Abstract
Autosomal recessive bestrophinopathy (ARB) has been reported as clinically heterogeneous. Eighteen patients (mean age: 22.5 years; 15 unrelated families) underwent ophthalmological examination, fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Molecular genetic testing of the BEST1 gene was conducted by the chain-terminating dideoxynucleotide Sanger methodology. Onset of symptoms (3 to 50 years of age) and best-corrected visual acuity (0.02–1.0) were highly variable. Ophthalmoscopic and retinal imaging defined five phenotypes. Phenotype I presented with single or confluent yellow lesions at the posterior pole and midperiphery, serous retinal detachment, and intraretinal cystoid spaces. In phenotype II fleck-like lesions were smaller and extended to the far periphery. Phenotype III showed a widespread continuous lesion with sharp peripheral demarcation. Single (phenotype IV) or multifocal (phenotype V) vitelliform macular dystrophy-like lesions were observed as well. Phenotypes varied within families and in two eyes of one patient. In addition, OCT detected hyperreflective foci (13/36 eyes) and choroidal excavation (11/36). Biallelic mutations were identified in each patient, six of which have not been reported so far [c.454C>T/p.(Pro152Ser), c.620T>A/p.(Leu207His), c.287_298del/p.(Gln96_Asn99del), c.199_200del/p.(Leu67Valfs*164), c.524del/p.(Ser175Thrfs*19), c.590_615del/p.(Leu197Profs*26)]. BEST1-associated ARB presents with a variable age of onset and clinical findings, that can be categorized in 5 clinical phenotypes. Hyperreflective foci and choroidal excavation frequently develop as secondary manifestations.
Highlights
Mutations in the Bestrophin 1 (BEST1, NM_004183.4) gene cause a variety of retinal dystrophies with distinct clinical features including autosomal dominant Best vitelliform macular dystrophy (BVMD, MIM 153700) [1], autosomal dominant vitreo-retinochoroidopathy (ADVIRC, MIM 193220) [2], autosomal dominant MRCS syndrome [3], autosomal dominant retinitis pigmentosa (MIM 613194) [4] and autosomal recessive bestrophinopathy (ARB, MIM 611809)
The BEST1 gene encodes bestrophin-1, a 585 amino acid transmembrane protein located in the basolateral membrane of the retinal pigment epithelium (RPE) [1,7], where it functions as a calcium-activated, volume regulated anion channel [8,9]
A better understanding of the molecular pathology of BEST1-related phenotypes was achieved by demonstrating that BEST1 gene defects in BVMD and Autosomal recessive bestrophinopathy (ARB) trigger a strong reduction of BEST1-mediated anion transport function compared to control, while ADVIRC mutations cause an increased anion permeability suggesting a stabilized open state condition of channel gating
Summary
Mutations in the Bestrophin 1 (BEST1, NM_004183.4) gene cause a variety of retinal dystrophies with distinct clinical features including autosomal dominant Best vitelliform macular dystrophy (BVMD, MIM 153700) [1], autosomal dominant vitreo-retinochoroidopathy (ADVIRC, MIM 193220) [2], autosomal dominant MRCS syndrome (microcornea, retinal dystrophy, cataract, posterior staphyloma, MIM 193220) [3], autosomal dominant retinitis pigmentosa (MIM 613194) [4] and autosomal recessive bestrophinopathy (ARB, MIM 611809). The latter is caused by biallelic homozygous or compound heterozygous mutations in the BEST1 gene [5] and was termed ARB by Burgess et al [6]. BVMD and ARB differ by the degree of mutant protein turnover and by the site of subcellular protein quality control with adverse effects on lysosomal pH only in BVMD [12,13] To this end, ARB-associated missense mutations result in the formation of greatly unstable mutant protein subunits that are recognized by the endoplasmic reticulum control machinery and thereby are prone for rapid degradation via the proteasome [12]
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