Putative Polycomb group protein ASXL3 (ASXL3).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Putative Polycomb group protein ASXL3 (ASXL3).	[20]

References

• [1] De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome. Genome Med. 2013 Feb 5;5(2):11. doi: 10.1186/gm415. eCollection 2013.
• [2] 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.
• [3] ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer.Cancer Res. 2017 Nov 15;77(22):6267-6281. doi: 10.1158/0008-5472.CAN-17-0570. Epub 2017 Sep 21.
• [4] De novo variants in neurodevelopmental disorders with epilepsy.Nat Genet. 2018 Jul;50(7):1048-1053. doi: 10.1038/s41588-018-0143-7. Epub 2018 Jun 25.
• [5] Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition.Eur J Hum Genet. 2017 Feb;25(2):183-191. doi: 10.1038/ejhg.2016.165. Epub 2016 Nov 30.
• [6] Methylation and transcriptome analysis reveal lung adenocarcinoma-specific diagnostic biomarkers.J Transl Med. 2019 Sep 27;17(1):324. doi: 10.1186/s12967-019-2068-z.
• [7] De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype. Am J Hum Genet. 2016 Oct 6;99(4):991-999. doi: 10.1016/j.ajhg.2016.08.017. Epub 2016 Sep 29.
• [8] Whole exome sequencing diagnoses the first fetal case of Bainbridge-Ropers syndrome presenting as pontocerebellar hypoplasia type 1.Birth Defects Res. 2018 Apr 3;110(6):538-542. doi: 10.1002/bdr2.1191. Epub 2018 Jan 8.
• [9] Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome.Am J Med Genet A. 2016 Jul;170(7):1863-7. doi: 10.1002/ajmg.a.37653. Epub 2016 Apr 13.
• [10] Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.Nat Genet. 2015 Sep;47(9):1061-6. doi: 10.1038/ng.3358. Epub 2015 Jul 20.
• [11] Functional and cancer genomics of ASXL family members.Br J Cancer. 2013 Jul 23;109(2):299-306. doi: 10.1038/bjc.2013.281. Epub 2013 Jun 4.
• [12] Identification and characterization of ASXL3 gene in silico.Int J Oncol. 2004 Jun;24(6):1617-22.
• [13] Genes and Pathways Regulated by Androgens in Human Neural Cells, Potential Candidates for the Male Excess in Autism Spectrum Disorder.Biol Psychiatry. 2018 Aug 15;84(4):239-252. doi: 10.1016/j.biopsych.2018.01.002. Epub 2018 Jan 9.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.