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Gene Review

EXT2  -  exostosin glycosyltransferase 2

Homo sapiens

Synonyms: Exostosin-2, Glucuronosyl-N-acetylglucosaminyl-proteoglycan/N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase, Multiple exostoses protein 2, SOTV
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Disease relevance of EXT2


Psychiatry related information on EXT2

  • Deletion 11(p11.2p12) is a rare, yet specific, deletion syndrome involving the EXT2 locus, a gene for parietal foramina, and a mental retardation locus, and therefore can be classified as a contiguous gene deletion syndrome [6].

High impact information on EXT2


Biological context of EXT2

  • This implies that the EXT2 gene is located at the short arm of chromosome 11, in band 11p11-p12 [11].
  • The missense mutations in EXT1 and EXT2 may pinpoint crucial domains in both proteins and therefore give clues for the understanding of the pathophysiology of this skeletal disorder [12].
  • We have screened 17 probands with the HME phenotype, for alterations in all translated exons and flanking intronic sequences, in the EXT1 and EXT2 genes, by conformation-sensitive gel electrophoresis [12].
  • Both the EXT1 and EXT2 genes have been cloned recently and define a new family of potential tumor suppressor genes [12].
  • EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT [13].

Anatomical context of EXT2

  • Here, by testing a cell line with a specific defect in EXT1 in in vivo and in vitro assays, we show that EXT2 does not harbor significant glycosyltransferase activity in the absence of EXT1 [10].
  • An immunohistochemical analysis on developing bones further showed that both EXT1 and EXT2 were concomitantly expressed in hypertrophic chondrocytes of forelimb bones from 1-day-old neonatal mouse, but down-regulated in maturing chondrocytes of developing cartilage from 21-day-old mouse [14].
  • Here, we found that the mRNA expression of EXT2, one of the crucial enzymes for heparan sulfate-glycosaminoglycan synthesis, was markedly up-regulated in injured hypoglossal motor neurons after axotomy [15].
  • These results indicate that, although multiple mutational events do not occur in the EXT1 or EXT2 genes, a complete loss of HS was found in the exostosis growth plates [16].
  • The EXT1 and EXT2 genes from lymphocytes of the affected individuals were analyzed by using denaturing high-performance liquid chromatography and direct sequencing [17].

Associations of EXT2 with chemical compounds

  • The EXT1 and EXT2 genes have been cloned and defined as glycosyltransferases involved in the synthesis of heparan sulfate [18].
  • 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 [19].
  • The EXT2 mutation identified in the SNU-OC15 family was a missense mutation at codon 85 of exon 2 (TGC-->CGC), resulting in an amino acid change from cysteine to arginine [20].
  • In contrast, incubations with recombinant EXT2 resulted in the addition of a single glucuronic acid but no further polymerization [5].
  • Reported elsewhere in detail, genetic linkage analysis mapped the causative gene to chromosome 11 and molecular studies revealed a guanine-to-thymine transversion in the ext2 gene [21].

Other interactions of EXT2

  • From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases [22].
  • Genetic analyses have revealed HME to be a multigenic disorder linked to three loci on chromosomes 8q24 (EXT1), 11p11-13 (EXT2), and 19p (EXT3) [18].
  • However, in situ hybridization of sectioned embryos revealed remarkable differences in expression profiles of EXT1, EXT2, and EXTL1 [18].
  • Using polymerase chain reaction and direct sequencing, we analyzed the EXT1 and EXT2 genes in three familial cases and one sporadic case of HME in Taiwanese patients [23].
  • The EXT2-GalNAc-T5 interaction provides the first direct physical link between EXT proteins and known components of glycosamino-glycan synthesis [24].

Analytical, diagnostic and therapeutic context of EXT2

  • In this study, we performed a mutational analysis of EXT1 and EXT2 genes in eight unrelated Korean EXT families by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis followed by direct DNA sequencing [20].
  • We investigated the expression of EXT1 and EXT2 (quantitative RT-PCR) and of different HSPGs (immunohistochemistry) in solitary and hereditary osteochondromas and in cases with malignant progression to secondary peripheral chondrosarcoma, in relation to possible mutations and promoter methylation [25].
  • In order to develop an efficient screening strategy for mutations in these genes, we performed two independent blind screens of EXT1 and EXT2 in 34 unrelated patients with HME, using denaturing high-performance liquid chromatography (DHPLC) and fluorescent single-strand conformation polymorphism analysis (F-SSCP) [26].
  • In patients suspected to be affected by MO, we recommend a quantitative analysis such as MLPA, followed by direct sequence analysis for the screening of the EXT1 and EXT2 genes [27].
  • We also determined subcellular localization and quantitation of EXT1 and EXT2 proteins by immunocytochemistry using antibodies raised against unique peptide epitopes [28].


