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Genetic mutation of the human  BEST1  gene, which encodes a Ca 2+ -activated Cl -  channel (BEST1) predominantly expressed in retinal pigment epithelium (RPE), causes a spectrum of retinal degenerative disorders commonly known as bestrophinopathies. Previously, we showed that BEST1 plays an indispensable role in generating Ca 2+ -dependent Cl -  currents in human RPE cells, and the deficiency of BEST1 function in patient-derived RPE is rescuable by gene augmentation (Li et al., 2017). Here, we report that  BEST1  patient-derived loss-of-function and gain-of-function mutations require different mutant to wild-type (WT) molecule ratios for phenotypic manifestation, underlying their distinct epigenetic requirements in bestrophinopathy development, and suggesting that some of the previously classified autosomal dominant mutations actually behave in a dominant-negative manner. Importantly, the strong dominant effect of  BEST1  gain-of-function mutations prohibits the restoration of BEST1-dependent Cl -  currents in RPE cells by gene augmentation, in contrast to the efficient rescue of loss-of-function mutations via the same approach. Moreover, we demonstrate that gain-of-function mutations are rescuable by a combination of gene augmentation with CRISPR/Cas9-mediated knockdown of endogenous  BEST1  expression, providing a universal treatment strategy for all bestrophinopathy patients regardless of their mutation types.

Distinct expression requirements and rescue strategies for BEST1 loss- and gain-of-function mutations