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.