Analysis of CYP1B1 in pediatric and adult glaucoma and other ocular phenotypes. Mol Vis 2016;22:1229-1238
Date
10/26/2016Pubmed ID
27777502Pubmed Central ID
PMC5070572Scopus ID
2-s2.0-85008178877 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
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.
Author List
Reis LM, Tyler RC, Weh E, Hendee KE, Kariminejad A, Abdul-Rahman O, Ben-Omran T, Manning MA, Yesilyurt A, McCarty CA, Kitchner TE, Costakos D, Semina EVAuthors
Deborah M. Costakos MD Chair, Professor in the Ophthalmology and Visual Sciences department at Medical College of WisconsinKathryn Hendee in the CTSI department at Medical College of Wisconsin - CTSI
Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Alleles
Anterior Eye Segment
Child
Child, Preschool
Cytochrome P-450 CYP1B1
DNA Mutational Analysis
Female
Glaucoma, Open-Angle
Humans
Hydrophthalmos
Male
Middle Aged
Mutation
Pedigree
Phenotype
Polymerase Chain Reaction
