Analysis of CYP1B1 in pediatric and adult glaucoma and other ocular phenotypes
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Published on: June 3, 2018
Linda M Reis1, Rebecca C Tyler1, Eric Weh1
1Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI.
Insights
Genetic analysis of CYP1B1 reveals new mutations linked to congenital glaucoma and expands understanding of its role in other ocular conditions. Loss-of-function variants may increase the risk for primary open-angle glaucoma (POAG).
Area of Science:
- Genetics
- Ophthalmology
- Molecular Biology
Background:
- The CYP1B1 gene encodes a cytochrome P450 enzyme implicated in various ocular phenotypes.
- Mutations in CYP1B1 are primarily associated with recessive pediatric conditions like primary congenital glaucoma (PCG) and congenital glaucoma with anterior segment dysgenesis (CG with ASD).
- Some CYP1B1 variants have also been linked to adult-onset primary open-angle glaucoma (POAG).
Purpose of the Study:
- To investigate the role of CYP1B1 mutations in a cohort of pediatric and adult patients with glaucoma and other ocular disorders.
- To expand the known spectrum of CYP1B1-associated mutations and clinical phenotypes.
Main Methods:
- Genetic analysis of the CYP1B1 gene in 158 pediatric patients with various ocular conditions and 193 adult patients with POAG.
- Comparison of mutation frequencies with 288 age- and ethnicity-matched POAG-negative controls.
- Identification and characterization of pathogenic variants, including novel mutations.
Main Results:
- Recessive pathogenic CYP1B1 variants were found in patients with PCG, CG with ASD, and other ocular defects, including sclerocornea and microphthalmia, which are newly associated phenotypes.
- Two novel CYP1B1 variants, c.1325delC and c.157G>A, were identified.
- The c.1064_1076del allele, a loss-of-function variant, was identified in heterozygous relatives with POAG and in one sporadic POAG case, suggesting a potential increased risk for POAG.
Conclusions:
- The study expands the mutational and phenotypic spectrum of CYP1B1, identifying new alleles and ocular phenotypes.
- While the direct contribution of CYP1B1 to POAG is uncertain, loss-of-function variants may be associated with an increased risk.
- These findings enhance the understanding of genetic factors contributing to diverse forms of glaucoma.
Purpose:
The CYP1B1 gene encodes an enzyme that is a member of the cytochrome P450 superfamily. Mutations in CYP1B1 have been mainly reported in recessive pediatric ocular phenotypes, such as primary congenital glaucoma (PCG) and congenital glaucoma with anterior segment dysgenesis (CG with ASD), with some likely pathogenic variants also identified in families affected with adult-onset primary open angle glaucoma (POAG).
Methods:
We examined CYP1B1 in 158 pediatric patients affected with PCG (eight), CG with ASD (22), CG with other developmental ocular disorders (11), juvenile glaucoma with or without additional ocular anomalies (26), and ASD or other developmental ocular conditions without glaucoma (91); in addition, a large cohort of adult patients with POAG (193) and POAG-negative controls (288) was examined.
Results:
Recessive pathogenic variants in CYP1B1 were identified in two PCG pedigrees, three cases with CG and ASD, and two families with CG and other ocular defects, such as sclerocornea in one patient and microphthalmia in another individual; neither sclerocornea nor microphthalmia has been previously associated with CYP1B1. Most of the identified causative mutations are new occurrences of previously reported pathogenic alleles with two novel variants identified: a c.1325delC, p.(Pro442Glnfs*15) frameshift allele in a family with PCG and a c.157G>A, p.(Gly53Ser) variant identified in a proband with CG, Peters anomaly, and microphthalmia. Analysis of the family history in the CYP1B1-positive families revealed POAG in confirmed or presumed heterozygous relatives in one family with PCG and two families with ASD/CG; POAG was associated with the c.1064_1076del, p.(Arg355Hisfs*69) allele in two of these pedigrees. Screening of an unrelated POAG cohort identified the same c.1064_1076del heterozygous allele in one individual with sporadic POAG but not in age- and ethnicity-matched POAG-negative individuals. Overall, there was no significant enrichment for mutant alleles in CYP1B1 within the POAG cases compared to the controls.
Conclusions:
In summary, these data expand the mutational and phenotypic spectra of CYP1B1 to include two novel alleles and additional developmental ocular phenotypes. The contribution of CYP1B1 to POAG is less clear, but loss-of-function variants in CYP1B1, especially c.1064_1076del, p.(Arg355Hisfs*69), may be associated with an increased risk for POAG.
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