A mutation in the gene encoding the α2 chain of the fibril-associated collagen IX, COL9A2, causes multiple epiphyseal dysplasia (EDM2)

Multiple epiphyseal dysplasia, an autosomal dominant disease, is among the more common inherited osteochondrodysplasias. Symptoms range from stiffness and pain in large joints to frank osteoarthritis associated with short stature and stubby fingers1–7. Linkage analyses of multiple epiphyseal dysplasia families suggest at least three loci. One locus, EDM1, maps to chromosome 19 (ref. 4), and is caused by mutations in cartilage oligomeric matrix protein (COMP)8. Mutations in COMP have also been identified in patients with pseudoachon-droplasia (PSACH)8,9, consistent with previous analyses which suggested that EDM1 and PSACH could be allelic disorders10. A second locus, EDM2, maps to chromosome 1 in the vicinity of the COL9A2 gene6. Finally, exclusion of EDM1 and EDM2 in other families suggests the existence of at least one additional locus11. We now show that affected members of a large kindred with multiple epiphyseal dysplasia linked to the EDM2 locus are heterozygous for a splice site mutation within COL9A2, causing exon skipping during RNA splicing and an in-frame loss of 12 amino acid residues within the α2(IX) collagen chain. The results provide the first in vivo evidence for the role of collagen IX in human articular cartilage.