Digenic Inheritance of Early-Onset Glaucoma: CYP1B1, a Potential Modifier Gene

Abstract

"Early-onset glaucoma" refers to genetically heterogeneous conditions for which glaucoma manifests at age 5-40 years and for which only a small subset is molecularly characterized. We studied the role of MYOC, CYP1B1, and PITX2 in a population (n=60) affected with juvenile or early-onset glaucoma from the greater Toronto area. By a combination of single-strand conformation polymorphism and direct cycle sequencing, MYOC mutations were detected in 8 (13.3%) of the 60 individuals, CYP1B1 mutations were detected in 3 (5%) of the 60 individuals, and no PITX2 mutations were detected. The range of phenotypic expression associated with MYOC and CYP1B1 mutations was greater than expected. MYOC mutations included cases of juvenile glaucoma with or without pigmentary glaucoma and mixed-mechanism glaucoma. CYP1B1 mutations involved cases of juvenile open-angle glaucoma, as well as cases of congenital glaucoma. The study of a family with autosomal dominant glaucoma showed the segregation of both MYOC and CYP1B1 mutations with disease; however, in this family, the mean age at onset of carriers of the MYOC mutation alone was 51 years (range 48-64 years), whereas carriers of both the MYOC and CYP1B1 mutations had an average age at onset of 27 years (range 23-38 years) (P=.001). This work emphasizes the genetic heterogeneity of juvenile glaucoma and suggests, for the first time, that (1) congenital glaucoma and juvenile glaucoma are allelic variants and (2) the spectrum of expression of MYOC and CYP1B1 mutations is greater than expected. We also propose that CYP1B1 may act as a modifier of MYOC expression and that these two genes may interact through a common pathway.

Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma

“…To date a digenic inheritance in open-angle glaucoma has been reported in patients with mutations in both MYOC and CYP1B1. 13,39 Thus, on the basis of present knowledge, it is likely that the POAG in patient ID99168 (Table 2) is mainly due to the presence of mutations p.Q368X in MYOC and p.N203S in CYP1B1, as these have been previously confirmed to have a pathological function. 13,40 In fact, according to our experimental results, the p.Q589H in RPGRIP1 seems to be non-pathological (Table 1 (Table 2) instead, the JOAG phenotype may be due mainly to the pathological p.T806I mutation in RPGRIP1 (Table 1) as the MYOC mutation, p.Q352K, has been previously reported to be a probable benign sequence change.…”

The genetic mechanisms of primary angle closure glaucoma

“…96 Similarly, no risk-conferring associations to MYOC were identified in a Chinese PACG cohort 97 despite reports of MYOC association in a study of PACG in a Quebec population. 98,99 On the basis of these results, it is unlikely that MYOC is a major contributor to the development of the PACG, contrary to its positive association with POAG.…”

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

“…102 Other loci, genes, and low-penetrance risk alleles associated with POAG 105 optic atrophy 1 (OPA1) gene at 3q28-q29, 106 and tumor protein p53 (TP53) at 17p13.1. 107 CYP1B1 at 2p22-p21 has been associated with JOAG first by Vincent et al 108 and later by other investigators as well. 109 Fingert et al 110 recently mapped a new NTG gene to chromosome 12q14, the TANK-binding kinase-1 (TBK1).…”