Nature Genetics
19, 158 - 161 (1998)
doi:10.1038/514
The putative tumour suppressor EXT1 alters the expression of cell-surface
heparan sulfateCraig McCormick, Yves Leduc, Diane Martindale, Kirsten Mattison, Lesley Esford, Angela Dyer
& Frank Tufaro
Department of Microbiology & Immunology, University
of British Columbia, Vancouver, V6T 1Z3, Canada.
Correspondence should be addressed to Frank Tufaro tufaro@unixg.ubc.caHereditary 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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