Detailed analysis of family with autosomal recessive bestrophinopathy associated with new BEST1 mutation.

Daiki Kubota,Shuhei Kameya,Kiyoko Gocho,Hiroshi Takahashi,Kunihiko Yamaki,Sachiko Kikuchi,Atsushi Mizota,Celso Soiti Matsumoto,Kei Shinoda,Keiichiro Akeo,Michitaka Sugahara

doi:10.1007/s10633-016-9540-3

Abstract

PurposeTo describe the clinical and genetic findings in a patient with autosomal recessive bestrophinopathy (ARB) and his healthy parents.MethodsThe patient and his healthy non-consanguineous parents underwent detailed ophthalmic evaluations including electro-oculography (EOG), spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. Mutation analysis of the BEST1 gene was performed by Sanger sequencing.ResultsThe FAF images showed multiple spots of increased autofluorescence, and the sites of these spots corresponded to the yellowish deposits detected by ophthalmoscopy. SD-OCT showed cystoid macular changes and a shallow serous macular detachment. The Arden ratio of the EOG was markedly reduced to 1.1 in both eyes. Genetic analysis of the proband detected two sequence variants of the BEST1 gene in the heterozygous state: a novel variant c.717delG, p.V239VfsX2 and an already described c.763C>T, p.R255W variant associated with Best vitelliform macular dystrophy and ARB. The proband’s father carried the c.717delG, p.V239VfsX2 variant in the heterozygous state, and the mother carried the c.763C>T, p.R255W variant in the heterozygous state. The parents who were heterozygous for the BEST1 variants had normal visual acuity, EOG, SD-OCT, and FAF images.ConclusionsIn a truncating BEST1 mutation, the phenotype associated with ARB is most likely due to a marked decrease in the expression of BEST1 promoted by the nonsense-mediated decay surveillance mechanism, and it may depend on the position of the premature termination of the codon created.

Highlights

Genetic analysis of the proband detected two sequence variants of the BEST1 gene in the heterozygous state: a novel variant c.717delG, p.V239VfsX2 and an already described c.763C[T, p.R255W variant associated with Best vitelliform macular dystrophy and autosomal recessive bestrophinopathy (ARB)
The parents who were heterozygous for the BEST1 variants had normal visual acuity, EOG, SDOCT, and fundus autofluorescence (FAF) images
In a truncating BEST1 mutation, the phenotype associated with ARB is most likely due to a marked decrease in the expression of BEST1 promoted by the nonsense-mediated decay surveillance mechanism, and it may depend on the position of the premature termination of the codon created

Summary

Introduction

BEST1 (VMD2) is a gene located on chromosome 11 (11q12.3) that encodes for the 585 amino acid transmembrane protein bestrophin 1 which is located on the basolateral aspect of retinal pigment epithelial (RPE) cells [1, 2]. Mutations in BEST1 affect the RPE metabolism and the outer retinal function with which the RPE is intimately associated. Mutations of the BEST1 gene have been associated with different ocular phenotypes [6]. BEST1 mutations are associated with several other eye diseases including adult-onset vitelliform macular dystrophy (AOVMD) [7], autosomal dominant vitreo-retinochoroidopathy (ADVIRC) [8], retinitis pigmentosa [9], and the microcornea, retinal dystrophy, cataract, and posterior staphyloma (MRCS) syndrome [10]

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