Hereditary multiple exostoses and heparan sulfate polymerization

Zak, Beverly M.; Crawford, Brett E.; Esko, Jeffrey D.

doi:10.1016/s0304-4165(02)00402-6

Cited by 166 publications

(143 citation statements)

References 75 publications

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“…Cells with functional EXT in sporadic and hereditary secondary peripheral chondrosarcomas EXT1 and EXT2 genes encode ubiquitously expressed type-II transmembrane glycosyltransferases (EXT1 and EXT2) (McCormick et al, 1998), which localize to the endoplasmic reticulum and Golgi complex, and are required for the synthesis of heparan sulfate chains on proteoglycans (Zak et al, 2002;Bulow and Hobert, 2006). To assess the potential function of EXT1, we evaluated the expression of the EXT1 protein, using an EXT1 antibody, and the production of heparan sulfate, using the 10E4 antibody, in the setting of sporadic and multiple lesions.…”

Section: Clinical Findings and Imaging Studiesmentioning

confidence: 99%

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

et al. 2011

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Secondary peripheral chondrosarcoma is the result of malignant transformation of a pre-existing osteochondroma, the most common benign bone tumor. Osteochondromas are caused by genetic abnormalities in EXT1 or EXT2: homozygous deletion of EXT1 characterizes sporadic osteochondromas (non-familial/solitary), and germline mutations in EXT1 or EXT2 combined with loss of heterozygosity define hereditary multiple osteochondromas. While cells with homozygous inactivation of EXT and wild-type cells shape osteochondromas, the cellular composition of secondary peripheral chondrosarcomas and the role of EXT in their formation have remained unclear. We report using a targeted-tiling-resolution oligo-array-CGH (array comparative genomic hybridization) that homozygous deletions of EXT1 or EXT2 are much less frequently detected (2/17, 12%) in sporadic secondary peripheral chondrosarcomas than expected based on the assumption that they originate in sporadic osteochondromas, in which homozygous inactivation of EXT1 is found in B80% of our cases. FISH with an EXT1 probe confirmed that, unlike sporadic osteochondromas, cells from sporadic secondary peripheral chondrosarcomas predominantly retained one (hemizygous deleted loci) or both copies (wild-type) of the EXT1 locus. By immunohistochemistry, we confirm the presence of cells with dysfunctional EXT1 in sporadic osteochondromas and show cells with functional EXT1 in sporadic secondary peripheral chondrosarcomas. These immuno results were verified in osteochondromas and secondary peripheral chondrosarcomas in the setting of hereditary multiple osteochondromas. Our data therefore point to a model of oncogenesis in which the osteochondroma creates a niche in which wild-type cells with functional EXT are predisposed to acquire other mutations giving rise to secondary peripheral chondrosarcoma, indicating that EXT-independent mechanisms are involved in the pathogenesis of secondary peripheral chondrosarcoma.

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Section: Clinical Findings and Imaging Studiesmentioning

confidence: 99%

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

et al. 2011

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“…Biochemical studies have shown that the vertebrate EXT1 and EXT2 can associate to form biologically functional hetero-oligomeric complex that exhibits glycosyltransferase activity in which both subunits are essential for full activity (Kobayashi et al 2000;McCormick et al 2000;Senay et al 2000;Wei et al 2000;Zak et al 2002). Han et al (2004b) have shown that Ttv and Sotv behave similarly in Drosophila.…”

Section: Ttv Protein Interacts With Hext1mentioning

confidence: 99%

Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu

et al. 2007

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Heparan sulfate proteoglycans play a vital role in signaling of various growth factors in both Drosophila and vertebrates. In Drosophila, mutations in the tout velu (ttv) gene, a homolog of the mammalian EXT1 tumor suppressor gene, leads to abrogation of glycosaminoglycan (GAG) biosynthesis. This impairs distribution and signaling activities of various morphogens such as Hedgehog (Hh), Wingless (Wg), and Decapentaplegic (Dpp). Mutations in members of the exostosin (EXT) gene family lead to hereditary multiple exostosis in humans leading to bone outgrowths and tumors. In this study, we provide genetic and biochemical evidence that the human EXT1 (hEXT1) gene is conserved through species and can functionally complement the ttv mutation in Drosophila. The hEXT1 gene was able to rescue a ttv null mutant to adulthood and restore GAG biosynthesis.

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“…Genetic ablation of either gene results in essentially complete abrogation of HS production in cells and tissues (16,17). The majority of cases of MHE carry frameshift or missense mutations in EXT1 or EXT2 (18,19).…”

mentioning

confidence: 99%

A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses

Matsumoto

Irie

Mackem

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Multiple hereditary exostoses (MHE) is one of the most common skeletal dysplasias, exhibiting the formation of multiple cartilagecapped bony protrusions (osteochondroma) and characteristic bone deformities. Individuals with MHE carry heterozygous lossof-function mutations in Ext1 or Ext2, genes which together encode an enzyme essential for heparan sulfate synthesis. Despite the identification of causative genes, the pathogenesis of MHE remains unclear, especially with regard to whether osteochondroma results from loss of heterozygosity of the Ext genes. Hampering elucidation of the pathogenic mechanism of MHE, both Ext1 +/− and Ext2 +/− heterozygous mutant mice, which mimic the genetic status of human MHE, are highly resistant to osteochondroma formation, especially in long bones. To address these issues, we created a mouse model in which Ext1 is stochastically inactivated in a chondrocytespecific manner. We show that these mice develop multiple osteochondromas and characteristic bone deformities in a pattern and a frequency that are almost identical to those of human MHE, suggesting a role for Ext1 LOH in MHE. Surprisingly, however, genotyping and fate mapping analyses reveal that chondrocytes constituting osteochondromas are mixtures of mutant and wildtype cells. Moreover, osteochondromas do not possess many typical neoplastic properties. Together, our results suggest that inactivation of Ext1 in a small fraction of chondrocytes is sufficient for the development of osteochondromas and other skeletal defects associated with MHE. Because the observed osteochondromas in our mouse model do not arise from clonal growth of chondrocytes, they cannot be considered true neoplasms.bone development | heparan sulfate | osteochondroma

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Hereditary multiple exostoses and heparan sulfate polymerization

Cited by 166 publications

References 75 publications

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu

A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses

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