title: Ornithine delta-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences.
abstract: 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.
authors.affiliation: Laboratory of Genetics, Howard Hughes Medical Institute, John Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: L C
authors.initials: LC
authors.lastname: Brody
authors.forename: G A
authors.initials: GA
authors.lastname: Mitchell
authors.forename: C
authors.initials: C
authors.lastname: Obie
authors.forename: J
authors.initials: J
authors.lastname: Michaud
authors.forename: G
authors.initials: G
authors.lastname: Steel
authors.forename: G
authors.initials: G
authors.lastname: Fontaine
authors.forename: M F
authors.initials: MF
authors.lastname: Robert
authors.forename: I
authors.initials: I
authors.lastname: Sipila
authors.forename: M
authors.initials: M
authors.lastname: Kaiser-Kupfer
authors.forename: D
authors.initials: D
authors.lastname: Valle
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D015799:Gyrate Atrophy / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009953:Ornithine-Oxo-Acid Transaminase / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D021382:Protein Sorting Signals / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D012689:Sequence Homology, Nucleic Acid; D014162:Transfection
chemical_list: D021382:Protein Sorting Signals; D012333:RNA, Messenger; D009953:Ornithine-Oxo-Acid Transaminase