Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene

Am J Hum Genet. 2002 Feb;70(2):448-60. doi: 10.1086/338709. Epub 2002 Jan 3.


"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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Alleles
  • Aryl Hydrocarbon Hydroxylases*
  • Canada
  • Child
  • Child, Preschool
  • Cytochrome P-450 CYP1B1
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytoskeletal Proteins
  • DNA Mutational Analysis
  • Eye Proteins / genetics*
  • Female
  • Genes, Dominant / genetics
  • Genetic Heterogeneity
  • Genotype
  • Glaucoma / congenital
  • Glaucoma / epidemiology*
  • Glaucoma / genetics*
  • Glaucoma / physiopathology
  • Glycoproteins / genetics*
  • Homeobox Protein PITX2
  • Homeodomain Proteins / genetics
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Nuclear Proteins*
  • Pedigree
  • Phenotype
  • Polymorphism, Single-Stranded Conformational
  • Transcription Factors / genetics


  • Cytoskeletal Proteins
  • Eye Proteins
  • Glycoproteins
  • Homeodomain Proteins
  • Nuclear Proteins
  • Transcription Factors
  • trabecular meshwork-induced glucocorticoid response protein
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1B1