Deficiency of ornithine-δ-aminotransferase (OAT) in humans results in gyrate atrophy (GA), an autosomal recessive disorder characterized by hyperornithinemia and a slowly progressive chorioretinal degeneration. Purpose. To develop a mouse model of GA to study the pathogenesis of the retinal degeneration. Methods. We produced an OAT-deficient mouse by targeted disruption of the murine OAT gene in embryonic stem cells followed by blastocyst injection and breeding. Results. Homozygous OAT-deficient (OAT-/-) mice are born in normal numbers, have no detectable OAT activity and develop paradoxical hypoornithinemia and neonatal lethality preventable by arginine supplementation. Post-weaning, rescued OAT-/- mice develop hyperornithinemia similar to human GA patients (plasma ornithine mean ± SD; OAT-/- mice, 1172 ± 251; normal mice, 95 ± 21) and a slowly progressive retinal degeneration. Mean electroretinogram (ERG) amplitude is normal at 2 months but reduced to 62% at 6 months and 40% by 12 months. At 2 months the retinas of OAT-/- mice are normal histologically but by EM show sporadic swelling and degeneration of isolated RPE cells. By 7 months the RPE cells are swollen with loss of basal infoldings and apical microvilli. The photoreceptor outer segments are highly disorganized and reduced in length by at least 60% and there is abundant expression of GFAP in the radial processes of Mueller cells. Loss of photoreceptor nuclei is slowly progressive, reaching 33% at 10 months. Retinal amino acids show ornithine accumulation 15 x control. An arginine-restricted diet instituted at 2 months reduces plasma ornithine in the OAT-/- mice and preserves ERG amplitudes at 6 months. Conclusions. Our studies indicate that the OAT-/- mice are an excellent biochemical and retinal model of GA. Furthermore, they indicate that the RPE is the initial site of damage in GA and that ornithine accumulation plays an important role in the retinal pathogenesis.
|Original language||English (US)|
|Journal||Investigative Ophthalmology and Visual Science|
|State||Published - Feb 15 1996|
ASJC Scopus subject areas
- Sensory Systems
- Cellular and Molecular Neuroscience