Stickler syndrome: further mutations in COL11A1 and evidence for additional locus heterogeneity

Stickler syndrome (hereditary arthro-ophthalmopathy) is a dominantly inheri ted connective tissue disorder with ocular, ore-facial, auditory and skelet al manifestations. It is genetically and phenotypically heterogeneous with the majority of families having mutations in the gene encoding type II coll agen (COL2A1) and exhibiting a characteristic 'membranous' or type 1 vitreo us phenotype, More recently a novel mutation in the gene encoding the alpha 1 chain of type XI collagen (COL11A1) was reported in a Stickler syndrome pedigree with a different 'beaded' or type 2 vitreous phenotype. In the pre sent study five more families with the type 2 vitreous phenotype were exami ned for linkage to four candidate genes: COL2A1, COL5A2, COL11A1 and COL11A 2, Two families were linked to COL11A1 and sequencing identified mutations resulting in shortened alpha 1(XI) collagen chains, one via exon skipping a nd the other via a multiexon deletion. One of the families showed weak link age to COL5A2 but sequencing the open reading frame failed to identify a mu tation, In the remaining two families all four loci were excluded by linkag e analysis. These data confirm that mutations in COL11A1 cause Stickler syn drome with the type 2 vitreous phenotype and also reveal further locus hete rogeneity.