EXT2 – Hereditary Multiple Osteochondromas

Hereditary multiple osteochondromas (HME) is an autosomal dominant skeletal dysplasia characterized by the development of multiple cartilage-capped bony outgrowths at the juxta-epiphyseal regions of long bones (PMID:9326317). Heterozygous loss-of-function variants in EXT2, encoding a Golgi-localized glycosyltransferase, underlie up to 30% of HME cases and result in haploinsufficiency leading to defective heparan sulfate (HS) biosynthesis.

Genetic studies have identified pathogenic EXT2 variants in over 150 unrelated probands across multiple cohorts, with segregation demonstrated in at least 19 additional affected relatives in a single three-generation family (PMID:20872591). Mutation screening in 17 HME probands revealed EXT2 mutations in 5 families (PMID:9326317), while a large Japanese cohort of 112 patients across 71 families confirmed EXT2 pathogenic variants in 21% of cases (PMID:26961984).

The EXT2 mutational spectrum encompasses nonsense, frameshift, splice-site, and missense changes. A recurrent nonsense variant, c.526C>T (p.Gln176Ter), truncates the glycosyltransferase domain and abolishes HS chain elongation, co-segregating with HME in a four-member family (PMID:32678989). Other splice-site mutations, such as c.743+1G>A, induce exon skipping and mRNA decay, confirming haploinsufficiency as the primary pathogenic mechanism (PMID:24728384).

Functional assays demonstrate that EXT1 and EXT2 form a hetero-oligomeric complex in the Golgi apparatus, with glycosyltransferase activity essential for HS polymerization. EXT2 alone lacks significant activity but enhances EXT1 function when co-expressed, explaining how variants in either gene yield a similar HME phenotype (PMID:10639137). In Drosophila, loss of the EXT2 ortholog disrupts Hedgehog, Wingless, and Dpp signaling, reinforcing the role of HS in skeletal patterning (PMID:15056609).

No studies have refuted the EXT2–HME association, and genotype–phenotype correlations indicate that EXT2 mutations generally result in milder clinical forms compared with EXT1 (PMID:9521425). Additional evidence from somatic tumor analyses shows loss of EXT2 in chondrosarcoma progression, underscoring its tumor suppressor function in cartilage (PMID:25744876).

Collectively, over two decades of genetic and experimental data support a Definitive association between EXT2 and autosomal dominant HME. EXT2 mutation analysis is clinically informative for molecular diagnosis, genetic counseling, and prenatal testing. Key Take-home: Heterozygous EXT2 variants causing haploinsufficiency reliably predict HME risk and guide patient management.

References

• American Journal of Human Genetics • 1997 • Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses. PMID:9326317
• Journal of Orthopaedic Research • 2010 • A splice-site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas. PMID:20872591
• BMC Genetics • 2016 • Large-scale mutational analysis in the EXT1 and EXT2 genes for Japanese patients with multiple osteochondromas. PMID:26961984
• PloS One • 2014 • A splice mutation and mRNA decay of EXT2 provoke hereditary multiple exostoses. PMID:24728384
• Proceedings of the National Academy of Sciences of the United States of America • 2000 • The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. PMID:10639137
• Development • 2004 • Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways. PMID:15056609
• Cancer Genetics • 2015 • Somatic loss of an EXT2 gene mutation during malignant progression in a patient with hereditary multiple osteochondromas. PMID:25744876
• Genetic Testing and Molecular Biomarkers • 2020 • A Novel Nonsense Mutation in the EXT2 Gene Identified in a Family with Hereditary Multiple Osteochondromas. PMID:32678989

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