Sequence analysis and homology modeling suggest that primary congenital glaucoma on 2p21 results from mutations disrupting either the hinge region or the conserved core structures of cytochrome P4501B1

PubMedID: 9497261We recently reported three truncating mutations of the cytochrome P4501B1 gene (CYP1B1) in five families with primary congenital glaucoma (PCG) linked to the GLC3A locus on chromosome 2p21. This could be the first direct evidence supporting the hypothesis that members of the cytochrome P450 superfamily may control the processes of growth and differentiation. We present a comprehensive sequence analysis of the translated regions of the CYP1B1 gene in 22 PCG families and 100 randomly selected normal individuals. Sixteen mutations and six polymorphisms were identified, illustrating an extensive allelic heterogeneity. The positions affected by these changes were evaluated by building a three-dimensional homology model of the conserved C- terminal half of CYP1B1. These mutations may interfere with heme incorporation, by affecting the hinge region and/or the conserved core structures (CCS) that determine the proper folding and heme-binding ability of P450 molecules. In contrast, all polymorphic sites were poorly conserved and located outside the CCS. Northern hybridization analysis showed strong expression of CYP1B1 in the anterior uveal tract, which is involved in secretion of the aqueous humor and in regulation of outflow facility, processes that could contribute to the elevated intraocular pressure characteristic of PCG.National Eye Institute: EY-11095 M01-RR-06192 M.S.I. FoundationWe are indebted to our patient population for their participation in this study. We thank numerous ophthalmologists in the United States and other countries for providing additional patient materials, and we thank Dr. M. Ozguc of the DNA/Cell Bank and Gene Research Laboratory of Hacettepe University (Ankara) for both facilitating fibroblast skin culture from affected patients and partial DNA extraction. The DNA/Cell Bank and Gene Research Laboratory is funded by the Turkish Scientific Committee. This work was supported by National Eye Institute grant EY-11095, University of Connecticut General Clinical Research Center grant M01-RR-06192, and an Insite Vision, Inc., grant (all to M.S.). A.C. and M.S. would also like to thank the International Glaucoma Association for its continuous help and financial support