Variation in the vitreous phenotype of stickler syndrome can be caused by different amino acid substitutions in the X position of the type II collagen Gly-X-Y triple helix

Stickler syndrome is a dominantly inherited disorder characterized by arthr opathy, midline clefting, hearing loss, midfacial hypoplasia, myopia, and r etinal detachment. These features are highly variable both between and with in families. Mutations causing the disorder have been found in the COL2A1 a nd COL11A1 genes. Premature termination codons in COL2A1 that result in hap loinsufficiency of type II, collagen are a common finding. These produce a characteristic congenital "membranous" anomaly of the vitreous of all affec ted individuals. Experience has shown that vitreous slit-lamp biomicroscopy can distinguish between patients with COL2A1 mutations and those with domi nant negative mutations in COL11A1, who produce a different "beaded" vitreo us phenotype. Here we characterize novel dominant negative mutations in COL 2A1 that result in Stickler syndrome. Both alter amino acids in the X posit ion of the Glp-X-Y triple-helical region. A recurrent R365C mutation occurr ed in two unrelated sporadic cases and resulted in the membranous vitreous anomaly associated with haploinsufficiency. In a large family with linkage to COL2A1, with a LOD score of 2.8, a unique L467F mutation produced a nove l "afibrillar" vitreous gel devoid of all normal lamella structure. These d ata extend the mutation spectrum of the COL2A1 gene and help explain the ba sis for the different vitreous phenotypes seen in Stickler syndrome.