Elucidation of a link between RCBTB1-associated inherited retinal dystrophy and ubiquitination by in vitro and in vivo studies

Mendelian eye disorders such as inherited retinal dystrophies (iRDs) are a major cause of blindness worldwide. Last year, our team identified RCBTB1 as a novel gene for autosomal recessive iRD, with extra-ocular manifestations in a few patients. RCBTB1 was recently suggested to be involved in ubiquitination, however, little is known about its function in this pathway.
Based on preliminary data, we hypothesize that biallelic RCBTB1 mutations affect retinal morphology and lead to impaired ubiquitination and NRF2 oxidative stress response. To address this, we will first study the role of RCBTB1 in the NRF2 pathway in human cellular models. Next, the resulting findings will be elaborated in vivo in an rcbtb1 knockout model in Xenopus, starting from an rcbtb1 mosaic knockout model created during the first year of my PhD fellowship. This model will provide new insights in disease pathogenesis and in potential targets for treatment.
Overall, this study will elucidate, for the first time, the pathogenetic mechanisms of RCBTB1-associated iRD, and will provide insights into the role of RCBTB1 in the ubiquitination and NRF2 pathway in the retina, which might be amenable to therapy.