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Mutations in the human  BEST1  gene lead to retinal degenerative diseases displaying progressive vision loss and even blindness. BESTROPHIN1, encoded by  BEST1 , is predominantly expressed in retinal pigment epithelium (RPE), but its physiological role has been a mystery for the last two decades. Using a patient-specific iPSC-based disease model and interdisciplinary approaches, we comprehensively analyzed two distinct  BEST1  patient mutations, and discovered mechanistic correlations between patient clinical phenotypes, electrophysiology in their RPEs, and the structure and function of BESTROPHIN1 mutant channels. Our results revealed that the disease-causing mechanism of  BEST1  mutations is centered on the indispensable role of BESTROPHIN1 in mediating the long speculated Ca 2+ -dependent Cl -  current in RPE, and demonstrate that the pathological potential of  BEST1  mutations can be evaluated and predicted with our iPSC-based ‘disease-in-a-dish’ approach. Moreover, we demonstrated that patient RPE is rescuable with viral gene supplementation, providing a proof-of-concept for curing  BEST1 -associated diseases.

Patient-specific mutations impair BESTROPHIN1’s essential role in mediating Ca 2+ -dependent Cl - currents in human RPE