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 11p11â13 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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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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McCormick, C., Leduc, Y., Martindale, D. et al. The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nat Genet 19, 158â161 (1998). https://doi.org/10.1038/514
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DOI: https://doi.org/10.1038/514
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