iPS cell modeling of best disease: Insights into the pathophysiology of an inherited macular degeneration

Ruchira Singh, Wei Shen, David Kuai, Jessica M. Martin, Xiangrong Guo, Molly A. Smith, Enio T. Perez, M. Joseph Phillips, Joseph M. Simonett, Kyle A. Wallace, Amelia D. Verhoeven, Elizabeth E. Capowski, Xiaoqing Zhang, Yingnan Yin, Patrick J. Halbach, Gerald A. Fishman, Lynda S. Wright, Bikash R. Pattnaik, David M. Gamm

Research output: Contribution to journalArticlepeer-review

180 Scopus citations


Best disease (BD) is an inherited degenerative disease of the human macula that results in progressive and irreversible central vision loss. It is caused by mutations in the retinal pigment epithelium (RPE) gene BESTROPHIN1 (BEST1), which, through mechanism(s) that remain unclear, lead to the accumulation of subretinal fluid and autofluorescent waste products from shed photoreceptor outer segments (POSs). We employed human iPS cell (hiPSC) technology to generate RPE from BD patients and unaffected siblings in order to examine the cellular and molecular processes underlying this disease. Consistent with the clinical phenotype of BD, RPE from mutant hiPSCs displayed disrupted fluid flux and increased accrual of autofluorescent material after long-term POS feeding when compared with hiPSC-RPE from unaffected siblings. On a molecular level, RHODOPSIN degradation after POS feeding was delayed in BD hiPSC-RPE relative to unaffected sibling hiPSC-RPE, directly implicating impaired POS handling in the pathophysiology of the disease. In addition, stimulated calcium responses differed between BD and normal sibling hiPSC-RPE, as did oxidative stress levels after chronic POS feeding. Subcellular localization, fractionation and co-immunoprecipitation experiments in hiPSC-RPE and human prenatal RPE further linked BEST1 to the regulation and release of endoplasmic reticulum calcium stores. Since calcium signaling and oxidative stress are critical regulators of fluid flow and protein degradation, these findings likely contribute to the clinical picture of BD. In a larger context, this report demonstrates the potential to use patient-specific hiPSCs to model and study maculopathies, an important class of blinding disorders in humans.

Original languageEnglish (US)
Article numberdds469
Pages (from-to)593-607
Number of pages15
JournalHuman molecular genetics
Issue number3
StatePublished - Feb 2013
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the Macula Vision Research Foundation, the Foundation Fighting Blindness Wynn-Gund Translational Research Award, NIH R01 EY021218, NIH P30 HD03352, the Lincy Foundation, and the Retina Research Foundation.


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