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

• Published in: The Journal of biological chemistry Vol. 267; no. 5; pp. 3302 - 3307
• Main Authors: BRODY, L. C, MITCHELL, G. A, OBIE, C, MICHAUD, J, STEEL, G, FONTAINE, G, ROBERT, M.-R, SIPILA, I, KAISER-KUPFER, M, VALLE, D
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Biochemistry and Molecular Biology 15-02-1992
• Subjects: Alleles; Amino Acid Sequence; Animals; Base Sequence; Biological and medical sciences; Cell Line; CHO Cells; Cricetinae; genes; gyrate atrophy; Gyrate Atrophy - enzymology; Gyrate Atrophy - genetics; Humans; Medical sciences; Molecular Sequence Data; Mutation; Ophthalmology; Ornithine-Oxo-Acid Transaminase - genetics; Ornithine-Oxo-Acid Transaminase - metabolism; Polymerase Chain Reaction; Polymorphism, Genetic; Protein Conformation; Protein Sorting Signals - genetics; RNA, Messenger - genetics; Saccharomyces cerevisiae - enzymology; Sequence Homology, Nucleic Acid; site-directed mutagenesis; Transfection; Uvea diseases; Human; Enzyme; Site directed mutagenesis; Ornithine-oxo-acid aminotransferase; Pigment epithelium; Choroid; Eye disease; Enzymatic activity; Gene; Structure activity relation; Uvea; Atrophia; Mutation; Molecular cloning
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/s0021-9258(19)50731-1

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