Mislocalisation of BEST1 in IPSC-derived Retinal Pigment Epithelial Cells from a Family with Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC)

Overview

Journal Sci Rep

Specialty Science

Date 2016 Sep 23

PMID 27653836

Citations 17

Authors

David A Carter

Matthew J K Smart

William V G Letton

Conor M Ramsden

Britta Nommiste

Li Li Chen

Kate Fynes

Manickam N Muthiah

Pollyanna Goh

Amelia Lane

Michael B Powner

Andrew R Webster

Lyndon da Cruz

Anthony T Moore

Peter J Coffey

Amanda-Jayne F Carr

Affiliations

Soon will be listed here.

Abstract

Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a rare, early-onset retinal dystrophy characterised by distinct bands of circumferential pigmentary degeneration in the peripheral retina and developmental eye defects. ADVIRC is caused by mutations in the Bestrophin1 (BEST1) gene, which encodes a transmembrane protein thought to function as an ion channel in the basolateral membrane of retinal pigment epithelial (RPE) cells. Previous studies suggest that the distinct ADVIRC phenotype results from alternative splicing of BEST1 pre-mRNA. Here, we have used induced pluripotent stem cell (iPSC) technology to investigate the effects of an ADVIRC associated BEST1 mutation (c.704T > C, p.V235A) in patient-derived iPSC-RPE. We found no evidence of alternate splicing of the BEST1 transcript in ADVIRC iPSC-RPE, however in patient-derived iPSC-RPE, BEST1 was expressed at the basolateral membrane and the apical membrane. During human eye development we show that BEST1 is expressed more abundantly in peripheral RPE compared to central RPE and is also expressed in cells of the developing retina. These results suggest that higher levels of mislocalised BEST1 expression in the periphery, from an early developmental stage, could provide a mechanism that leads to the distinct clinical phenotype observed in ADVIRC patients.

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