The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate
The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate
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DOI：
10.1038/514
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发表时间：
1998-06-01
期刊：
影响因子：
30.8
通讯作者：
Tufaro, F
中科院分区：
文献类型：
--
作者：
McCormick, C;Leduc, Y;Tufaro, F
遗传性多发性外生骨疣（HME）是一种常染色体显性遗传疾病，其特征是形成软骨帽肿瘤（外生骨疣），这些肿瘤从软骨内骨的生长板发展而来（1）。这种情况可导致骨骼异常、身材矮小和外生骨疣恶性转化为软骨肉瘤（2，3）或骨肉瘤（4，5）。连锁分析已经鉴定了HME的三个不同基因，8q24.1上的EXT 1、11 p11 -13上的EXT 2和19 p上的EXT 3（参考文献6-9）。大多数HME病例被归因于这些肿瘤抑制基因的错义或移码突变，其功能仍然不清楚。在这里，我们表明，EXT 1是一个ER-居民II型跨膜糖蛋白，其在细胞中的表达导致细胞表面硫酸乙酰肝素糖胺聚糖（GAG）的合成和显示的改变。两种含有病因错义突变的EXT 1变体（10）未能改变细胞表面糖胺聚糖，尽管保留了它们的ER定位。
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 bone(1). This condition can lead to skeletal abnormalities, short stature and malignant transformation of exostoses to chondrosarcomas(2,3) or osteosarcomas(4,5). Linkage analyses have identified three different genes for HME, EXT1 on 8q24.1, EXT2 on 11p11-13 and EXT3 on 19p (refs 6-9). 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 mutations(10) failed to alter cell-surface glycosaminoglycans, despite retaining their ER-localization.