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

Lawrence C. Brody, Grant A. Mitchell, Cassandra Obie, Jacques Michaud, Gary Steel, Gisèle Fontaine, Marie France Robert, Ilkka Sipila, Muriel Kaiser-Kupfer, David Valle

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

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-amino-transferase 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.

Original languageEnglish (US)
Pages (from-to)3302-3307
Number of pages6
JournalJournal of Biological Chemistry
Volume267
Issue number5
StatePublished - Feb 15 1992

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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