Autosomal recessive bestrophinopathy (ARB) is a retinopathy caused by mutations in the bestrophin-1 protein which is thought to function as a Ca2+-gated Cl− channel in the basolateral surface of the retinal pigment epithelium (RPE). Using a stably-transfected polarised epithelial cell model, we show that 4 ARB mutant bestrophin-1 proteins were mislocalised and subjected to proteasomal degradation. In contrast to the wildtype bestrophin-1, each of the 4 mutant proteins also failed to conduct Cl− ions in transiently transfected cells as determined by whole-cell patch-clamp.
We demonstrate that a combination of two clinically approved drugs, bortezomib and 4-phenylbutyrate (4PBA), successfully restored the expression and localisation of all 4 ARB mutant bestrophin-1 proteins. Importantly, the Cl− conductance function of each of the mutant bestrophin-1 proteins was fully restored to that of wildtype bestrophin-1 by treatment of cells with 4PBA alone.
The functional rescue achieved with 4PBA is significant because it suggests that this drug, which is already approved for long-term use in infants and adults, may represent a promising therapy for the treatment of ARB and other bestrophinopathies resulting from missense mutations in BEST1.
- Received November 27, 2015.
- Accepted July 21, 2016.
- © 2016. Published by The Company of Biologists Ltd
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