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Journal Article

Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells


Schrewe,  Heinrich
Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Milenkovic, A., Brandl, C., Milenkovic, V. M., Jendryke, T., Sirianant, L., Wanitchakool, P., et al. (2015). Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells. Proceedings of the National Academy of Sciences of the United States of America, 112(20), E2630-E2639. doi:10.1073/pnas.1418840112.

Cite as: http://hdl.handle.net/11858/00-001M-0000-0028-92F9-3
In response to cell swelling, volume-regulated anion channels (VRACs) participate in a process known as regulatory volume decrease (RVD). Only recently, first insight into the molecular identity of mammalian VRACs was obtained by the discovery of the leucine-rich repeats containing 8A (LRRC8A) gene. Here, we show that bestrophin 1 (BEST1) but not LRRC8A is crucial for volume regulation in human retinal pigment epithelium (RPE) cells. Whole-cell patch-clamp recordings in RPE derived from human-induced pluripotent stem cells (hiPSC) exhibit an outwardly rectifying chloride current with characteristic functional properties of VRACs. This current is severely reduced in hiPSC-RPE cells derived from macular dystrophy patients with pathologic BEST1 mutations. Disruption of the orthologous mouse gene (Best1−/−) does not result in obvious retinal pathology but leads to a severe subfertility phenotype in agreement with minor endogenous expression of Best1 in murine RPE but highly abundant expression in mouse testis. Sperm from Best1−/− mice showed reduced motility and abnormal sperm morphology, indicating an inability in RVD. Together, our data suggest that the molecular identity of VRACs is more complex—that is, instead of a single ubiquitous channel, VRACs could be formed by cell type- or tissue-specific subunit composition. Our findings provide the basis to further examine VRAC diversity in normal and diseased cell physiology, which is key to exploring novel therapeutic approaches in VRAC-associated pathologies.