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 A Baines, Eileithyia 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 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 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
JournalDisease Models and Mechanisms
Issue number11
Early online date2 Nov 2016
Publication statusE-pub ahead of print - 2 Nov 2016


  • Animals
  • Bestrophins/genetics
  • Biotinylation
  • Cell Polarity/drug effects
  • Dogs
  • Endoplasmic Reticulum/drug effects
  • Epithelial Cells/drug effects
  • Eye Diseases, Hereditary/genetics
  • HEK293 Cells
  • Humans
  • Madin Darby Canine Kidney Cells
  • Models, Biological
  • Mutant Proteins/metabolism
  • Mutation/genetics
  • Patch-Clamp Techniques
  • Phenylbutyrates/pharmacology
  • Protein Transport/drug effects
  • Retinal Diseases/genetics
  • Small Molecule Libraries/pharmacology
  • Transfection


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