Gyrate atrophy (GA) of the choroid and retina is a rare, inherited, blinding chorioretinal degeneration caused by deficiency of the mitochondrial matrix enzyme, ornithine-delta-aminotransferase (OAT). Aside from their visual symptoms, most GA patients are asymptomatic; thus, GA is perhaps the only isolated chorioretinal degeneration for which the biochemical defect is known. The human OAT cDNA and structural gene have been cloned, sequenced and mapped (10q26). A cluster of OAT processed pseudogenes map to Xp11 - Xp21. There are four long-term objectives of this proposal. The first is to extend our understanding of the molecular basis of GA by determining the cis- and trans- acting regulators of OAT transcription in various tissues; delineating the mutations causing OAT deficiency in GA; determining the distribution of these mutations in our large collection of GA families (72 pedigrees); determining the functional consequences of these mutations; and correlating the molecular defects with phenotypic variation in our large patient population. The second goal is to investigate potential pathophysiologic mechanisms in GA to determine why the retina is particularly sensitive to this systemic biochemical defect. Studies to this end will include comparison of guanidino compound metabolism in patients with GA and a related inborn error of ornithine metabolism (the hyperornithinemia-hyperammonemia-homocitrullinemia syndrome) which does not involve the eye; examination of expression of OAT mRNA in human ocular tissues; determination of the ocular consequences of pharmacologic perturbation of guanidino compound metabolism in animals and investigation of ornithine and guanidino compound metabolism in cultured retinal cells. The third goal is to continue our long-term evaluation of the therapeutic effects of reduction of ornithine accumulation with an arginine-restricted diet, focusing particularly on the outcomes of younger patients. Lastly, an animal model of GA will be developed either by identifying a naturally-occurring mutation or by molecular methods including expression in transgenic mice of mutant OAT subunits which have negative effects on the function of wild-type subunits assembled in the same multimeric enzyme (suicide subunits) or, alternatively, by knocking out the expression of an endogenous OAT gene by homologous recombination in embryonic stem (ES) cells and subsequently developing a strain of homozygous deficient mice by way of chimeric animals.

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National Eye Institute (NEI)
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Visual Sciences A Study Section (VISA)
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Johns Hopkins University
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