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G A Mitchell

Publications and source records attributed to G A Mitchell.

13 recordsLinked to original sources
PubMed1992

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

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.

Alleles↗
PubMed1992

Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients.

We report the clinical, electrophysiologic, ophthalmologic, and neuropsychologic features of six patients with hyperammonemia-hyperornithinemia-homocitrullinuria syndrome, an inborn error of ornithine metabolism. Pyramidal signs, decreased vibration sense, bucco-facio-lingual dyspraxia, and learning difficulties or subnormal intelligence were found in the majority. Anomalies of peripheral nerve conduction velocity and of evoked potentials were common, and one patient had markedly abnormal white matter images on cranial magnetic resonance imaging. One patient had retinal depigmentation and chorioretinal thinning. The clinical severity varied greatly among patients; in general, the three younger patients had less neurologic and intellectual impairment than did the three older patients. Only two of our patients have had episodes of symptomatic hyperammonemia. We conclude that hyperammonemia-hyperornithinemia-homocitrullinuria syndrome can be associated with widespread manifestations in the central and peripheral nervous systems. Although the control of hyperammonemia is an essential element in the treatment of these patients, the relationship of hyperammonemia to the chronic neuropsychologic problems of these patients is unclear.

Adolescent↗
PubMed1991

Splice-mediated insertion of an Alu sequence inactivates ornithine delta-aminotransferase: a role for Alu elements in human mutation.

In studies of mutations causing deficiency of ornithine delta-aminotransferase (EC 2.6.1.13), we found an allele whose mature mRNA has a 142-nucleotide insertion at the junction of sequences from exons 3 and 4. The insert derives from an Alu element in ornithine delta-aminotransferase intron 3 oriented in the direction opposite to transcription (an "antisense Alu"). A guanine----cytosine transversion creates a donor splice site in this Alu, activating a cryptic acceptor splice site at its 5' end and causing splice-mediated insertion of an Alu fragment into the mature ornithine-delta-aminotransferase mRNA. We note that the complement of the Alu consensus sequence has at least two cryptic acceptor sites and several potential donor sequences and predict that similar mutations will be found in other genes.

Amino Acid Sequence↗
PubMed1989

At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns.

Gyrate atrophy of the choroid and retina (GA) is an inherited chorioretinal degeneration caused by deficiency of ornithine delta-aminotransferase (OAT; L-ornithine: 2-oxo-acid aminotransferase; EC 2.6.1.13). GA is one of the "Finnish genetic diseases," a group of several rare monogenic disorders that occur with increased frequency in the Finnish population. Using a combination of RNase A protection, genomic cloning, and polymerase chain reaction amplification of genomic DNA, we found one of two missense mutant OAT alleles to be present in each of 16 Finnish GA pedigrees. The first mutation R180T, in which arginine-180 is replaced by threonine, was present in homozygous form in patients from two pedigrees. The second mutation L402P, in which leucine-402 is replaced by proline, was present in homozygous form in patients from 14 pedigrees. Neither mutation was present in 19 Finnish controls. L402P was not present in 18 non-Finnish GA patients but R180T was found in an American GA patient. We constructed full-length mutant cDNAs by amplifying patient cDNA with the polymerase chain reaction and cloning a restriction fragment containing the mutation into an otherwise normal human OAT cDNA. These mutant cDNAs were then expressed in CHO-K1 cells, which lack endogenous OAT. Both R180T and L402P inactivate OAT. These results show molecular heterogeneity in GA alleles even in the Finnish population.

Alleles↗
PubMed1989

Selection against lethal alleles in females heterozygous for incontinentia pigmenti.

Studies of five heterozygous females from three kindreds segregating incontinentia pigmenti indicate that cells expressing the mutation have been eliminated from skin fibroblast cultures and in varying degrees from hematopoietic tissues. Clonal analysis was carried out using G6PD variants and methylation patterns at the HPRT locus. Our results confirm X linkage in these families and suggest that selection against cells expressing mutations that are lethal to males in utero may help ameliorate the deleterious phenotype in carrier females.

Adolescent↗
PubMed1976

Decreased radioassay values for folate after serum extraction when pteroylglutamic acid standards are used.

Radoiassay values for folate in protein-denautured (extracted) sera are compared with values obtained by individual serum blank correction. Lower folate values are reported for sera extracted at pH 1.3, 7.6, 10.5, and 12.4 when pterolyglutamic acid (PGA) calibration standards are used. The results are unchanged when ascorbate added to the sera is increased from 1 to 20 g/liter and when [3H]PGA is substituted for 125I-labeled PGA. However, a higher mean value for extracted serum is reported when N-5-methyltetrahydrofolic acid calibration standards are substituted for PGA. Because both patients' samples and assay calibrators were subjected to the same extraction methods, our results suggest that serum folate behaves differently from PGA during the extractions.

Folic Acid↗