Primary Congenital Glaucoma (PCG) is an autosomal recessive disorder caused by developmental defect(s) of the anterior chamber angle. We and others have shown that homozygous or compound heterozygous mutations in CYP1B1, the gene for cytochrome P4501B1, are the principal cause for PCG. We documented variable expressivity and decreased penetrance for the PCG phenotype in the Saudi population and showed evidence for genetic heterogeneity in the Saudi and Ecuadorian populations. However, our observations also suggest that a major modifier locus causing decreased penetrance is present in the Saudi population and that this locus is dominant and unique to this population. This proposal aims to map and to clone the modifier of CYP1B1 action in the Saudi population, and to map and clone other PCG-causing genes. This application also seeks to define the developmental expression of CYP1B1 in mouse development as a first step towards understanding the role of this enzyme in normal and glaucomatous eye development. Finally, biochemical studies on sera from PCG patients will address the identity of the physiologic substrate of CYP1B1. For these ends, we will map the putative modifier of the PCG phenotype by parametric and nonparametric methods in an unique cohort of Saudi Arabian families. Our initial studies have already shown that the families in hand provide enough information to map such a modifier. Positional candidate genes will be excluded by combined positional/functional approaches. Families from Saudi Arabia and Ecuador will be used also to map additional PCG loci. Study of the developmental expression of CYP1B1 by RNA in situ hybridization in mouse will establish an expression profile for this gene in various ocular and extra-ocular tissues. The discovery of a modifier for the glaucoma phenotype and the identification of the physiologic substrate for CYP1B1 have the potential of improving our understanding of the normal development of the anterior chamber and of the structure and function of the aqueous humor outflow pathways at the cellular and molecular level. They could also provide new avenues for treatment of PCG and possibly other forms of glaucoma.
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