The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes

Stickens, Dominique; Clines, Gregory A.; Burbee, David G.; Ramos, Purita; Thomas, S.; Hogue, Deborah; Hecht, Jacqueline; Lovett, Michael; Evans, Glen A.

doi:10.1038/ng0996-25

Cited by 319 publications

(252 citation statements)

References 27 publications

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“…8 In addition to the DEFECT 11 syndrome, these benign bone tumours can also be found in another contiguous gene syndrome, the Langer-Giedion syndrome (LGS) 9 or they can be present as an isolated autosomal dominant condition. In approximately 2-5% of the patients, malignant transformation of an exostosis occurs, resulting in the development of a chondrosarcoma 10,11 So far two EXT genes have already been identified, EXT1 on chromosome 8q24 12 and EXT2 on chromosome 11p11-p12, 13,14 while a third locus, EXT3, has been mapped on chromosome 19p. 15 The EXT genes are members of a larger family of homologous genes which also currently includes three EXT-like genes -EXTL1, 16 EXTL2 17 and EXTL3.…”

Section: Introductionmentioning

confidence: 99%

Molecular and clinical examination of an Italian DEFECT 11 family

et al. 1999

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The DEFECT 11 syndrome is a contiguous gene syndrome associated with deletions in the proximal part of chromosome 11p. In this study, we describe in an Italian family the co-existence of multiple exostoses (EXT) and enlarged parietal foramina (FPP), the two major symptoms of this syndrome, with abnormalities of the central nervous system. The latter may be a yet undescribed feature of DEFECT 11 syndrome. FISH and molecular analysis allowed us to identify a small deletion on 11p11-p12, further refining the localisation of the FPP gene involved in the DEFECT 11 syndrome.

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Section: Introductionmentioning

confidence: 99%

Molecular and clinical examination of an Italian DEFECT 11 family

et al. 1999

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“…EXT1 and EXT2 encode type II transmembrane glycosyltransferases [45,46], whose functions are not fully known. EXT1 and EXT2 form a hetero-oligomeric complex in the Golgi apparatus of most human cells that participate in chain elongation in heparan sulphate biosynthesis [47,48].…”

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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“…Both EXT1 and EXT2 mRNA is ubiquitously expressed [17][18][19]. A high level of expression of Ext1 and Ext2 mRNA has been found in developing limb buds of mouse embryos [44,45] and expression was demonstrated to be confined to the proliferating and prehypertrophic chondrocytes of the growth plate [46].…”

Section: Aetiologymentioning

confidence: 96%

“…Two genes, EXT1 and EXT2 located respectively at 8q24 and 11p11-p12, have been isolated to cause MO [16][17][18][19]. Additional linkage to chromosome 19p has been found, suggesting the existence of an EXT3-gene [20].…”

Section: Aetiologymentioning

confidence: 99%

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Multiple Osteochondromas

Encyclopedia of Cancer

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Multiple osteochondromas (MO) is characterised by development of two or more cartilage capped bony outgrowths (osteochondromas) of the long bones. The prevalence is estimated at 1:50,000, and it seems to be higher in males (male-to-female ratio 1.5:1). Osteochondromas develop and increase in size in the first decade of life, ceasing to grow when the growth plates close at puberty. They are pedunculated or sessile (broad base) and can vary widely in size. The number of osteochondromas may vary significantly within and between families, the mean number of locations is 15-18. The majority are asymptomatic and located in bones that develop from cartilage, especially the long bones of the extremities, predominantly around the knee. The facial bones are not affected. Osteochondromas may cause pain, functional problems and deformities, especially of the forearm, that may be reason for surgical removal. The most important complication is malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma, which is estimated to occur in 0.5-5%. MO is an autosomal dominant disorder and is genetically heterogeneous. In almost 90% of MO patients germline mutations in the tumour suppressor genes EXT1 or EXT2 are found. The EXT genes encode glycosyltransferases, catalyzing heparan sulphate polymerization. The diagnosis is based on radiological and clinical documentation, supplemented with, if available, histological evaluation of osteochondromas. If the exact mutation is known antenatal diagnosis is technically possible. MO should be distinguished from metachondromatosis, dysplasia epiphysealis hemimelica and Ollier disease. Osteochondromas are benign lesions and do not affect life expectancy. Management includes removal of osteochondromas when they give complaints. Removed osteochondromas should be examined for malignant transformation towards secondary peripheral chondrosarcoma. Patients should be well instructed and regular follow-up for early detection of malignancy seems justified. For secondary peripheral chondrosarcoma, en-bloc resection of the lesion and its pseudocapsule with tumour-free margins, preferably in a bone tumour referral centre, should be performed.

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The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes

Cited by 319 publications

References 27 publications

Molecular and clinical examination of an Italian DEFECT 11 family

Molecular and clinical examination of an Italian DEFECT 11 family

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

Multiple Osteochondromas

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