Mice lacking ornithine–δ–amino–transferase have paradoxical neonatal hypoornithinaemia and retinal degeneration

Abstract

Deficiency of ornithine-delta-aminotransferase (OAT) in humans causes hyperornithinaemia and gyrate atrophy (GA), a blinding chorioretinal degeneration. Surprisingly, OAT-deficient mice produced by gene targeting exhibit neonatal hypoornithinaemia and lethality, rescuable by short-term arginine supplementation. Post-weaning, these mice develop hyperornithinaemia similar to human GA patients. Subsequent studies in one human GA infant also showed transient hypoornithinaemia. Thus, the OAT reaction plays opposite roles in neonatal and adult mammals. Over several months, OAT-deficient mice develop a retinal degeneration with involvement of photoreceptors and pigment epithelium. OAT-deficient mice appear to be an excellent model of human GA.

Arginine metabolism: nitric oxide and beyond

“…This assertion is supported by the occurrence of hyperornithinaemia in adult humans [91] and mice [92] when OAT is deficient or absent. As shown in Figure 5, P5C can subsequently be utilized for synthesis of proline or glutamate.…”

“…The essential role of the small intestine in arginine synthesis is graphically demonstrated by the arginine deficiencies that result when intestinal citrulline synthesis is blocked by inhibitors of OCT [87] or OAT [61] or by massive resection of the small bowel [88,89]. Similarly, arginine deficiencies occur in individuals with inherited defects in OCT [90], OAT [91,92] or P5C synthetase [93]. An analogous situation exists in strict carnivores, such as cats, which synthesize very little arginine and thus must rely on the diet to meet their needs for this amino acid [94].…”

Diazonamide toxins reveal an unexpected function for ornithine δ-amino transferase in mitotic cell division

“…The finding that OAT mediates the mitotic arrest caused by diazonamide A in human cancer cells is surprising for two reasons: (i) the previously characterized biochemical activity and cellular location of OAT did not anticipate this discovery and (ii) genetic data from OAT-null mice and OAT-deficient human patients (17,18) did not indicate an essential function, as might be expected for a regulator of cell division. Nonetheless, our data clearly demonstrate that OAT has a role in regulating mitotic cell division.…”

“…OAT appears to not be essential for cellular proliferation during normal development, as evidenced by the viability of OAT-null mice (6,17). It is possible that there are redundancies in normal cells able to compensate for OAT loss during mitosis or, more provocatively, that rapidly proliferating cancer cells may exploit OAT more prominently during mitosis than normal cells.…”

“…8). It is therefore anticipated that diazonamide A will inhibit mitosis in cells using OAT for spindle assembly yet not induce the progressive retinal degeneration (gyrate atrophy) associated with loss of OAT enzymatic activity in rodents and humans (17,18).…”