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.

Figure 1

Pedigrees of probands with MYOC mutation, in families 1–6 and 8. Blackened symbols denote affected status for JOAG, grayed symbols denote affected status for POAG, unblackened symbols denote unaffected or unknown clinical status for glaucoma, and hatched symbols denote pigmentary glaucoma. Slash marks through symbols denote deceased individuals, and bars above symbols indicate that the individuals who had genetic testing. Arrow indicates the proband. Numbers below the symbols indicate current age (in years), for pedigrees 1–4 and 8; age (in years) at onset, for pedigree 5; and age (in years) at diagnosis, for pedigree 6.

Figure 2

Pedigree of family 7, with CYP1B1 (Arg368His) and MYOC (Gly399Val) mutations. Blackened symbols denote affected status for JOAG, unblackened symbols denote unaffected or unknown status, and hatched symbols denote affected status for POAG. Arrow indicates the proband. Numbers above the symbol indicate the identifier, whereas numbers (“1” for wild type and “2” for mutant allele) below the symbol indicate the genotype for MYOC (top) and for CYP1B1 (bottom).

Figure 3

Pedigree of family 9, with CYP1B1 mutations (Arg368His and 1546dup10). Blackened symbols denote affected status for JOAG, whitened symbols denote unaffected or unknown status, and grayed symbols denote CG, rather than JOAG. Arrow indicates the proband.