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

Yasmin Moshfegh; Gabriel Velez; Yao Li; Alexander G Bassuk; Vinit B Mahajan; Stephen H Tsang

doi:10.1093/hmg/ddw126

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

Journal article

Open access

Peer reviewed

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

Yasmin Moshfegh, Gabriel Velez, Yao Li, Alexander G Bassuk, Vinit B Mahajan and Stephen H Tsang

Human molecular genetics, Vol.25(13), pp.2672-2680

07/01/2016

DOI: 10.1093/hmg/ddw126

PMCID: PMC5181636

PMID: 27193166

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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.

Chloride Channels - metabolism

Retinal Pigment Epithelium - metabolism

Bestrophins

Eye Proteins - metabolism

Vitelliform Macular Dystrophy - genetics

Chlorides

Humans

Chloride Channels - genetics

Eye Proteins - genetics

Mutation

Calcium Signaling

Induced Pluripotent Stem Cells - metabolism

Details

Title: Subtitle: BESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE
Creators: Yasmin Moshfegh - Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY 10032, USA
Gabriel Velez - Medical Scientist Training Program
Yao Li - Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY 10032, USA
Alexander G Bassuk - Department of Pediatrics, University of Iowa, Iowa City, IA, USA
Vinit B Mahajan - Medical Scientist Training Program
Stephen H Tsang - Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY 10032, USA
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.25(13), pp.2672-2680
Publisher: England
DOI: 10.1093/hmg/ddw126
PMID: 27193166
PMCID: PMC5181636
ISSN: 0964-6906
eISSN: 1460-2083
Grant note: R01 EY018213 / NEI NIH HHS R01 EY016822 / NEI NIH HHS P30 CA013696 / NCI NIH HHS R01 EY024698 / NEI NIH HHS T32 GM007337 / NIGMS NIH HHS K08 EY020530 / NEI NIH HHS R01 EY024665 / NEI NIH HHS R21 AG050437 / NIA NIH HHS P30 EY019007 / NEI NIH HHS
Language: English
Date published: 07/01/2016
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
Record Identifier: 9984020503902771

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