Hecht J T, Hall C R, Snuggs M, Hayes E, Haynes R, Cole W G
Department of Pediatrics, University of Texas-Houston Medical School, Houston, TX 77030, USA.
Bone. 2002 Jul;31(1):199-204. doi: 10.1016/s8756-3282(02)00796-2.
Hereditary multiple exostoses (HME), a condition associated with development and growth of bony exostoses at the ends of the long bones, is caused by germline mutations in the EXT genes. EXT1 and EXT2 function as glycosyltransferases that participate in the biosynthesis of heparan sulfate (HS) to modify proteoglycans. HS proteoglycans, synthesized by chondrocytes and secreted to the extracellular matrix of the growth plate, play critical roles in growth plate signaling and remodeling. As part of studies to delineate the mechanism(s) by which an exostosis develops, we have systematically evaluated four growth plates from two HME and two solitary exostoses. Mutational events were correlated with the presence/absence and distribution of HS and the normally abundant proteoglycan, perlecan (PLN). DNA from the HME exostoses demonstrated heterozygous germline EXT1 or EXT2 mutations, and DNA from one solitary exostosis demonstrated a somatic EXT1 mutation. No loss of heterozygosity was observed in any of these samples. The chondrocyte zones of four exostosis growth plates showed absence of HS, as well as diminished and abnormal distribution of PLN. 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. This functional knockout of the exostosis chondrocytes' ability to synthesize HS chains further supports the observations of cytoskeletal abnormalities and chondrocyte disorganization associated with abnormal cell signaling.
遗传性多发性骨软骨瘤（HME）是一种与长骨末端骨软骨瘤的发生和生长相关的疾病，由EXT基因的种系突变引起。EXT1和EXT2作为糖基转移酶，参与硫酸乙酰肝素（HS）的生物合成以修饰蛋白聚糖。由软骨细胞合成并分泌到生长板细胞外基质中的HS蛋白聚糖在生长板信号传导和重塑中起关键作用。作为描绘骨软骨瘤发生机制研究的一部分，我们系统地评估了来自两个HME和两个孤立性骨软骨瘤的四个生长板。突变事件与HS和通常丰富的蛋白聚糖基底膜聚糖（PLN）的存在/缺失及分布相关。来自HME骨软骨瘤的DNA显示种系EXT1或EXT2杂合突变，来自一个孤立性骨软骨瘤的DNA显示体细胞EXT1突变。在这些样本中均未观察到杂合性缺失。四个骨软骨瘤生长板的软骨细胞区显示HS缺失，以及PLN分布减少和异常。这些结果表明，尽管EXT1或EXT2基因中未发生多个突变事件，但在骨软骨瘤生长板中发现了HS的完全缺失。骨软骨瘤软骨细胞合成HS链能力的这种功能性敲除进一步支持了与异常细胞信号传导相关的细胞骨架异常和软骨细胞紊乱的观察结果。
