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Title: Patient-specific mutations impair BESTROPHIN1’s essential role in mediating Ca2+-dependent Cl- currents in human RPE

Abstract

Mutations in the human BEST1 gene lead to retinal degenerative diseases displaying progressive vision loss and even blindness. BESTROPHIN1, encoded by BEST1, is predominantly expressed in retinal pigment epithelium (RPE), but its physiological role has been a mystery for the last two decades. Using a patient-specific iPSC-based disease model and interdisciplinary approaches, we comprehensively analyzed two distinct BEST1 patient mutations, and discovered mechanistic correlations between patient clinical phenotypes, electrophysiology in their RPEs, and the structure and function of BESTROPHIN1 mutant channels. Our results revealed that the disease-causing mechanism of BEST1 mutations is centered on the indispensable role of BESTROPHIN1 in mediating the long speculated Ca2+-dependent Cl- current in RPE, and demonstrate that the pathological potential of BEST1 mutations can be evaluated and predicted with our iPSC-based ‘disease-in-a-dish’ approach. Moreover, we demonstrated that patient RPE is rescuable with viral gene supplementation, providing a proof-of-concept for curing BEST1-associated diseases.

Authors:
 [1];  [2];  [3];  [2];  [2];  [4];  [1]; ORCiD logo [2]
  1. Jonas Children’s Vision Care, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology and Pathology & Cell Biology, Edward S. Harkness Eye Institute, New York Presbyterian Hospital/Columbia University, New York, United States
  2. Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, United States
  3. Jonas Children’s Vision Care, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology and Pathology & Cell Biology, Edward S. Harkness Eye Institute, New York Presbyterian Hospital/Columbia University, New York, United States; Department of Ophthalmology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
  4. Molecular Imaging Center, Department of Experimental Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
UNIVERSITYFOREIGNOTHER
OSTI Identifier:
1408120
Resource Type:
Journal Article
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 6; Journal Issue: 2017; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Li, Yao, Zhang, Yu, Xu, Yu, Kittredge, Alec, Ward, Nancy, Chen, Shoudeng, Tsang, Stephen H., and Yang, Tingting. Patient-specific mutations impair BESTROPHIN1’s essential role in mediating Ca2+-dependent Cl- currents in human RPE. United States: N. p., 2017. Web. doi:10.7554/eLife.29914.
Li, Yao, Zhang, Yu, Xu, Yu, Kittredge, Alec, Ward, Nancy, Chen, Shoudeng, Tsang, Stephen H., & Yang, Tingting. Patient-specific mutations impair BESTROPHIN1’s essential role in mediating Ca2+-dependent Cl- currents in human RPE. United States. doi:10.7554/eLife.29914.
Li, Yao, Zhang, Yu, Xu, Yu, Kittredge, Alec, Ward, Nancy, Chen, Shoudeng, Tsang, Stephen H., and Yang, Tingting. Tue . "Patient-specific mutations impair BESTROPHIN1’s essential role in mediating Ca2+-dependent Cl- currents in human RPE". United States. doi:10.7554/eLife.29914.
@article{osti_1408120,
title = {Patient-specific mutations impair BESTROPHIN1’s essential role in mediating Ca2+-dependent Cl- currents in human RPE},
author = {Li, Yao and Zhang, Yu and Xu, Yu and Kittredge, Alec and Ward, Nancy and Chen, Shoudeng and Tsang, Stephen H. and Yang, Tingting},
abstractNote = {Mutations in the human BEST1 gene lead to retinal degenerative diseases displaying progressive vision loss and even blindness. BESTROPHIN1, encoded by BEST1, is predominantly expressed in retinal pigment epithelium (RPE), but its physiological role has been a mystery for the last two decades. Using a patient-specific iPSC-based disease model and interdisciplinary approaches, we comprehensively analyzed two distinct BEST1 patient mutations, and discovered mechanistic correlations between patient clinical phenotypes, electrophysiology in their RPEs, and the structure and function of BESTROPHIN1 mutant channels. Our results revealed that the disease-causing mechanism of BEST1 mutations is centered on the indispensable role of BESTROPHIN1 in mediating the long speculated Ca2+-dependent Cl- current in RPE, and demonstrate that the pathological potential of BEST1 mutations can be evaluated and predicted with our iPSC-based ‘disease-in-a-dish’ approach. Moreover, we demonstrated that patient RPE is rescuable with viral gene supplementation, providing a proof-of-concept for curing BEST1-associated diseases.},
doi = {10.7554/eLife.29914},
journal = {eLife},
issn = {2050-084X},
number = 2017,
volume = 6,
place = {United States},
year = {2017},
month = {10}
}

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