Modification of Ocular Defects in Mouse Developmental Glaucoma Models by Tyrosinase

• Published in: Science (American Association for the Advancement of Science) Vol. 299; no. 5612; pp. 1578 - 1581
• Main Authors: Libby, Richard T., Smith, Richard S., Savinova, Olga V., Zabaleta, Adriana, Martin, Janice E., Gonzalez, Frank J., Simon W. M. John
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 07-03-2003; The American Association for the Advancement of Science
• Subjects: Albinism; Albinism, Ocular - genetics; Albinism, Ocular - pathology; Animals; Anterior Eye Segment - abnormalities; Aryl Hydrocarbon Hydroxylases - deficiency; Aryl Hydrocarbon Hydroxylases - genetics; Basement membrane; Biological and medical sciences; Canals; Care and treatment; Childhood glaucoma; Cornea - abnormalities; Cytochrome P-450 CYP1B1; Disease Models, Animal; DNA-Binding Proteins; Dopa; Dosage and administration; Drainage structures; Etiology; Eyes & eyesight; Female; Forkhead Transcription Factors; Genetic disorders; Genetic mutation; Genotypes; Glaucoma; Glaucoma - congenital; Glaucoma - enzymology; Glaucoma - genetics; Glaucoma - pathology; Glaucoma and intraocular pressure; Glaucoma in children; House mouse; Human genetics; Intraocular Pressure; Iris - abnormalities; L-dopa; Levodopa - administration & dosage; Levodopa - metabolism; Male; Medical research; Medical sciences; Mice; Mice as laboratory animals; Mice, Inbred C57BL; Mice, Inbred Strains; Monophenol Monooxygenase - deficiency; Monophenol Monooxygenase - genetics; Monophenol Monooxygenase - metabolism; Mutation; Ophthalmology; Phenotype; Phenotypes; Pregnancy; Trabecular meshwork; Trabecular Meshwork - abnormalities; Transcription Factors - genetics; United States; Animal model; Enzyme; Cytochrome P450; Rodentia; Lyases; Carbon-carbon lyases; Eye disease; Vertebrata; Mammalia; Mouse; Glaucoma (eye); Polypeptide; Animal; Mutation; Tyrosine phenol-lyase
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1080095

Mutations in the cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1) gene are a common cause of human primary congenital glaucoma (PCG). Here we show that$Cyp1b1^{-/-}$mice have ocular drainage structure abnormalities resembling those reported in human PCG patients. Using$Cyp1b1^{-/-}$mice, we identified the tyrosinase gene (Tyr) as a modifier of the drainage structure phenotype, with Tyr deficiency increasing the magnitude of dysgenesis. The severe dysgenesis in eyes lacking both CYP1B1 and TYR was alleviated by administration of the tyrosinase product dihydroxyphenylalanine (L-dopa). Tyr also modified the drainage structure dysgenesis in mice with a mutant Foxc1 gene, which is also involved in PCG. These experiments raise the possibility that a tyrosinase/L-dopa pathway modifies human PCG, which could open new therapeutic avenues.