Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model

Carolina Uggenti, Kit Briant, Anne-Kathrin Streit, Steven Thomson, Yee Hui Koay, Richard Baines, Lisa Swanton, Forbes D Manson

Research output: Contribution to journalArticlepeer-review


Autosomal recessive bestrophinopathy (ARB) is a retinopathy caused by mutations in the bestrophin-1 protein, which is thought to function as a Ca(2+)-gated Cl(-) channel in the basolateral surface of the retinal pigment epithelium (RPE). Using a stably transfected polarised epithelial cell model, we show that four ARB mutant bestrophin-1 proteins were mislocalised and subjected to proteasomal degradation. In contrast to the wild-type bestrophin-1, each of the four 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 four ARB mutant bestrophin-1 proteins. Importantly, the Cl(-) conductance function of each of the mutant bestrophin-1 proteins was fully restored to that of wild-type 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, might represent a promising therapy for the treatment of ARB and other bestrophinopathies resulting from missense mutations in BEST1.

Original languageEnglish
Pages (from-to)1317-1328
Number of pages12
JournalDMM Disease Models and Mechanisms
Issue number11
Early online date12 Aug 2016
Publication statusPublished - 1 Nov 2016


Dive into the research topics of 'Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model'. Together they form a unique fingerprint.

Cite this