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 study rcbtb1 (loss of) function in vivo using a stable Xenopus knockout
model. In specific, we will assess the consequences of rcbtb1 knockout on tissue morphology and
function, perform rescue experiments with wild type and mutant rcbtb1 cDNA, and study the
function of rcbtb1 in the Nrf2 pathway in vivo. 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.