• Anna-Lena Nachtigal, Andrea Milenkovic, Caroline Brandl, Heidi L Schulz, Lisa M J Duerr, Gabriele E Lang, Charlotte Reiff, Philipp Herrmann, Ulrich Kellner, and Weber Bernhard H F BHF 0000-0002-8808-7723 Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germa.
• Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
• Int J Mol Sci. 2020 Feb 26; 21 (5).

AbstractBest vitelliform macular dystrophy (BD), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and the autosomal recessive bestrophinopathy (ARB), together known as the bestrophinopathies, are caused by mutations in the bestrophin-1 (BEST1) gene affecting anion transport through the plasma membrane of the retinal pigment epithelium (RPE). To date, while no treatment exists a better understanding of BEST1-related pathogenesis may help to define therapeutic targets. Here, we systematically characterize functional consequences of mutant BEST1 in thirteen RPE patient cell lines differentiated from human induced pluripotent stem cells (hiPSCs). Both BD and ARB hiPSC-RPEs display a strong reduction of BEST1-mediated anion transport function compared to control, while ADVIRC mutations trigger an increased anion permeability suggesting a stabilized open state condition of channel gating. Furthermore, BD and ARB hiPSC-RPEs differ by the degree of mutant protein turnover and by the site of subcellular protein quality control with adverse effects on lysosomal pH only in the BD-related cell lines. The latter finding is consistent with an altered processing of catalytic enzymes in the lysosomes. The present study provides a deeper insight into distinct molecular mechanisms of the three bestrophinopathies facilitating functional categorization of the more than 300 known BEST1 mutations that result into the distinct retinal phenotypes.

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