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The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate

Nature Genetics volume 19, pages 158–161 (1998)Cite this article

Abstract

Hereditary multiple exostoses (HME) is an autosomal dominant disorder characterized by the formation of cartilage-capped tumours (exostoses) that develop from the growth plate of endochondral bone1. This condition can lead to skeletal abnormalities, short stature and malignant transformation of exostoses to chondrosarcomas2,3 or osteosarcomas4,5. Linkage analyses have identified three different genes for HME, EXT1 on 8q24.1, EXT2 on 11p11–13 and EXT3 on 19p (refs 6, 7, 8, 9). Most HME cases have been attributed to missense or frameshift mutations in these tumour-supressor genes, whose functions have remained obscure. 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). Two EXT1 variants containing aetiologic missense mutations10 failed to alter cell-surface glycosaminoglycans, despite retaining their ER-localization.

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Figure 1: Sog9 cells transfected with EXT1 are susceptible to HSV-1 infection.
Figure 2: EXT1-expressing cell lines synthesize a heparan-sulfate glycosaminoglycan.
Figure 3: EXT1 is localized to the endoplasmic reticulum.
Figure 4: EXT1myc is modified by high-mannose N-linked oligosaccharides.
Figure 5: Mutations in EXT1 render the protein inactive.

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Acknowledgements

We thank B. Roizman and L. Enquist for helpful discussions. This work was supported by grants to F.T. from the Medical Research Council of Canada and the Canadian Genetic Diseases Network.

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  1. Department of Microbiology & Immunology, University of British Columbia, Vancouver, V6T 1Z3, Canada

    Craig McCormick, Yves Leduc, Diane Martindale, Kirsten Mattison, Lesley Esford, Angela Dyer & Frank Tufaro

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  1. Craig McCormick
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Correspondence to Frank Tufaro.

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McCormick, C., Leduc, Y., Martindale, D. et al. The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nat Genet 19, 158–161 (1998). https://doi.org/10.1038/514

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