Nachtigal, Anna-Lena and Milenkovic, Andrea and Brandl, Caroline and Schulz, Heidi L. and Duerr, Lisa M. J. and Lang, Gabriele E. and Reiff, Charlotte and Herrmann, Philipp and Kellner, Ulrich and Weber, Bernhard H. F. (2020) Mutation-Dependent Pathomechanisms Determine the Phenotype in the Bestrophinopathies. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 21 (5): 1597. ISSN , 1422-0067
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RETINAL-PIGMENT EPITHELIUM; PLURIPOTENT STEM-CELLS; BEST-DISEASE; MISSENSE MUTATIONS; ACIDIC PH; RPE CELLS; GENE; DEGRADATION; PROTEIN; VMD2; 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 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Augenheilkunde Medicine > Lehrstuhl für Humangenetik Medicine > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Mar 2021 10:37 |
| Last Modified: | 29 Mar 2021 10:37 |
| URI: | https://pred.uni-regensburg.de/id/eprint/45004 |
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