Novel CYP1B1 mutations in consanguineous Pakistani families with primary congenital glaucoma

Purpose: To identify the disease-causing mutations in three consanguineous Pakistani families with multiple members affected by primary congenital glaucoma. Methods: Blood samples were collected, and DNA was extracted. Linkage analysis for reported primary congenital glaucoma loci was performed using closely spaced polymorphic microsatellite markers on genomic DNA from affected and unaffected family members. All coding exons, the exon-intron boundaries, and the 5′ untranslated region of CYP1B1 were sequenced. Results: The alleles of chromosome 2p markers segregate with the disease phenotype in all three families with positive LOD scores. The sequencing results identified three novel mutations (L177R, L487P, and D374E) and one previously reported mutation (E229K) in CYP1B1 that segregate with the disease phenotype in their respective families. None of these sequence variations were present in 96 ethnically matched control samples. Conclusions: These results strongly suggest that missense mutations in CYP1B1 are most likely to be responsible for primary congenital glaucoma in these families.