Phenotype of CYP1B1 Gene Mutations in U.S. and Brazilian Patients With Primary Congenital Glaucoma

Abstract

Abstract: : Purpose: The goal of this study is to investigate the phenotypes associated with cytochrome P4501B1 gene (CYP1B1) mutations in U.S. and Brazilian patients with familial primary congenital glaucoma (PCG). Methods: 21 pedigrees from the U.S. and Brazil affected with congenital glaucoma were screened for mutations in CYP1B1 by direct genomic sequencing. Patients with CYP1B1 mutations were also screened for myocilin (MYOC) mutations and for DNA sequence variants in the gene for Tyrosinase (TYR). A total of 126 individuals were screened for mutations of which 51 were affected and 75 were unaffected. In each family the inheritance of the disease was consistent with an autosomal recessive pattern. Clinical features of the disease including age of onset, initial intraocular pressure, rupture of Descemet’s membrane and other anterior segment abnormalities were recorded for each patient. Results: In affected members from three Brazilian families four different mutations were found: 8037_8046dupTCATGCCACC, 8182delG, W57Stop and Glu387Lys. All of the affected individuals carrying these mutations presented with severe disease with very early age of onset (less than one month), high intraocular pressures and ruptures in Descemet’s membrane. In one American pedigree three mutations were found: 8037_8046dupTCATGCCACC, Glu387Lys, and 268delSNF. Four affected siblings in this pedigree were compound heterozygotes carrying the Glu387Lys and 268delSNF mutations. Interestingly, 2 of the four affected siblings had severe early onset glaucoma (intraocular pressures of 25 (at age 2 months) and 28 (at age 1 month), with associated corneal edema), while the other two affected siblings didn’t have evidence of glaucoma until their midteens. The variation in disease severity among these four siblings was not associated with DNA sequence variants in the MYOC or TYR genes. Conclusions: These results indicate that most CYP1B1 mutations are associated with severe early onset glaucoma. In our study the phenotype associated with the 268delSNF/Glu387Lys compound heterozygote was variable, and we did not find an association between disease severity and DNA sequence variants in the TYR or MYOC genes which may serve as modifiers. Future studies to define the prevalence of CYP1B1 mutations and the phenotypes associated with these mutations will aid genetic counseling of these patients.

Keywords: mutations • gene modifiers • genetics