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Human Molecular Genetics, 2000, Vol. 9, No. 3 367-374
© 2000 Oxford University Press

Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus

Bassem A. Bejjani1,5,+, David W. Stockton1,3,5, Richard Alan Lewis1,2,3,4,5,6, Karim F. Tomey6,§, David K. Dueker6, Monzer Jabak6, William F. Astle6,¶ and James R. Lupski1,4,5

Departments of 1Molecular and Human Genetics, 2Ophthalmology, 3Medicine and 4Pediatrics, Baylor College of Medicine, Houston, TX, USA, 5The Texas Children’s Hospital, Houston, TX, USA and 6King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia

Primary congenital glaucoma (PCG) is an autosomal recessive disorder associated with unknown developmental defect(s) in the anterior chamber. Recently, we reported three distinct mutations in CYP1B1, the gene for cytochrome P4501B1, in 25 Saudi families segregating PCG. For this report, we analyzed 37 additional families and confirmed the initial finding of decreased penetrance. Mutations and intragenic single-nucleotide polymorphisms (SNPs) were also analyzed from direct sequencing of all CYP1B1 coding exons. Eight distinct mutations were identified: G61E, R469W and D374N, the most common Saudi mutations, account for 72, 12 and 7%, respectively, of all the PCG chromosomes. Five additional homozygous mutations (two deletions and three missense mutations) were detected, each in a single family. Affected individuals from five families had no CYP1B1 coding mutations, and each family had a unique SNP profile. The identification of eight distinct mutations in a single gene, on four distinct haplotypes, suggests a relatively recent occurrence of multiple mutations in CYP1B1 in Saudi Arabia. These data demonstrate decreased penetrance of the PCG phenotype in the Saudi population, because 40 apparently unaffected individuals in 22 families have mutations and haplotypes identical to their affected siblings. Two individuals were subsequently diagnosed with glaucoma and two others had abnormal ocular findings that are consistent with milder forms of glaucoma. Analysis of these 22 kindreds suggests the presence of a dominant modifier locus that is not linked genetically to CYP1B1. Linkage and Southern analyses excluded three candidate modifier loci.

+ To whom correspondence should be addressed at: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, BCM 225, Houston, TX 77030, USA. Tel: +1 713 798 6871; Fax: +1 713 798 5073; Email: bbejjani@bcm.tmc.edu

§ Present address: Beirut Eye Specialist Center, Rizk Hospital, Beirut, Lebanon

Present address: Eye Clinic, Alberta Children’s Hospital, Calgary, Alberta, Canada


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