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A. Bhattacharjee, M. Acharya, S. Mookherjee, D. Banerjee, A. Bandopadhyay, S. K. D. Thakur, A. Sen, K. Ray; Evaluation of the Role of CYP1B1 in POAG Pathogenesis. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5589.
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CYP1B1 mutations have been identified in glaucoma patients. While defects in the gene causes Primary Congenital Glaucoma (PCG) by autosomal recessive mode of inheritance, its role in Primary Open Angle Glaucoma (POAG) is more complex and reported to be involved in pathogenesis along with myocilin (MYOC) mutation (Vincent et al, Am. J. Hum. Genet, 70, 448, 2002). The purpose of the study was to explore further the role of CYP1B1 variants in POAG.
Unrelated POAG patients (n=264) were screened for CYP1B1 along with other candidate genes for glaucoma by PCR, SSCP and DNA sequencing. Coding SNPs (R48G, A119S, L432V, D449D, and N453S) in CYP1B1 detected during screening were utilized for association study in the unrelated patient samples.
A JOAG patient was found to be a compound heterozygote for two consecutive amino acid alterations in CYP1B1 (E229K, E230K) along with a homozygous mutation in MYOC(G399D). But neither of the parents (double heterozygous for MYOC & CYP1B1) nor the younger sib (homozygous for MYOC and heterozygous for CYP1B1) had any glaucomatous changes. Among five SNPs, one CYP1B1 variant (V432), reported to have higher activity compared to L432 and generating higher ROS in cells by the resultant metabolite (4-hydroxy estradiol) (Li et al, Pharmacogenet, 10, 343, 2000), was significantly over represented in unrelated patients compared to controls. Prevalent haplotype for CYP1B1 locus among POAG patients was observed to be same as reported for PCG patients harboring defective CYP1B1.
On rare occasions CYP1B1 may be primarily responsible for JOAG by monogenic association, and identification of higher frequency of V432 variant among POAG patients compared to controls suggests possible involvement of the variant towards disease susceptibility.
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