Identification of a single ancestral CYP1B1 mutation in Slovak Gypsies (Roms) affected with primary congenital glaucoma

Primary congenital glaucoma (PCG) is an autosomal recessive eye disease tha t occurs at an unusually high frequency in the ethnic isolate of Roms (Gyps ies) in Slovakia. Recently, we linked the disease in this population to the GLC3A locus on 2p21. At this locus, mutations in the cytochrome P4501B1 (C YP1B1) gene have been identified as a molecular basis for this condition. H ere, we report the results of CYP1B1 mutation screening of 43 PCG patients from 26 Slovak Rom families. A homozygous G-->A transition at nucleotide 15 05 in the highly conserved region of exon 3 was detected in all families. T his mutation results in the E387K substitution, which affects the conserved It helix region of the cytochrome P450 molecule. Determination of the CYP1 B1 polymorphic background showed a common DNA haplotype in all patients, th us indicating that the E387K mutation in Roms has originated from a single ancestral mutational event. The Slovak Roms represent the first population in which PCG is found to result from a single mutation in the CYP1B1 gene, so that a founder effect is the most plausible explanation of its increased incidence. An ARMS-PCR assay has been developed for fast detection of this mutation, thus allowing direct DNA based prenatal diagnosis as well as gen e carrier detection in this particular population. Screening of 158 healthy Roms identified 17 (10.8%) mutation carriers, indicating that the frequenc y of PCG in this population may be even higher than originally estimated.