Autosomal Recessive Bestrophinopathy (ARB): A Novel Retinal Disorder Associated With Null Mutations in BEST1

Abstract

Purpose: : To describe and functionally characterize a novel autosomal recessive retinopathy associated with BEST1 mutations.

Methods: : Patients and family members underwent full retinal examinations including electrooculogram (EOG) and electroretinogram (ERG). The BEST1 gene was sequenced and some cohort members were screened for chromosomal deletions by Multiplex Ligation-dependent Probe Amplification (MLPA). The functional consequences of ARB mutations were determined by whole-cell patch-clamping of transiently transfected HEK293 cells.

Results: : Patients had a distinct retinopathy with subsequential loss of central vision, an absent or severely reduced EOG light rise and a reduced ERG. Heterozygous carriers were asymptomatic. A missense or nonsense sequence variation was found in 15/16 patient alleles and these were absent in 210 control chromosomes. No deletions were detected at the BEST1 locus by MLPA in 2 ARB patients who were homozygous for a missense mutation and 2 or more SNPs. One patient with a heterozygous change and a further 2 patients with a preliminary diagnosis of ARB in whom we could detect no sequence variations were also found to have intact loci by MLPA. Currents recorded from HEK293 cells transfected with ARB mutants had severely reduced Cl^- currents compared to the wildtype bestrophin-1 protein. Cells co-transfected with ARB and wildtype constructs had similar currents to those expressing wildtype bestrophin-1 alone, consistent with a recessive disease inheritance pattern. This is in contrast to Best disease mutations which acted in a dominant-negative manner with the wildtype protein.

Conclusions: : We conclude that ARB represents the bestrophin-1 null phenotype in humans and is the third phenotype (along with Best disease and autosomal dominant vitreoretinochoroidopathy) associated with mutations in BEST1. This new phenotype will help in the understanding of the molecular mechanisms behind these conditions.

Keywords: retinal degenerations: hereditary • retinal pigment epithelium • macula/fovea