CYP1B1 mutations in French patients with early-onset primary open-angle glaucoma

Abstract

Introduction: Primary open-angle glaucoma (POAG) is a leading cause of visual impairment worldwide and a complex genetic disorder that affects mostly adults. Mutations in the MYOCILIN (MYOC) and OPTINEURIN genes account for rare forms with a Mendelian inheritance and for ,5% of all POAG cases. The CYP1B1 gene, a member of the cytochrome P450 gene family, is a major cause of primary congenital glaucoma (PCG), a rare and severely blinding disease with recessive inheritance. However, CYP1B1 mutations have also been associated with cases of juvenile-onset glaucoma in some PCG families or shown to modify the age of onset of glaucoma linked to a MYOC mutation in a large family. Objective: To investigate the role of CYP1B1 mutations in POAG predisposition, irrespective of the presence of a MYOC mutation. Methods and subjects: CYP1B1 coding region variation was characterised by denaturing high performance liquid chromatography (DHPLC) and sequencing in 236 unrelated French Caucasian POAG patients and 47 population-matched controls. Results: Eleven (4.6%) patients carried one or two mutated CYP1B1 gene(s) and no MYOC mutation. They showed juvenile or middle-age onset of disease (median age at diagnosis, 40 years, range 13-52), significantly earlier than in non-carrier patients. Apart from one, all mutations detected in POAG patients were previously associated with PCG. Conclusion: CYP1B1 mutations might pose a significant risk for early-onset POAG and might also modify glaucoma phenotype in patients who do not carry a MYOC mutation.

Characterization of Common CYP1B1 Variants with Different Capacity for Benzo[a]pyrene-7,8-Dihydrodiol Epoxide Formation from Benzo[a]pyrene

“…Most cases of primary congenital glaucoma are caused by deleterious mutations in the CYP1B1 gene (40), and Cyp1b1 knockout mice show ocular drainage structure abnormalities consistent with those seen in humans with primary congenital glaucoma and mutations (41). Recently, CYP1B1 alleles carrying the Ala443Gly substitution have been reported in German and French primary congenital glaucoma patients, and an association with the disease phenotype was suggested (42,43). Interestingly, we have found that the Ala443Gly substitution is relatively common in an African population (18).…”

The Role of Genetic Counseling in Prevention of Primary Congenital Glaucoma

“…The haplotype background of this mutation in the two populations is the same. The R390H, another common mutation observed in 19.2% of the patients with PCG in Iran, was formerly identified in a Pakistani patient (15) and then, reported in Indian patients with PCG (15), and in an early -onset primary open angle glaucoma French patient (16). The E173K, among the more rare mutations in the Iranians, is only recently reported as a new mutation in an Egyptian family (17), and g.4673_4674insC was formerly reported in a Turkish family (18).…”

Interleukin-20 Receptor Expression in the Trabecular Meshwork and Its Implication in Glaucoma

“…The genetic complexity of POAG is demonstrated by the mapping of more than 20 glaucoma loci, 3 the identification of common risk alleles, [4][5][6][7][8][9] the finding of affected individuals with mutations in multiple genes, 10,11 and compound heterozygous mutations in myocilin often leading to a more severe disease. [12][13][14] Thus, finding causative glaucoma genes is not a simple task.…”