Biochemical Genetics of Carbonic Anhydrase Deficiencies

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DESCRIPTION (provided by applicant): The broad goal of this research is to study the functional genomics of the carbonic anhydrase gene family to determine the importance of individual members to health and disease. The sixteen known carbonic anhydrases (CAs) and CA-related proteins play important roles in diverse physiological processes including respiration, bone resorption, renal acidification, gluconeogenesis, signal transduction, and formation of cerebrospinal fluid and gastric acid. We have five specific aims: 1) Characterize the properties and functional genomics of newly discovered carbonic anhydrase XlV. 2) Characterize the CA IV knockout mouse and the phenotypic consequences of the CA IV/CA XIV double knockout. 3) Test the hypothesis that a signal sequence mutation in CA IV is the underlying defect in dominantly inherited retinitis pigmentosa (RP17q). 4) Characterize the properties and functional genomics of mitochondrial carbonic anhydrases CA VA and CA VB. 5) Create transgenic mouse models to test the functional importance of the CA I I/anion-exchanger "metabolon" in the whole animal. We seek renewed support for a program with a strong record of productivity since our initial discovery of the CA II deficiency syndrome. This disease affects bone, brain, and kidney and was the first disease associated with a CA deficiency. We will use a variety of biochemical, cell biological, immunological, and molecular genetic approaches. Novel mouse knock-in and knockout mouse models of individual CA deficiencies will be produced by targeted mutagenesis. Functional consequences of these deficiencies will be characterized by multiple physiological measurements. Mice deficient for multiple CAs will be produced, where appropriate, by intercrosses between singly deficient mice. These studies should enhance our understanding of how individual CAs contribute to normal physiology and how single and double CA deficiencies produce disease. The answers sought have fundamental significance, and should provide information leading to novel therapeutic approaches to CA deficiency.