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Shazia Micheal, Humaira Ayub, Muhammad Imran Khan, Farah Akhtar, Mahmood Ali, Robert K Koenekoop, Manal Hedrawi, Osama M Badeeb, Raheel Qamar, Anneke I den Hollander; CYP1B1 Mutations Cause Glaucoma in Pakistani and Saudi Arabian Patients. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4499.
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CYP1B1 is the most commonly mutated gene in primary congenital glaucoma (PCG) and mutations have also been identified in primary open angle glaucoma (POAG). This study was undertaken to identify mutations in CYP1B1 in PCG and POAG patients from Pakistan and the Kingdom of Saudi Arabia.
Patients were diagnosed based on an increased intraocular pressure, optic nerve damage, visual field changes and funduscopy. Patients and healthy individuals of two consanguineous Pakistani families were genotyped with high-resolution SNP microarrays. Homozygosity mapping was performed using HomozygosityMapper. Direct sequencing of CYP1B1 was performed in 30 POAG families and 85 sporadic POAG cases from Pakistan. In addition five PCG families and a 12 sporadic cases were studied from Saudi Arabia.
Homozygosity mapping in a consanguineous Pakistani family diagnosed with juvenile POAG revealed a 11-Mb homozygous region encompassing the CYP1B1. A CYP1B1 missense mutation (p.Arg390His) was identified in this family. Sequence analysis of CYP1B1 in 30 other families identified two additional mutations (p.Asp316Val and p.Glu229Lys) in two of the families.Analysis of CYP1B1 in a panel of 85 sporadic Pakistani POAG patients revealed two heterozygous variants (p.Glu229Lys and p.Thr234Lys). The p.Glu229Lys variant was present in 15% (n=13/85) of the sporadic patients which indicates that it is a frequent cause of POAG in Pakistani patients.Three Saudi Arabian PCG families were found to harbor the frequent homozygous mutation p.Gly61Glu in CYP1B1, a fourth family carried the homozygous missense mutation p.Arg469Trp, and a sporadic PCG patient carried the variant p.Ala443Gly heterozygously.
This study confirms that CYP1B1 mutations are a frequent cause of PCG and are strongly associated with POAG. All mutations described in this study are most likely pathogenic as they alter the domain topology of Cytochrome P450 domain of CYP1B1.
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