Granular corneal dystrophy with homozygous mutations in the kerato-epithelin gene

PURPOSE: To report a family with several members affected with granular corneal dystrophy Groenouw type 1. Three members of the family were affected with a severe placoid type of corneal dystrophy. To determine the relationship between gene mutations and phenotypic variations of the disease, we analyzed the kerato-epithelin gene. METHODS: The pedigree included a consanguineous marriage of two affected individuals. The three family members affected with a severe form of corneal dystrophy were offspring of these parents. However, the phenotype of other affected family members was typical granular corneal dystrophy. We isolated genomic DNA from leukocytes of the family members. Exons of the kerato epithelin gene were amplified by the polymerase chain reaction and were analyzed using the single-strand conformation polymorphism technique. Mutations were identified by direct sequencing method and restriction digestion analysis. RESULTS: The three severely affected family members exhibited homozygous mutations at codon 555 (arginine to tryptophan) in the kerato-epithelin gene, whereas those with typical granular corneal dystrophy had the heterozygous mutation at the same codon, Unaffected family members did not have the mutation. CONCLUSIONS: We determined that the severe phenotype of granular corneal dystrophy is caused by homozygous mutations in the kerato-epithelin gene. Clinical manifestation of the severe phenotype is a placoid type of corneal dystrophy and early recurrence after surgery. Granular corneal dystrophy appears to be the first ophthalmic disease in which homozygosity for a dominant allele has been genetically identified. (Am J Ophthalmol 1998; 126: 169 -176, (C) 1998 by Elsevier Science Inc. All rights reserved.).