Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes

Wuyts, Wim; Hul, Wim Van

doi:10.1002/(sici)1098-1004(200003)15:3<220::aid-humu2>3.0.co;2-k

Cited by 203 publications

(138 citation statements)

References 40 publications

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“…This mutation detection rate of 74% in a cohort of patients, clinically affected with MO is in accordance with Wuyts et al, 18 who, on the basis of other literature, state that mutations in EXT1 and EXT2 are responsible for over 70% of the cases. In five of the index patients analysed, no possibly disease-causing mutation could be detected.…”

Section: Discussionsupporting

confidence: 90%

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Mutation screening of EXT1 and EXT2 by direct sequence analysis and MLPA in patients with multiple osteochondromas: splice site mutations and exonic deletions account for more than half of the mutations

et al. 2004

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Multiple osteochondromas (MO) is an autosomal dominant condition, caused by mutations in either the EXT1 or the EXT2 gene. The DNA of a cohort of 35 patients, clinically suspected to be affected with MO, was screened for mutations by a combination of direct sequence analysis and multiplex ligation-dependent probe amplification (MLPA). In this cohort, 26 pathogenic gene alterations were found (74%). With sequence analysis mutations were detected in 22 patients (63%). In total, 10 mutations were detected in the EXT1 and 12 in the EXT2 gene. The number of the splice site mutations detected was larger than expected from the literature. In addition, with the MLPA four deletions of one or more exons were found in this cohort. Two patients, of whom one had a negative family history, showed deletions of exon 1 of the EXT1 gene, which is possibly a deletion hot spot. In patients suspected to be affected by MO, we recommend a quantitative analysis such as MLPA, followed by direct sequence analysis for the screening of the EXT1 and EXT2 genes.

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Section: Discussionsupporting

confidence: 90%

“…In the EXT2 gene, all mutations were detected in the exons 2, 3, 4 and 7. This uneven distribution is in accordance with Wuyts et al (2000). The carboxy terminal region of EXT2 contains fewer mutations than would be expected in a random distribution.…”

Section: Discussionsupporting

confidence: 81%

Mutation screening of EXT1 and EXT2 by direct sequence analysis and MLPA in patients with multiple osteochondromas: splice site mutations and exonic deletions account for more than half of the mutations

et al. 2004

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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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“…Mutations in EXT1 (8q24.1) and EXT2 (11p11) genes are associated with osteochondromas [41][42][43][44]. EXT1 and EXT2 encode type II transmembrane glycosyltransferases [45,46], whose functions are not fully known.…”

Section: Osteochondromagenesismentioning

confidence: 99%

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

Andrea¹,

Hogendoorn²

2011

The Journal of Pathology

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Chondrocytes interact with their neighbours through their cartilaginous extracellular matrix (ECM).Chondrocyte-matrix interactions compensate the lack of cell-cell contact and are modulated by proteoglycans and other molecules. The epiphyseal growth plate is a highly organized tissue responsible for long bone elongation. The growth plate is regulated by gradients of morphogens that are established by proteoglycans. Morphogens diffuse across the ECM, creating short-and long-range signalling that lead to the formation of a polarized tissue. Mutations affecting genes that modulate cell-matrix interactions are linked to several human disorders. Homozygous mutations of EXT1/EXT2 result in reduced synthesis and shortened heparan sulphate chains on both cell surface and matrix proteoglycans. This disrupts the diffusion gradients of morphogens and signal transduction in the epiphyseal growth plate, contributing to loss of cell polarity and osteochondroma formation. Osteochondromas are cartilage-capped bony projections arising from the metaphyses of endochondral bones adjacent to the growth plate. The osteochondroma cap is formed by cells with homozygous mutation of EXT1/EXT2 and committed stem cells/wild-type chondrocytes. Osteochondroma serves as a niche (a permissive environment), which facilitates the committed stem cells/wild-type chondrocytes to acquire secondary genetic changes to form a secondary peripheral chondrosarcoma. In such a scenario, the micro-environment is the site of the initiating processes that ultimately lead to cancer.

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Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes

Cited by 203 publications

References 40 publications

Mutation screening of EXT1 and EXT2 by direct sequence analysis and MLPA in patients with multiple osteochondromas: splice site mutations and exonic deletions account for more than half of the mutations

Mutation screening of EXT1 and EXT2 by direct sequence analysis and MLPA in patients with multiple osteochondromas: splice site mutations and exonic deletions account for more than half of the mutations

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

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

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