CYP1B1 Mutation Profile of Iranian Primary Congenital Glaucoma Patients and Associated Haplotypes

Fereshteh Chitsazian^*, Betsabeh Khoramian Tusi^*, Elahe Elahi^*, Heidar Amini Saroei, Mohammad H. Sanati^*, Shahin Yazdani^¶, Mohammad Pakravan^¶, Navid Nilforooshan^||, Yadollah Eslami, Mohammad Ali Zare Mehrjerdi, Reza Zareei, Mahmood Jabbarvand, Ali Abdolahi, Ali R. Lasheyee, Arash Etemadi, Behnaz Bayat^*, Mehdi Sadeghi^*, Mohammad M. Banoei^*, Behnam Ghafarzadeh^**, Mohammad R. Rohani^**, Akram Rismanchian, Yvonne Thorstenson and Mansoor Sarfarazi

From the National Institute for Genetic Engineering and Biotechnology, * Tehran, Iran; the Department of Biological Sciences and the Bioinformatics Center, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; the Department of Ophthalmology, Farabi Eye Research Center, Tehran University of Medical Sciences, Tehran, Iran; the Ophthalmic Research Center, ^¶ Shaheed Beheshti University of Medical Sciences, Tehran, Iran; the Department of Ophthalmology, ^|| Iran University of Medical Sciences, Hazrat Rasool Hospital, Tehran, Iran; the Al-Zahra Ophthalmology Center, ** Zahedan University of Medical Sciences, Zahedan, Iran; Esfahan Farabi Hospital, Esfahan University of Medical Sciences, Esfahan, Iran; DNA Variation and Function Group, Stanford Genome Technology Center, Stanford University, Palo Alto, California; and the Molecular Ophthalmic Genetics Laboratory, University of Connecticut Health Center, Farmington, Connecticut

The mutation spectrum of CYP1B1 among 104 primary congenitalglaucoma patients of the genetically heterogeneous Iranian populationwas investigated by sequencing. We also determined intragenicsingle nucleotide polymorphism (SNP) haplotypes associated withthe mutations and compared these with haplotypes of other populations.Finally, the frequency distribution of the haplotypes was comparedamong primary congenital glaucoma patients with and withoutCYP1B1 mutations and normal controls. Genotype classificationof six high-frequency SNPs was performed using the PHASE 2.0software. CYP1B1 mutations in the Iranian patients were veryheterogeneous. Nineteen nonconservative mutations associatedwith disease, and 10 variations not associated with diseasewere identified. Ten mutations and three variations not associatedwith disease were novel. The 13 novel variations make a notablecontribution to the $~$ 70 known variations in the gene. CYP1B1mutations were identified in 70% of the patients. The four mostcommon mutations were G61E, R368H, R390H, and R469W, which togetherconstituted 76.2% of the CYP1B1 mutated alleles found. Six uniquecore SNP haplotypes were identified, four of which were commonto the patients with and without CYP1B1 mutations and controlsstudied. Three SNP blocks determined the haplotypes. Comparisonof haplotypes with those of other populations suggests a commonorigin for many of the mutations.