  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. Ext-mutation analysis in Italian sporadic and hereditary osteochondromas. Gigante, M., Matera, M.G., Seripa, D., Izzo, A.M., Venanzi, R., Giannotti, A., Digilio, M.C., Gravina, C., Lazzari, M., Monteleone, G., Monteleone, M., Dallapiccola, B., Fazio, V.M. Int. J. Cancer (2001) [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. 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]
  5. In vitro polymerization of heparan sulfate backbone by the EXT proteins. Busse, M., Kusche-Gullberg, M. J. Biol. Chem. (2003) [Pubmed]
  6. Interstitial deletion of 11(p11.2p12): a newly described contiguous gene deletion syndrome involving the gene for hereditary multiple exostoses (EXT2). Potocki, L., Shaffer, L.G. Am. J. Med. Genet. (1996) [Pubmed]
  7. 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]
  8. The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Stickens, D., Clines, G., Burbee, D., Ramos, P., Thomas, S., Hogue, D., Hecht, J.T., Lovett, M., Evans, G.A. Nat. Genet. (1996) [Pubmed]
  9. 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]
  10. The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. McCormick, C., Duncan, G., Goutsos, K.T., Tufaro, F. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  11. Refinement of the multiple exostoses locus (EXT2) to a 3-cM interval on chromosome 11. Wuyts, W., Ramlakhan, S., Van Hul, W., Hecht, J.T., van den Ouweland, A.M., Raskind, W.H., Hofstede, F.C., Reyniers, E., Wells, D.E., de Vries, B. Am. J. Hum. Genet. (1995) [Pubmed]
  12. 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]
  13. Positional cloning of a gene involved in hereditary multiple exostoses. Wuyts, W., Van Hul, W., Wauters, J., Nemtsova, M., Reyniers, E., Van Hul, E.V., De Boulle, K., de Vries, B.B., Hendrickx, J., Herrygers, I., Bossuyt, P., Balemans, W., Fransen, E., Vits, L., Coucke, P., Nowak, N.J., Shows, T.B., Mallet, L., van den Ouweland, A.M., McGaughran, J., Halley, D.J., Willems, P.J. Hum. Mol. Genet. (1996) [Pubmed]
  14. Association of EXT1 and EXT2, hereditary multiple exostoses gene products, in Golgi apparatus. Kobayashi, S., Morimoto, K., Shimizu, T., Takahashi, M., Kurosawa, H., Shirasawa, T. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  15. Nerve injury induces the expression of EXT2, a glycosyltransferase required for heparan sulfate synthesis. Murakami, K., Namikawa, K., Shimizu, T., Shirasawa, T., Yoshida, S., Kiyama, H. Neuroscience (2006) [Pubmed]
  16. Heparan sulfate abnormalities in exostosis growth plates. Hecht, J.T., Hall, C.R., Snuggs, M., Hayes, E., Haynes, R., Cole, W.G. Bone (2002) [Pubmed]
  17. 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]
  18. EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis. Stickens, D., Brown, D., Evans, G.A. Dev. Dyn. (2000) [Pubmed]
  19. 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]
  20. Germline mutations in the EXT1 and EXT2 genes in Korean patients with hereditary multiple exostoses. Park, K.J., Shin, K.H., Ku, J.L., Cho, T.J., Lee, S.H., Choi, I.H., Phillipe, C., Monaco, A.P., Porter, D.E., Park, J.G. J. Hum. Genet. (1999) [Pubmed]
  21. Chondrosarcoma in a family with multiple hereditary exostoses. Kivioja, A., Ervasti, H., Kinnunen, J., Kaitila, I., Wolf, M., Böhling, T. The Journal of bone and joint surgery. British volume. (2000) [Pubmed]
  22. 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]
  23. 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]
  24. A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses. Simmons, A.D., Musy, M.M., Lopes, C.S., Hwang, L.Y., Yang, Y.P., Lovett, M. Hum. Mol. Genet. (1999) [Pubmed]
  25. Decreased EXT expression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and peripheral chondrosarcomas. Hameetman, L., David, G., Yavas, A., White, S.J., Taminiau, A.H., Cleton-Jansen, A.M., Hogendoorn, P.C., Bovée, J.V. J. Pathol. (2007) [Pubmed]
  26. 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. Dobson-Stone, C., Cox, R.D., Lonie, L., Southam, L., Fraser, M., Wise, C., Bernier, F., Hodgson, S., Porter, D.E., Simpson, A.H., Monaco, A.P. Eur. J. Hum. Genet. (2000) [Pubmed]
  27. Mutation screening of EXT1 and EXT2 by direct sequence analysis and MLPA in patients with multiple osteochondromas: splice site mutations and exonic deletions account for more than half of the mutations. Vink, G.R., White, S.J., Gabelic, S., Hogendoorn, P.C., Breuning, M.H., Bakker, E. Eur. J. Hum. Genet. (2005) [Pubmed]
  28. Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes. Bernard, M.A., Hall, C.E., Hogue, D.A., Cole, W.G., Scott, A., Snuggs, M.B., Clines, G.A., Lüdecke, H.J., Lovett, M., Van Winkle, W.B., Hecht, J.T. Cell Motil. Cytoskeleton (2001) [Pubmed]
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