Ornithine δ-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences

Ornithine δ-aminotransferase is a nuclear-encoded mitochondrial matrix enzyme which catalyzes the reversible interconversion of ornithine and α- ketoglutarate to glutamate semialdehyde and glutamate. Inherited deficiency of ornithine δ-aminotransferase results in ornithine accumulation and a characteristic chorioretinal degeneration, gyrate atrophy of the choroid and retina. We have surveyed the ornithine δ-aminotransferase genes of gyrate atrophy patients for mutations. Using a variety of techniques, we discovered and molecularly characterized 21 newly recognized ornithine δ- aminotransferase alleles. We determined the consequences of these and three previously described mutations on ornithine δ-aminotransferase mRNA, antigen, and enzyme activity in cultured fibroblasts. The majority (20/24) of these alleles produce normal amounts of normally sized ornithine δ- aminotransferase mRNA. By contrast, only 2/24 had normal amounts of ornithine δ-aminotransferase antigen. Reproducing these mutations by site-directed mutagenesis and expressing the mutant ornithine δ-aminotransferase in Chinese hamster ovary cells confirms that several of these mutations inactivate ornithine δ-aminotransferase and cause gyrate atrophy in these patients.