ArticleThe American journal of pathology2010
No haploinsufficiency but loss of heterozygosity for EXT in multiple osteochondromas.
Article in The American journal of pathology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 72 citations in OpenAlex.
- Article
- Orthopedic preoperative evaluation and surgical strategies of hereditary multiple osteochondromas involving the spinal region.EFORT open reviews · 2026Review
- Genotype and phenotype correlation analysis in 27 families with multiple osteochondroma and validation by ATDC5 chondrocyte models.Bone & joint research · 2025Article
- Challenges and Solutions in Managing Recurrent Distal Tibia Interosseous Osteochondroma: A Case Study and Review of Literature.Journal of orthopaedic case reports · 2024Article
- The Missing Piece of the Puzzle: Unveiling the Role ofHuman mutation · 2024Article
- Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes.Journal of medical genetics · 2023Article
- Dedifferentiated Chondrosarcoma: Diagnostic Controversies and Emerging Therapeutic Targets.Current oncology reports · 2023Review
- Article
- Osteochondroma formation is independent of heparanase expression as revealed in a mouse model of hereditary multiple exostoses.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2022Article
- Mutations in the heparan sulfate backbone elongating enzymes EXT1 and EXT2 have no major effect on endothelial glycocalyx and the glomerular filtration barrier.Molecular genetics and genomics : MGG · 2022Article
- Genetic and functional analyses detect an EXT1 splicing pathogenic variant in a Chinese hereditary multiple exostosis (HME) family.Molecular genetics & genomic medicine · 2022Article
- Osteochondroma Pathogenesis: Mouse Models and Mechanistic Insights into Interactions with Retinoid Signaling.The American journal of pathology · 2021Review
- Review
- Mutation spectrum of EXT1 and EXT2 in the Saudi patients with hereditary multiple exostoses.Orphanet journal of rare diseases · 2021Article
- Hereditary multiple osteochondromas in Jordanian patients: Mutational and immunohistochemical analysis ofOncology letters · 2021Article
- A novel mutation in ext2 caused hereditary multiple exostoses through reducing the synthesis of heparan sulfate.Genetics and molecular biology · 2021Article
- Identification of Novel EXT Mutations in Patients with Hereditary Multiple Exostoses Using Whole-Exome Sequencing.Orthopaedic surgery · 2020Article
- [Cartilage tumors: morphology, genetics, and current aspects of target therapy].Der Pathologe · 2020Review
- A novel splice mutation induces exon skipping of the EXT1 gene in patients with hereditary multiple exostoses.International journal of oncology · 2019Article
- A 40-Year-Old Male Presenting with Hereditary Multiple Exostosis: Management and Considerations.Case reports in orthopedics · 2019Article
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Authors and funding
12 authors at 5 institutions in 4 countries.
Funding
Abstract
Multiple osteochondromas (MO) is an autosomal dominant disorder caused by germline mutations in EXT1 and/or EXT2. In contrast, solitary osteochondroma (SO) is nonhereditary. Products of the EXT gene are involved in heparan sulfate (HS) biosynthesis. In this study, we investigated whether osteochondromas arise via either loss of heterozygosity (2 hits) or haploinsufficiency. An in vitro three-dimensional chondrogenic pellet model was used to compare heterozygous bone marrow-derived mesenchymal stem cells (MSCs EXT(wt/-)) of MO patients with normal MSCs and the corresponding tumor specimens (presumed EXT(-/-)). We demonstrated a second hit in EXT in five of eight osteochondromas. HS chain length and structure, in vitro chondrogenesis, and EXT expression levels were identical in both EXT(wt/-) and normal MSCs. Immunohistochemistry for HS, HS proteoglycans, and HS-dependent signaling pathways (eg, TGF-β/BMP, Wnt, and PTHLH) also showed no differences. The cartilaginous cap of osteochondroma contained a mixture of HS-positive and HS-negative cells. Because a heterozygous EXT mutation does not affect chondrogenesis, EXT, HS, or downstream signaling pathways in MSCs, our results refute the haploinsufficiency theory. We found a second hit in 63% of analyzed osteochondromas, supporting the hypothesis that osteochondromas arise via loss of heterozygosity. The detection of the second hit may depend on the ratio of HS-positive (normal) versus HS-negative (mutated) cells in the cartilaginous cap of the osteochondroma.
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