Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8IR5QN)

• DOT Name: Exostosin-2 (EXT2)
• Synonyms: EC 2.4.1.224; Exostosin glycosyltransferase 2; Glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase; Heparan sulfate co-polymerase subunit EXT1; Multiple exostoses protein 2
• Gene Name: EXT2
• Related Disease:
  Exostoses, multiple, type 2
  Benign neoplasm
  Bone disease
  Chromosomal disorder
  Developmental and epileptic encephalopathy, 36
  Familial hypercholesterolemia
  Frontotemporal dementia
  Hypercholesterolemia, familial, 1
  Hyperostosis
  Metachondromatosis
  Pick disease
  Seizures-scoliosis-macrocephaly syndrome
  Autoimmune disease
  Chondrosarcoma
  Dent disease
  Lupus nephritis
  Membranous glomerulonephritis
  Neoplasm
  Osteosarcoma
  Type-1/2 diabetes
  Refractory multiple myeloma
  Exostosis
  Intellectual disability
  Mucopolysaccharidosis type 3A
  Potocki-Shaffer syndrome
  Skeletal system disorder
• UniProt ID: EXT2_HUMAN
• PDB ID: 7SCH; 7SCJ; 7SCK; 7UQX; 7UQY; 7ZAY
• EC Number: 2.4.1.224
• Pfam ID: PF03016 ; PF09258
• Sequence:
  MCASVKYNIRGPALIPRMKTKHRIYYITLFSIVLLGLIATGMFQFWPHSIESSNDWNVEK
  RSIRDVPVVRLPADSPIPERGDLSCRMHTCFDVYRCGFNPKNKIKVYIYALKKYVDDFGV
  SVSNTISREYNELLMAISDSDYYTDDINRACLFVPSIDVLNQNTLRIKETAQAMAQLSRW
  DRGTNHLLFNMLPGGPPDYNTALDVPRDRALLAGGGFSTWTYRQGYDVSIPVYSPLSAEV
  DLPEKGPGPRQYFLLSSQVGLHPEYREDLEALQVKHGESVLVLDKCTNLSEGVLSVRKRC
  HKHQVFDYPQVLQEATFCVVLRGARLGQAVLSDVLQAGCVPVVIADSYILPFSEVLDWKR
  ASVVVPEEKMSDVYSILQSIPQRQIEEMQRQARWFWEAYFQSIKAIALATLQIINDRIYP
  YAAISYEEWNDPPAVKWGSVSNPLFLPLIPPQSQGFTAIVLTYDRVESLFRVITEVSKVP
  SLSKLLVVWNNQNKNPPEDSLWPKIRVPLKVVRTAENKLSNRFFPYDEIETEAVLAIDDD
  IIMLTSDELQFGYEVWREFPDRLVGYPGRLHLWDHEMNKWKYESEWTNEVSMVLTGAAFY
  HKYFNYLYTYKMPGDIKNWVDAHMNCEDIAMNFLVANVTGKAVIKVTPRKKFKCPECTAI
  DGLSLDQTHMVERSECINKFASVFGTMPLKVVEHRADPVLYKDDFPEKLKSFPNIGSL
• Function: Glycosyltransferase forming with EXT1 the heterodimeric heparan sulfate polymerase which catalyzes the elongation of the heparan sulfate glycan backbone. Glycan backbone extension consists in the alternating transfer of (1->4)-beta-D-GlcA and (1->4)-alpha-D-GlcNAc residues from their respective UDP-sugar donors. Both EXT1 and EXT2 are required for the full activity of the polymerase since EXT1 bears the N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase activity within the complex while EXT2 carries the glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity. Heparan sulfate proteoglycans are ubiquitous components of the extracellular matrix and play an important role in tissue homeostasis and signaling.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective EXT2 causes exostoses 2 (R-HSA-3656237)
  Defective EXT1 causes exostoses 1, TRPS2 and CHDS (R-HSA-3656253)
  HS-GAG biosynthesis (R-HSA-2022928)
• BioCyc Pathway: MetaCyc:HS07726-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Exostoses, multiple, type 2	DISDMZ4W	Definitive	Autosomal dominant	[1]
Benign neoplasm	DISDUXAD	Strong	Genetic Variation	[2]
Bone disease	DISE1F82	Strong	Genetic Variation	[3]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[4]
Developmental and epileptic encephalopathy, 36	DISG4MY5	Strong	Genetic Variation	[5]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[6]
Frontotemporal dementia	DISKYHXL	Strong	Biomarker	[7]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Genetic Variation	[6]
Hyperostosis	DIS60EOE	Strong	Genetic Variation	[8]
Metachondromatosis	DISUM6CO	Strong	Biomarker	[9]
Pick disease	DISP6X50	Strong	Biomarker	[7]
Seizures-scoliosis-macrocephaly syndrome	DIST7VJV	Strong	Autosomal recessive	[10]
Autoimmune disease	DISORMTM	moderate	Biomarker	[11]
Chondrosarcoma	DIS4I7JB	moderate	Genetic Variation	[2]
Dent disease	DISRDLFN	moderate	Genetic Variation	[12]
Lupus nephritis	DISCVGPZ	moderate	Biomarker	[11]
Membranous glomerulonephritis	DISFSUKQ	moderate	Biomarker	[11]
Neoplasm	DISZKGEW	moderate	Genetic Variation	[13]
Osteosarcoma	DISLQ7E2	moderate	Genetic Variation	[14]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[15]
Refractory multiple myeloma	DIS606GH	Supportive	Autosomal dominant	[16]
Exostosis	DIS3VKEI	Disputed	Biomarker	[17]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[18]
Mucopolysaccharidosis type 3A	DIS2TLNF	Limited	Genetic Variation	[19]
Potocki-Shaffer syndrome	DISKGU59	Limited	Genetic Variation	[20]
Skeletal system disorder	DIS5PU87	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Exostosin-2 (EXT2).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Exostosin-2 (EXT2).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Exostosin-2 (EXT2).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Exostosin-2 (EXT2).	[24]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Exostosin-2 (EXT2).	[25]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Exostosin-2 (EXT2).	[26]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Exostosin-2 (EXT2).	[27]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Exostosin-2 (EXT2).	[28]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Exostosin-2 (EXT2).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Exostosin-2 (EXT2).	[30]

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] Familial solitary chondrosarcoma resulting from germline EXT2 mutation. Genes Chromosomes Cancer. 2017 Feb;56(2):128-134. doi: 10.1002/gcc.22419. Epub 2016 Oct 25.
