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Gene Review

EXT1  -  exostosin glycosyltransferase 1

Homo sapiens

Synonyms: EXT, Exostosin-1, Glucuronosyl-N-acetylglucosaminyl-proteoglycan/N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase, LGCR, LGS, ...
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Disease relevance of EXT1


Psychiatry related information on EXT1

  • However, these results suggest the involvement of EXT1 in the development of mental disorders, including mental retardation and autism [6].

High impact information on EXT1

  • It maps proximal of EXT1, which is affected in a subgroup of patients with multiple cartilaginous exostoses and deleted in all patients with TRPS type II (TRPS II, or Langer-Giedion syndrome, MIM 150230; ref.2-5) [7].
  • Linkage analyses have identified three different genes for HME, EXT1 on 8q24.1, EXT2 on 11p11-13 and EXT3 on 19p (refs 6-9) [8].
  • The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate [8].
  • Two EXT1 variants containing aetiologic missense mutations failed to alter cell-surface glycosaminoglycans, despite retaining their ER-localization [8].
  • Here, we show that EXT1 is an ER-resident type II transmembrane glycoprotein whose expression in cells results in the alteration of the synthesis and display of cell surface heparan sulfate glycosaminoglycans (GAGs) [8].

Chemical compound and disease context of EXT1

  • Sog9 cells were previously isolated as CS-deficient cells from gro2C cells, which were partially resistant to HSV-1 infection and defective in the expression of heparan sulfate (HS) because of a splice site mutation in the EXT1 gene encoding the HS-synthesizing enzyme [9].
  • Here, we have investigated the in vitro polymerization capacities of recombinant soluble EXT1, EXT2, and EXT1/2 complex on exogenous oligosaccharide acceptors derived from Escherichia coli K5 capsular polysaccharide [10].

Biological context of EXT1


Anatomical context of EXT1

  • Five mutations in the EXT1 gene have been identified--four germ-line mutations, including two unrelated families with the same mutation, and one somatic mutation in a patient with chondrosarcoma [2].
  • The present studies were undertaken to evaluate which chondrocyte-specific functions are associated with diminished HS synthesis in human chondrocytes harboring either EXT1 or EXT2 mutations [12].
  • Here, a functional assay that detects HS expression on the cell surface of an EXT1-deficient cell line was used to test the remaining missense mutant exostosin proteins for their ability to rescue HS biosynthesis in vivo [1].
  • Hereditary multiple exostoses (EXT) is an autosomal dominant disorder that is characterized by the appearance of multiple outgrowths of the long bones (exostoses) at their epiphyses [13].
  • Two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild-type allele in three osteochondromas, indicating that, in cartilaginous cells of the growth plate, inactivation of both copies of the EXT1 gene is required for osteochondroma formation in hereditary cases [14].

Associations of EXT1 with chemical compounds

  • The tumor suppressors EXT1 and EXT2 are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate (HS) and its analog, heparin (Hep) [15].
  • Although both EXT1 and EXT2 exhibit GlcNAc transferase and GlcUA transferase activities required for the HS synthesis, no HS chain polymerization has been demonstrated in vitro using recombinant enzymes [16].
  • Interestingly, all four EXT1 missense mutations occurred in an arginine residue at codon 340 (R340) that is known as a critical site for expression of heparan sulfate glycosaminoglycans, suggesting that the region encompassing the arginine residue may play an important role in the function of the EXT1 protein [17].
  • These findings provide insight into the location of the GlcA transferase subdomain of the enzyme and indicate that loss of the GlcA transferase domain may be sufficient to cause hereditary multiple exostoses [18].
  • Our data show that Ext1 at a dilution ratio of one part semen to 15 parts extender should be used for walleye semen cryopreservation and that the fertilizing media does not benefit from theophylline supplementation [19].

Other interactions of EXT1

  • From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases [20].
  • It is genetically heterogeneous with at least three chromosomal loci: EXT1 on 8q24.1, EXT2 on 11p11, and EXT3 on 19p [21].
  • Structure, chromosomal location, and expression profile of EXTR1 and EXTR2, new members of the multiple exostoses gene family [13].
  • Recombinant soluble enzymes expressed by co-transfection of EXT1 and EXT2 synthesized heparan polymers with average molecular weights greater than 1.7 x 105 using UDP-[3H]GlcNAc and UDP-GlcUA as donors on the recombinant glypican-1 core protein and also on the synthetic linkage region analog GlcUA-Gal-O-C2H4NH-benzyloxycarbonyl [16].
  • Identification and localization of the gene for EXTL, a third member of the multiple exostoses gene family [22].

