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BESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE.

TitleBESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE.
Publication TypeJournal Article
Year of Publication2016
AuthorsMoshfegh, Yasmin, Velez Gabriel, Li Yao, Bassuk Alexander G., Mahajan Vinit B., and Tsang Stephen H.
JournalHum Mol Genet
Volume25
Issue13
Pagination2672-2680
Date Published2016 07 01
ISSN1460-2083
KeywordsBestrophins, Calcium Signaling, Chloride Channels, Chlorides, Eye Proteins, Humans, Induced Pluripotent Stem Cells, Mutation, Retinal Pigment Epithelium, Vitelliform Macular Dystrophy
Abstract

Bestrophin1 (BEST1) is expressed in human retinal pigment epithelium (RPE) and mutations in the BEST1 gene commonly cause retinal dysfunction and macular degeneration. BEST1 is presumed to assemble into a calcium-activated chloride channel and be involved in chloride transport but there is no direct evidence in live human RPE cells to support this idea. To test whether BEST1 functions as a chloride channel in living tissue, BEST1-mutant RPE (R218H, L234P, A243T) were generated from patient-derived induced pluripotent stem cells and compared with wild-type RPE in a retinal environment, using a biosensor that visualizes calcium-induced chloride ion flux in the cell. Calcium stimulation elicited chloride ion export in normal RPE but not in RPE derived from three patients with BEST1 mutations. These data, along with three-dimensional modeling, provide evidence that BEST1 assembles into a key calcium-sensing chloride channel in human RPE.

DOI10.1093/hmg/ddw126
Alternate JournalHum. Mol. Genet.
PubMed ID27193166
PubMed Central IDPMC5181636
Grant ListR21 AG050437 / AG / NIA NIH HHS / United States
R01 EY018213 / EY / NEI NIH HHS / United States
R01 EY016822 / EY / NEI NIH HHS / United States
R01 EY024665 / EY / NEI NIH HHS / United States
K08 EY020530 / EY / NEI NIH HHS / United States
R01 EY024698 / EY / NEI NIH HHS / United States
P30 EY019007 / EY / NEI NIH HHS / United States
P30 CA013696 / CA / NCI NIH HHS / United States
T32 GM007337 / GM / NIGMS NIH HHS / United States