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.