Molecular basis of ornithine aminotransferase deficiency in B-6-responsive and -nonresponsive forms of gyrate atrophy.

Abstract

Gyrate atrophy (GA), a recessive eye disease involving progressive loss of vision due to chorioretinal degeneration, is associated with a deficiency of the mitochondrial enzyme ornithine aminotransferase (OATase; ornithine-oxo-acid aminotransferase; L-ornithine:2-oxo-acid aminotransferase, EC 2.6.1.13) with consequent hyperornithinemia. Genetic heterogeneity of GA has been suggested by the demonstration that administration of pyridoxine to increase the level of pyridoxal phosphate, a cofactor of OATase, reduces hyperornithinemia in a subset of patients. We have cloned and sequenced cDNAs for OATase from two GA patients, one responsive and one nonresponsive to pyridoxine treatment. The respective cDNAs contained different single missense mutations, which were sufficient to eliminate OATase activity when each cDNA was tested in a eukaryotic expression system. However, like the enzyme in fibroblasts from the pyridoxine-responsive patient, OATase encoded by the corresponding cDNA from this individual showed a significant increase in activity when assayed in the presence of an increased pyridoxal phosphate concentration. These data firmly establish that both pyridoxine responsive and nonresponsive forms of GA result from mutations in the OATase structural gene. Moreover, they provide a molecular characterization of the primary lesion in a pyridoxine-responsive genetic disorder.

• Authors: V Ramesh, A I McClatchey, N Ramesh, L A Benoit, E L Berson, V E Shih, J F Gusella
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 85 Issue 11 Pg. 3777-80 (Jun 1988) ISSN: 0027-8424 [Print] United States
• PMID: 3375240 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA
• Transaminases
• Ornithine-Oxo-Acid Transaminase
• Pyridoxine

Topics

• Cloning, Molecular
• DNA (genetics)
• Gene Expression Regulation
• Humans
• Ornithine-Oxo-Acid Transaminase (deficiency, genetics)
• Pyridoxine (physiology)
• Retinal Degeneration (enzymology, genetics)
• Transaminases (deficiency)