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Article

Mutation-Dependent Pathomechanisms Determine the Phenotype in the Bestrophinopathies

1
Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
2
Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Regensburg, Franz-Josef-Strauß-Allee 11, 93042 Regensburg, Germany
3
Lehrstuhl für Genetische Epidemiologie, Universität Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
4
Universitätsklinikum Ulm, Augenklinik, Prittwitzstraße 43, 89075 Ulm, Germany
5
Medical Practice Stadttheater, Bertoldstr. 45, 79098 Freiburg im Breisgau, Germany
6
Universitäts-Augenklinik Bonn, Ernst-Abbe-Str. 2, 53127 Bonn, Germany
7
Zentrum für seltene Netzhauterkrankungen, AugenZentrum Siegburg, MVZ Augenärztliches Diagnostik- und Therapiecentrum Siegburg GmbH, Europaplatz 3, 53721 Siegburg, Germany
8
RetinaScience, 53113 Bonn, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(5), 1597; https://doi.org/10.3390/ijms21051597
Received: 30 December 2019 / Revised: 21 February 2020 / Accepted: 24 February 2020 / Published: 26 February 2020
(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches)
Best 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. View Full-Text
Keywords: bestrophin-1; BEST1; induced pluripotent stem cell; retinal pigment epithelium; ER-associated degradation; endo-lysosomal degradation pathway; pathomechanism; Best vitelliform macular dystrophy; Best disease; autosomal recessive bestrophinopathy; autosomal dominant vitreoretinochoroidopathy bestrophin-1; BEST1; induced pluripotent stem cell; retinal pigment epithelium; ER-associated degradation; endo-lysosomal degradation pathway; pathomechanism; Best vitelliform macular dystrophy; Best disease; autosomal recessive bestrophinopathy; autosomal dominant vitreoretinochoroidopathy
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MDPI and ACS Style

Nachtigal, A.-L.; Milenkovic, A.; Brandl, C.; Schulz, H.L.; Duerr, L.M.J.; Lang, G.E.; Reiff, C.; Herrmann, P.; Kellner, U.; Weber, B.H.F. Mutation-Dependent Pathomechanisms Determine the Phenotype in the Bestrophinopathies. Int. J. Mol. Sci. 2020, 21, 1597. https://doi.org/10.3390/ijms21051597

AMA Style

Nachtigal A-L, Milenkovic A, Brandl C, Schulz HL, Duerr LMJ, Lang GE, Reiff C, Herrmann P, Kellner U, Weber BHF. Mutation-Dependent Pathomechanisms Determine the Phenotype in the Bestrophinopathies. International Journal of Molecular Sciences. 2020; 21(5):1597. https://doi.org/10.3390/ijms21051597

Chicago/Turabian Style

Nachtigal, Anna-Lena, Andrea Milenkovic, Caroline Brandl, Heidi L. Schulz, Lisa M.J. Duerr, Gabriele E. Lang, Charlotte Reiff, Philipp Herrmann, Ulrich Kellner, and Bernhard H.F. Weber. 2020. "Mutation-Dependent Pathomechanisms Determine the Phenotype in the Bestrophinopathies" International Journal of Molecular Sciences 21, no. 5: 1597. https://doi.org/10.3390/ijms21051597

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