Finnish gyrate atrophy mutation OAT;c.1205C>T leads to accumulation of intracellular GABA

Abstract

Hyperornithinaemia with gyrate atrophy of choroid and retina (HOGA) is a recessive metabolic disease caused by dysfunction of the ornithine aminotransferase (OAT) gene, leading to ornithine accumulation and a complex metabolic imbalance. This causes retinal degeneration that ultimately evolve to blindness. However, the mechanisms of this degeneration remain unknown. Here, we have conducted untargeted metabolomic analysis in patient-derived induced pluripotent stem cells and their isogenic counterparts. Mutant cells show altered levels of ornithine-related metabolites, including low creatine, proline and glutamate, and elevated arginine and citrulline. The untargeted metabolomics approach revealed changes in the urea cycle and polyamine synthesis pathways with a significant intracellular accumulation of gamma-aminobutyric acid (GABA). Hence, we propose GABA as a key player in the disease pathogenicity, potentially affecting neuronal function in the eye.