EXT1 – Hereditary Multiple Osteochondromas

Hereditary multiple osteochondromas (HMO) is an autosomal dominant skeletal disorder characterized by the growth of multiple cartilage-capped bony protuberances (osteochondromas). EXT1, encoding an endoplasmic reticulum-localized type II transmembrane glycosyltransferase, is one of two principal tumor suppressor genes underlying HMO. Heterozygous loss-of-function variants in EXT1 disrupt heparan sulfate (HS) chain elongation, leading to aberrant chondrocyte proliferation and exostosis formation.

Clinical inheritance of HMO is autosomal dominant, with high penetrance but variable expressivity. Segregation analyses across numerous multigenerational families demonstrate concordant co-segregation of EXT1 pathogenic variants with multiple affected relatives ([PMID:9326317]). Additional families (e.g., three-generation Indian kindred and nine affected Iranian individuals) reinforce this pattern, supporting definitive inheritance.

Genetic evidence includes over 200 probands harboring distinct EXT1 variants—nonsense, frameshift, splice, and missense mutations—distributed across functional domains. A representative recurrent variant is c.115G>T (p.Glu39Ter), which truncates the protein and abolishes HS polymerase activity. Large cohorts in Europe, Asia, and the Americas document EXT1 mutations in 40–70% of HMO cases, with segregation in >30 families ([PMID:9326317], [PMID:28053536]).

Functional studies demonstrate that EXT1 forms a hetero-oligomeric complex with EXT2 in the Golgi to catalyze HS synthesis. In vitro assays show that missense mutations at conserved residues (e.g., p.Arg340Cys) abrogate HS production, while EXT1-deficient mice fail gastrulation and lack HS biosynthesis ([PMID:10639137], [PMID:10926768]). Minigene splicing assays confirm that pathological splice-site variants result in exon skipping and premature termination ([PMID:35106951]).

No significant conflicting evidence has been reported; all functional and segregation data consistently support EXT1 haploinsufficiency as the disease mechanism.

In summary, heterozygous EXT1 loss-of-function variants cause autosomal dominant HMO by impairing HS chain elongation, leading to multiple osteochondromas. Genetic testing for EXT1 variants is clinically useful for diagnosis, family counseling, and management.

Key Take-home: EXT1 pathogenic variants provide definitive diagnostic markers for hereditary multiple osteochondromas, guiding genetic counseling and early orthopedic intervention.

References

• American Journal of Human Genetics • 1997 • Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses PMID:9326317
• The Journal of Clinical Endocrinology and Metabolism • 2005 • A novel EXT1 splice site mutation in a kindred with hereditary multiple exostosis and osteoporosis PMID:15985493
• 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
• Developmental Biology • 2000 • Disruption of gastrulation and heparan sulfate biosynthesis in EXT1-deficient mice PMID:10926768

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