Intraretinal variation in disease severity in the Oat^rhg mouse model of gyrate atrophy

Gyrate atrophy is an autosomal recessive retinal degeneration caused by pathogenic variants in the gene encoding ornithine aminotransferase (OAT), a mitochondrial enzyme required for ornithine degradation. Deficiency of OAT leads to hyperornithinemia and progressive chorioretinal atrophy that results in permanent vision loss. Strict dietary arginine restriction can slow the progression of the disease, but long-term adherence to the diet is challenging and not curative. Here, we characterize the retinal structure and function of the retarded hair growth (Oat^rhg) mouse model of gyrate atrophy in order to identify appropriate outcome measures for future therapeutic approaches. Optical coherence tomography (OCT), histological sections, and retinal pigment epithelium (RPE) flat mounts of 12-month-old Oat^rhg mice revealed a well-defined patch of atrophy in the superonasal and occasionally inferior retina, characterized by RPE cell mounding, migration, and hypertrophy. The remainder of the retina was indistinguishable from age-matched wild type controls, and full-field electroretinograms (ERGs) were not significantly different between Oat^rhg and wild type mice. Therefore, unlike mice harboring the perinatal-lethal null mutation in OAT (Oat^Δ) which exhibit a loss of central photoreceptor cells and decreased ERG signal starting at 4 months, the Oat^rhg mouse exhibits a milder phenotype with intraretinal variation in disease severity that is reminiscent of the regional predilection observed in patients. These structural abnormalities are not sufficient to negatively impact retina-wide function but are accessible to monitoring by multimodal retinal imaging for testing of novel treatments.