Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes

Bernard, Mark A.; Hall, Catherine; Hogue, Deborah; Cole, William G.; Scott, Allison M.; Snuggs, Mark B.; Clines, Gregory A.; Lüdecke, Hermann Josef; Lovett, Michael; Winkle, W. Van Barry; Hecht, Jacqueline

doi:10.1002/1097-0169(200102)48:2<149::aid-cm1005>3.0.co;2-3

Cited by 56 publications

(48 citation statements)

References 41 publications

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“…3 Mutations resulting in reduced EXT1 and EXT2 protein levels have been previously reported, which might be attributed to potential reduction in mRNA levels due to nonsense, frameshift, or splice-site mutations. 24 In some cases, reduced EXT1 protein was accompanied by reduced EXT2 in exostosis chondrocytes. 24 The reason for this is not understood but may be related to multiple genetic hits.…”

Section: Discussionmentioning

confidence: 96%

A splice‐site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas

Liu

Hui

Chan

et al. 2010

Journal Orthopaedic Research

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Multiple osteochondromas (MO) is an autosomal-dominant disorder and mutations in EXT1 and EXT2 account up to 78% of the cases studied, including missense, nonsense, frameshift, and splice-site mutations. EXT1 and EXT2 encode glycosyltransferases required for the synthesis of heparan sulfate (HS) chains. The molecular pathogenesis underlying these mutations is still largely unknown. A heterozygous c.1173 + 1G > T (EXT2) mutation was identified in a three-generation 34-member MO family and is present in all 19 affected members. The consequence of this mutation is exon 7 being spliced out, and the result is a shift in the codon-reading frame from position 360 (R360) of the amino acid sequence leading to a premature termination codon, and the mutant mRNA is degraded to an undetectable level. Interestingly, HS glycosaminoglycans were also undetectable in the cartilage cap of the tumors by immunostaining. Full penetrance of this mutation in all affected members ranging from 5 to 70 years of age suggests this primary defect in EXT2 mRNA level, in conjunction with other cellular changes such as enhanced heparanase expression, can produce profound effect on the synthesis of HS chains in cartilage, the consequence of which impacts on the regulation of chondrocyte proliferation and differentiation.

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Section: Discussionmentioning

confidence: 96%

A splice‐site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas

Liu

Hui

Chan

et al. 2010

Journal Orthopaedic Research

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“…The analysis of 11 SO tissue samples identified in five of them the deletion of one copy of EXT1 gene or part of it; this observation is in agreement with previous studies reporting that small or big deletions of EXT1 are the most common alteration in SO (Bove´e et al, 1999a, b;Bernard et al, 2001;Hameetman et al, 2007), while single-base pair mutations are indeed rare (1 out of 11 SO samples in the present analysis). No mutations were found for 5 of 11 SOs (45%), with a percentage of negative SO similar to those reported from other authors (Hall et al, 2002;Trebicz-Geffen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT genes inactivation

et al. 2010

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Osteochondroma, the most common benign bone tumor, may occur as a sporadic lesion or as multiple neoplasms in the context of multiple osteochondromas syndrome. The most severe complication is malignant transformation into peripheral secondary chondrosarcoma. Although both benign conditions have been linked to defects in EXT1 or EXT2 genes, contradictory reports are present in the literature regarding the requirement of their biallelic inactivation for osteochondroma development. A major limitation of these studies is represented by the small number of samples available for the screening. Taking advantage of a large series of tissues, our aim was to contribute to the definition of a genetic model for osteochondromas onset and transformation. EXT genes point mutations and big deletions were analyzed in 64 tissue samples. A double hit was found in 5 out of 35 hereditary cases, 6 out of 16 chondrosarcomas and 2 recurrences; none of the 11 sporadic osteochondromas showed two somatic mutations. Our results clearly indicate that, in most cases, biallelic inactivation of EXT genes does not account for osteochondromas formation; this mechanism should be regarded as a common feature for hereditary osteochondromas transformation and as an event that occurs later in tumor progression of solitary cases. These findings suggest that mechanisms alternative to EXT genetic alteration likely have a role in osteochondromas pathogenesis.

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“…In the growth plate, IHH requires interaction with HSPGs to diffuse through the extracellular matrix to its receptor (21). Somatic mutations in the EXT genes are extremely rare in non-hereditary osteochondromas and have been described in only 3 cases (24)(25)(26). However, the observation that loss of heterozygosity (LOH) and clonal rearrangement at 8q24 (EXT1 locus) are as frequent in non-hereditary osteochondromas as are EXT1 gene mutations in patients with hereditary osteochondromas, suggests that EXT1 may be involved in the development of non-hereditary osteochondromas (10,11,27).…”

Section: Discussionmentioning

confidence: 78%

Detection of exostosin glycosyltransferase gene mutations in patients with non-hereditary osteochondromas of the mandibular condyle

Zhou

Chen

et al. 2016

Molecular and Clinical Oncology

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Abstract. Exostosin glycosyltransferase (EXT) 1 and EXT2 have been identified as causative genes in osteochondroma; however, it is not known whether these genes are also involved in condylar osteochondromas. The aim of this study was to identify EXT1 and EXT2 mutations in patients with non-hereditary osteochondromas of the mandibular condyle. DNA was obtained from resected tissues (cartilage cap) of 12 patients with solitary condylar osteochondromas. The exons, 3',5'-untranslated regions and intron-exon boundaries of EXT1 and EXT2 were amplified by polymerase chain reaction and the products were sequenced directly. Through direct sequencing, four genetic variations of EXT1 in 4 cases and three variations of EXT2 in 5 cases were identified. The intronic alteration of the EXT2 gene, occurring in 2 cases, was novel, whereas the other alterations had been previously reported. Nonsense somatic mutations were detected in tumor DNA. Our study extended the mutational spectrum in EXT1 and EXT2 and may facilitate a better understanding of the pathophysiology of condylar osteochondromas.

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Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes

Cited by 56 publications

References 41 publications

A splice‐site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas

A splice‐site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas

Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT genes inactivation

Detection of exostosin glycosyltransferase gene mutations in patients with non-hereditary osteochondromas of the mandibular condyle

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