Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells
Copyright policy )Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells
Significance First insight into the molecular identity of volume-regulated anion channel (VRAC) emerged only recently by demonstrating a role for leucine-rich repeats containing 8A (LRRC8A) in channel activity. Our results now expand on VRAC biology, suggesting a model where VRAC subunit composition is cell type- or tissue-specific rather than a single ubiquitous channel formed solely by LRRC8A. Here, we show that bestrophin 1 (BEST1), but not LRCC8A, is crucial in cell volume regulation in retinal pigment epithelium (RPE) cells differentiated from human-induced pluripotent stem cells (hiPSCs). VRAC-mediated currents were strongly reduced in hiPSC-RPE from macular dystrophy patients with pathologic BEST1 mutations. Our model is further supported by in vivo effects of Best1 deficiency in the mouse that manifest as severe subfertility phenotype due to enhanced abnormal sperm morphology related to impaired volume regulation.
- Max Planck Society Germany
- University of Regensburg Germany
- Institut für Humangenetik Germany
- University of Freiburg Germany
- LMU Klinikum Germany
Male, Patch-Clamp Techniques, Molecular Sequence Data, Fluorescent Antibody Technique, Membrane Proteins, Retinal Pigment Epithelium, Models, Biological, Spermatozoa, Ion Channels, Mice, Chloride Channels, Gene Knockdown Techniques, Oocytes, Animals, Humans, Female, Amino Acid Sequence, Bestrophins, Eye Proteins, Cell Size
Male, Patch-Clamp Techniques, Molecular Sequence Data, Fluorescent Antibody Technique, Membrane Proteins, Retinal Pigment Epithelium, Models, Biological, Spermatozoa, Ion Channels, Mice, Chloride Channels, Gene Knockdown Techniques, Oocytes, Animals, Humans, Female, Amino Acid Sequence, Bestrophins, Eye Proteins, Cell Size
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