Analytical, diagnostic and therapeutic context of EXT1


  1. Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity. Cheung, P.K., McCormick, C., Crawford, B.E., Esko, J.D., Tufaro, F., Duncan, G. Am. J. Hum. Genet. (2001) [Pubmed]
  2. Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies. Hecht, J.T., Hogue, D., Wang, Y., Blanton, S.H., Wagner, M., Strong, L.C., Raskind, W., Hansen, M.F., Wells, D. Am. J. Hum. Genet. (1997) [Pubmed]
  3. Identification of a third EXT-like gene (EXTL3) belonging to the EXT gene family. Van Hul, W., Wuyts, W., Hendrickx, J., Speleman, F., Wauters, J., De Boulle, K., Van Roy, N., Bossuyt, P., Willems, P.J. Genomics (1998) [Pubmed]
  4. A 4-megabase YAC contig that spans the Langer-Giedion syndrome region on human chromosome 8q24.1: use in refining the location of the trichorhinophalangeal syndrome and multiple exostoses genes (TRPS1 and EXT1). Hou, J., Parrish, J., Lüdecke, H.J., Sapru, M., Wang, Y., Chen, W., Hill, A., Siegel-Bartelt, J., Northrup, H., Elder, F.F. Genomics (1995) [Pubmed]
  5. Three novel EXT1 and EXT2 gene mutations in Taiwanese patients with multiple exostoses. Chen, W.C., Chi, C.H., Chuang, C.C., Jou, I.M. J. Formos. Med. Assoc. (2006) [Pubmed]
  6. Association of autism in two patients with hereditary multiple exostoses caused by novel deletion mutations of EXT1. Li, H., Yamagata, T., Mori, M., Momoi, M.Y. J. Hum. Genet. (2002) [Pubmed]
  7. Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I. Momeni, P., Glöckner, G., Schmidt, O., von Holtum, D., Albrecht, B., Gillessen-Kaesbach, G., Hennekam, R., Meinecke, P., Zabel, B., Rosenthal, A., Horsthemke, B., Lüdecke, H.J. Nat. Genet. (2000) [Pubmed]
  8. The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. McCormick, C., Leduc, Y., Martindale, D., Mattison, K., Esford, L.E., Dyer, A.P., Tufaro, F. Nat. Genet. (1998) [Pubmed]
  9. Chondroitin 4-o-sulfotransferase-1 regulates e disaccharide expression of chondroitin sulfate required for herpes simplex virus infectivity. Uyama, T., Ishida, M., Izumikawa, T., Trybala, E., Tufaro, F., Bergstr??m, T., Sugahara, K., Kitagawa, H. J. Biol. Chem. (2006) [Pubmed]
  10. In vitro polymerization of heparan sulfate backbone by the EXT proteins. Busse, M., Kusche-Gullberg, M. J. Biol. Chem. (2003) [Pubmed]
  11. Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses. Philippe, C., Porter, D.E., Emerton, M.E., Wells, D.E., Simpson, A.H., Monaco, A.P. Am. J. Hum. Genet. (1997) [Pubmed]
  12. Differentiation-induced loss of heparan sulfate in human exostosis derived chondrocytes. Hecht, J.T., Hayes, E., Haynes, R., Cole, W.G., Long, R.J., Farach-Carson, M.C., Carson, D.D. Differentiation (2005) [Pubmed]
  13. Structure, chromosomal location, and expression profile of EXTR1 and EXTR2, new members of the multiple exostoses gene family. Saito, T., Seki, N., Yamauchi, M., Tsuji, S., Hayashi, A., Kozuma, S., Hori, T. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  14. EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Bovée, J.V., Cleton-Jansen, A.M., Wuyts, W., Caethoven, G., Taminiau, A.H., Bakker, E., Van Hul, W., Cornelisse, C.J., Hogendoorn, P.C. Am. J. Hum. Genet. (1999) [Pubmed]
  15. Human tumor suppressor EXT gene family members EXTL1 and EXTL3 encode alpha 1,4- N-acetylglucosaminyltransferases that likely are involved in heparan sulfate/ heparin biosynthesis. Kim, B.T., Kitagawa, H., Tamura , J., Saito, T., Kusche-Gullberg, M., Lindahl, U., Sugahara, K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  16. In vitro heparan sulfate polymerization: crucial roles of core protein moieties of primer substrates in addition to the EXT1-EXT2 interaction. Kim, B.T., Kitagawa, H., Tanaka, J., Tamura, J., Sugahara, K. J. Biol. Chem. (2003) [Pubmed]
  17. Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses. Seki, H., Kubota, T., Ikegawa, S., Haga, N., Fujioka, F., Ohzeki, S., Wakui, K., Yoshikawa, H., Takaoka, K., Fukushima, Y. Am. J. Med. Genet. (2001) [Pubmed]
  18. Location of the glucuronosyltransferase domain in the heparan sulfate copolymerase EXT1 by analysis of Chinese hamster ovary cell mutants. Wei, G., Bai, X., Gabb, M.M., Bame, K.J., Koshy, T.I., Spear, P.G., Esko, J.D. J. Biol. Chem. (2000) [Pubmed]
  19. Comparison of extenders, dilution ratios and theophylline addition on the function of cryopreserved walleye semen. Bergeron, A., Vandenberg, G., Proulx, D., Bailey, J.L. Theriogenology (2002) [Pubmed]
  20. Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses. Wuyts, W., Van Hul, W., De Boulle, K., Hendrickx, J., Bakker, E., Vanhoenacker, F., Mollica, F., Lüdecke, H.J., Sayli, B.S., Pazzaglia, U.E., Mortier, G., Hamel, B., Conrad, E.U., Matsushita, M., Raskind, W.H., Willems, P.J. Am. J. Hum. Genet. (1998) [Pubmed]
  21. Mutation analysis of hereditary multiple exostoses in the Chinese. Xu, L., Xia, J., Jiang, H., Zhou, J., Li, H., Wang, D., Pan, Q., Long, Z., Fan, C., Deng, H.X. Hum. Genet. (1999) [Pubmed]
  22. Identification and localization of the gene for EXTL, a third member of the multiple exostoses gene family. Wise, C.A., Clines, G.A., Massa, H., Trask, B.J., Lovett, M. Genome Res. (1997) [Pubmed]
  23. Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells. Ropero, S., Setien, F., Espada, J., Fraga, M.F., Herranz, M., Asp, J., Benassi, M.S., Franchi, A., Patiño, A., Ward, L.S., Bovee, J., Cigudosa, J.C., Wim, W., Esteller, M. Hum. Mol. Genet. (2004) [Pubmed]
  24. Disruption of gastrulation and heparan sulfate biosynthesis in EXT1-deficient mice. Lin, X., Wei, G., Shi, Z., Dryer, L., Esko, J.D., Wells, D.E., Matzuk, M.M. Dev. Biol. (2000) [Pubmed]
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