In 2 unrelated French Caucasian patients with adult-onset primary open angle glaucoma (see 231300), Melki et al. (2004) identified a heterozygous 4046T-A transversion in exon 2 of the CYP1B1 gene, resulting in a tyr81-to-asn (Y81N) substitution. One of the 2 patients, diagnosed with glaucoma at the age of 52 years, had 2 sons heterozygous for the Y81N mutation who had onset of primary open angle glaucoma at 39 and 44 years of age, respectively. No mutation in the MYOC gene (601652) was present.
Chavarria-Soley et al. (2008) analyzed 5 CYP1B1 mutations that had been reported in PCG patients: Y81N, G61E, N203S, L343del, E229K. The G61E, N203S, and L343del mutations had molar enzymatic activity that was less than 10% of that of their respective background haplotype, and there was a significant reduction in microsomal CYP1B1 abundance with the L343del, Y81N, and E229K variants compared to background haplotype. Chavarria-Soley et al. (2008) classified Y81N and E229K as hypomorphic alleles rather than mutations because their relative activity values were intermediate between bona fide mutations and the common haplotype with the lowest activity. The authors proposed that CYP1B1 mutations can act either by reducing enzymatic activity (G61E and N203S), reducing the abundance of the enzyme (Y81N and E229K), or both (L343del), and that mutations that cause a 10-fold or greater reduction in relative activity result in PCG.
