advertisement
Abstract #18539 Published in IGR 3-3
Novel cytochrome P4501B1 (CYP1B1) gene mutations in Japanese patients with primary congenital glaucoma
Mashima Y; Suzuki Y; Sergeer Y; Ohtake Y; Tamino T; Kimura H; Miyata H; Aihara M; Tamihara H; Inalani MInvestigative Ophthalmology and Visual Science 2001; 42: 2211-2216
PURPOSE: To investigate CYP1B1 gene mutations in Japanese patients with primary congenital glaucoma (PCG). METHODS: Sixty-five unrelated Japanese patients with PCG were screened by PCR-single strand conformational polymorphism (SSCP) analysis followed by direct sequencing. No patients were offspring of consanguineous marriages, a common occurrence among patients in previous reports. PCG haplotypes were constructed with intragenic polymorphisms in affected individuals. Three-dimensional atomic structures of human CYP1B1 and four mutant CYP1B1 sequences representing missense mutations were assembled using homology modelling, and were regularized by an energy-minimization procedure. RESULTS: Eleven novel mutations, including seven definite and four probable mutations, were detected in 13 (20%) of the 65 unrelated patients. Of the seven definite mutations, three were predicted to truncate the CYP1B1 open reading frame. The other four were missense mutations (Asp192Val, Ala330Phc, Val361Met, and Arg444Gln), all located in conserved core structures determining proper folding and heme-binding ability of cytochrome P450 molecules. Molecular modelling demonstrated that two of four mutations in positions 330 and 364 were structurally neutral, but Arg444Gln caused significant structural change. Of the four probable mutations, three were missense (Val198Hc, Val320Leu, and Glu-199Gly); the other was a base substitution in the noncoding region of exon 1. CONCLUSIONS: The ll varied CYP1B1 mutations found in 13 unrelated Japanese patients with sporadic occurrence of PCG represent an allelic heterogeneity and may be unique to a specific population.
Dr Y. Mashima, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku ku, Tokyo 160-8582, Japan. mashima@med.keio.ac.jp
Classification:
1.2 Population genetics (Part of: 1 General aspects)
