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 arthropathy, midline clefting, hearing loss, midfacial hypoplasia, myopia, and retinal detachment. These features are highly variable both between and within families. Mutations causing the disorder have been found in the COL2A1 and COL11A1 genes. Premature termination codons in COL2A1 that result in haploinsufficiency of type II collagen are a common finding. These produce a characteristic congenital "membranous" anomaly of the vitreous of all affected individuals. Experience has shown that vitreous slit-lamp biomicroscopy can distinguish between patients with COL2A1 mutations and those with dominant negative mutations in COL11A1, who produce a different "beaded" vitreous phenotype. Here we characterize novel dominant negative mutations in COL2A1 that result in Stickler syndrome. Both alter amino acids in the X position of the Gly-X-Y triple-helical region. A recurrent R365C mutation occurred 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 novel "afibrillar" vitreous gel devoid of all normal lamella structure. These data extend the mutation spectrum of the COL2A1 gene and help explain the basis for the different vitreous phenotypes seen in Stickler syndrome.