AUTOSOMAL-DOMINANT AND RECESSIVE OSTEOCHONDRODYSPLASIAS ASSOCIATED WITH THE COL11A2 LOCUS

Identifying mutations that cause specific osteochondrodysplasias will provide novel insights into the function of genes that are essential f or skeletal morphogenesis. We report here that an autosomal dominant f orm of Stickler syndrome, characterized by mild spondyloepiphyseal dys plasia, osteoarthritis, and sensorineural hearing loss, but no eye inv olvement, is caused by a splice donor site mutation resulting in ''in- frame'' exon skipping within the COL11A2 gene, encoding the alpha 2(XI ) chain of the quantitatively minor fibrillar collagen XI. We also sho w that an autosomal recessive disorder with similar, but more severe, characteristics is linked to the COL11A2 locus and is caused by a glyc ine to arginine substitution In alpha 2(XI) collagen. The results sugg est that mutations in collagen XI genes are associated with a spectrum of abnormalities in human skeletal development and support the conclu sion of others, based on studies of murine chondrodysplasia, that coll agen XI is essential for skeletal morphogenesis.