Outflow Pathway Anomalies Associated with Multiple CYP1B1 Mutations in Congenital Glaucoma

Abstract

Abstract: : Purpose: Linkage studies have demonstrated a strong association between primary congenital glaucoma and chromosome 2p21(GLC3A locus) which encodes a cytochrome P4501B1 (CYP1B1) enzyme. This study seeks to correlate the structural features of the anterior chamber angle structures of congenital glaucoma patients with mutations in the CYP1B1 gene. Methods: Mutation screening in the CYP1B1 gene was performed by single strand conformation polymorphism analysis and direct sequencing from genomic DNA obtained from peripheral blood samples from five patients with congenital glaucoma, as well as from each of their parents and siblings. Tissue samples of the outflow pathways of each of the patients, obtained during trabeculectomies, were analyzed by light microscopy and electron microscopy and correlated with the CYP1B1 mutations. Results: Four of the five (80%) congenital glaucoma patients were compound heterozygotes for mutations in the CYP1B1 region. A total of 8 different mutations in the CYP1B1 were found among the five families leading to diverse phenotypes including trabecular meshwork hypoplasia, absence of Schlemm's canal, endothelialization of the trabecular meshwork and iris coloboma. CYP1B1 mutations were absent from one of the five patients (20%) who had congenital glaucoma which spontaneously resolved. Conclusions: Multiple mutations within the same locus can produce a wide array of phenotypes resulting in congenital glaucoma. Determining whether a certain type of goniodysgenesis is associated with a given genotype is an important consideration in developing a better understanding of the pathogenesis of the congenital glaucomas. The existence of any correlation between genotypes and phenotypes may help the glaucoma specialist tailor the medical or surgical management of each patient with congenital glaucoma.

Keywords: genetics • anatomy • outflow: trabecular meshwork