MARSHALL-SYNDROME ASSOCIATED WITH A SPLICING DEFECT AT THE COL11A1 LOCUS

Marshall syndrome is a rare, autosomal dominant skeletal dysplasia tha t is phenotypically similar to the more common disorder Stickler syndr ome. For a large kindred with Marshall syndrome, we demonstrate a spli ce-donor-site mutation in the COL11A1 gene that cosegregates with the phenotype. The G(+1)-->A transition causes in-frame skipping of a 54-b p exon and deletes amino acids 726-743 from the major triple-helical d omain of the alpha 1(XI) collagen polypeptide. The data support the hy pothesis that the alpha 1(XI) collagen polypeptide has an important ro le in skeletal morphogenesis that extends beyond its contribution to s tructural integrity of the cartilage extracellular matrix. Our results also demonstrate allelism of Marshall syndrome with the subset of Sti ckler syndrome families associated with COL11A1 mutations.