Primary congenital glaucoma and Rieger's anomaly: extended haplotypes reveal founder effects for eight distinct CYP1B1 mutations.

PURPOSE: Mutations in the cytochrome P450 1B1 (CYP1B1) gene are a frequent cause of primary congenital glaucoma (PCG) in different ethnic groups. Cytochrome P450 proteins are monooxygenases, which catalyze many reactions involved in the metabolism of drugs as well as steroids and other lipids. The repeated occurence of several mutations in various ethnic groups raises the question if founder effects or mutation-prone sites in CYP1B1 are the cause for this observation. METHODS: A total of 30 individuals (26 PCG patients, three Rieger's anomaly patients, and one variant carrier), presenting 17 variants in CYP1B1 (15 mutations and two variations) were included in our study. We sequenced the entire genomic region of CYP1B1 and analyzed microsatellites flanking the gene in all individuals and constructed haplotypes for all variations using a combination of single nucleotide polymorphisms and microsatellites. RESULTS: For the CYP1B1 genomic region, we identified five extended haplotypes associated with 17 variations. These haplotypes were complemented with microsatellite information from the region surrounding this gene. A total of eight CYP1B1 mutations were found more than once, each of them presenting one identical haplotype in different individuals. Six mutations were represented in different ethnic groups. CONCLUSIONS: Our results confirm founder effects for most of CYP1B1 mutations. Most of these mutations must have occurred as unique events in the past.

Primary congenital glaucoma: a novel single-nucleotide deletion and varying phenotypic expression for the 1,546-1,555dup mutation in the GLC3A (CYP1B1) gene in 2 families of different ethnic origin.

PURPOSE: To present new molecular genetic data on primary congenital glaucoma from 2 families, 1 isolated case and 3 familial cases due to mutations in the cytochrome P-450 1B1 (CYP1B1) gene. METHODS: All diagnoses were made by slit-lamp biomicroscopy, gonioscopy, cornea and optic disk measurements, ultrasound-biometry, and automated static threshold perimetry where possible. Mutation screening was performed by direct sequence analysis of DNA extracted from peripheral blood of the patients and their relatives. RESULTS: For the isolated case, a child of 4 years, a homozygous nucleotide deletion within a tetrad of cytosines (nt622-625, 622delC) was found leading to a predicted nonsense codon 93 truncating the protein by 450 amino acids. For the familial cases, the 3 affected members showed a homozygous mutation 1,546-1,555dupTCATGCCACC for which 9 healthy relatives proved to be heterozygous. The phenotypic expression of these 3 patients varied widely. CONCLUSION: Our results confirm the crucial role of CYP1B1 mutations for congenital glaucoma.