• [3] Comparison of fluorescent single-strand conformation polymorphism analysis and denaturing high-performance liquid chromatography for detection of EXT1 and EXT2 mutations in hereditary multiple exostoses.Eur J Hum Genet. 2000 Jan;8(1):24-32. doi: 10.1038/sj.ejhg.5200409.
• [4] Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas.Cancer. 1998 May 1;82(9):1657-63. doi: 10.1002/(sici)1097-0142(19980501)82:9<1657::aid-cncr10>3.0.co;2-3.
• [5] A broad spectrum of genomic changes in latinamerican patients with EXT1/EXT2-CDG.Sci Rep. 2014 Sep 18;4:6407. doi: 10.1038/srep06407.
• [6] Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans.J Lipid Res. 2015 Mar;56(3):665-673. doi: 10.1194/jlr.M053504. Epub 2015 Jan 7.
• [7] Of brain and bone: the unusual case of Dr. A.Neurocase. 2009 Jun;15(3):190-205. doi: 10.1080/13554790802632967.
• [8] Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways.Development. 2004 May;131(9):1927-38. doi: 10.1242/dev.01061. Epub 2004 Mar 31.
• [9] EXT2-positive multiple hereditary osteochondromas with some features suggestive of metachondromatosis.Skeletal Radiol. 2012 May;41(5):607-10. doi: 10.1007/s00256-011-1261-9. Epub 2011 Sep 4.
• [10] Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses. J Med Genet. 2015 Oct;52(10):666-75. doi: 10.1136/jmedgenet-2015-103279. Epub 2015 Aug 5.
• [11] Exostosin 1/Exostosin 2-Associated Membranous Nephropathy.J Am Soc Nephrol. 2019 Jun;30(6):1123-1136. doi: 10.1681/ASN.2018080852. Epub 2019 May 6.
• [12] Characterization of 26 deletion CNVs reveals the frequent occurrence of micro-mutations within the breakpoint-flanking regions and frequent repair of double-strand breaks by templated insertions derived from remote genomic regions.Hum Genet. 2015 Jun;134(6):589-603. doi: 10.1007/s00439-015-1539-4. Epub 2015 Mar 20.
• [13] Somatic loss of an EXT2 gene mutation during malignant progression in a patient with hereditary multiple osteochondromas.Cancer Genet. 2015 Mar;208(3):62-7. doi: 10.1016/j.cancergen.2015.01.002. Epub 2015 Jan 16.
• [14] Functional Requirements for Heparan Sulfate Biosynthesis in Morphogenesis and Nervous System Development in C. elegans.PLoS Genet. 2017 Jan 9;13(1):e1006525. doi: 10.1371/journal.pgen.1006525. eCollection 2017 Jan.
• [15] LOC387761 polymorphism is associated with type 2 diabetes in the Mexican population.Genet Test Mol Biomarkers. 2011 Jan-Feb;15(1-2):79-83. doi: 10.1089/gtmb.2010.0107. Epub 2011 Jan 3.
• [16] Hereditary Multiple Osteochondromas. 2000 Aug 3 [updated 2020 Aug 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [17] Heparanase stimulates chondrogenesis and is up-regulated in human ectopic cartilage: a mechanism possibly involved in hereditary multiple exostoses.Am J Pathol. 2015 Jun;185(6):1676-85. doi: 10.1016/j.ajpath.2015.02.014. Epub 2015 Apr 8.
• [18] Novel exostosin-2 missense variants in a family with autosomal recessive exostosin-2-related syndrome: further evidences on the phenotype.Clin Genet. 2019 Jan;95(1):165-171. doi: 10.1111/cge.13458. Epub 2018 Oct 24.
• [19] A genetic model of substrate reduction therapy for mucopolysaccharidosis.J Biol Chem. 2012 Oct 19;287(43):36283-90. doi: 10.1074/jbc.M112.403360. Epub 2012 Sep 5.
• [20] A microdeletion encompassing PHF21A in an individual with global developmental delay and craniofacial anomalies.Am J Med Genet A. 2015 Dec;167A(12):3011-8. doi: 10.1002/ajmg.a.37344. Epub 2015 Sep 3.
• [21] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [22] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [23] 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.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [26] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [27] 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.
• [28] 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.
• [29] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [30] 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.