Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology

Giulia Delledonne,Matteo Bertelli,Giovanni Staurenghi,Benedetto Falsini,Giancarlo Iarossi,Marta Oldani,Fabiana D’Esposito,Emilia Maggio,Anna Paola Salvetti,Paolo Enrico Maltese,Lucia Ziccardi,Angelo Maria Minnella,Leonardo Colombo,Adriano Magli,Francesco Viola,Marcella Attanasio,Jan Miertus,Vladimir Frecer

doi:10.1186/s12967-019-2080-3

Abstract

BackgroundBest vitelliform macular dystrophy (BVMD) is an autosomal dominant macular degeneration. The typical central yellowish yolk-like lesion usually appears in childhood and gradually worsens. Most cases are caused by variants in the BEST1 gene which encodes bestrophin-1, an integral membrane protein found primarily in the retinal pigment epithelium.MethodsHere we describe the spectrum of BEST1 variants identified in a cohort of 57 Italian patients analyzed by Sanger sequencing. In 13 cases, the study also included segregation analysis in affected and unaffected relatives. We used molecular mechanics to calculate two quantitative parameters related to calcium-activated chloride channel (CaCC composed of 5 BEST1 subunits) stability and calcium-dependent activation and related them to the potential pathogenicity of individual missense variants detected in the probands.ResultsThirty-six out of 57 probands (63% positivity) and 16 out of 18 relatives proved positive to genetic testing. Family study confirmed the variable penetrance and expressivity of the disease. Six of the 27 genetic variants discovered were novel: p.(Val9Gly), p.(Ser108Arg), p.(Asn179Asp), p.(Trp182Arg), p.(Glu292Gln) and p.(Asn296Lys). All BEST1 variants were assessed in silico for potential pathogenicity. Our computational structural biology approach based on 3D model structure of the CaCC showed that individual amino acid replacements may affect channel shape, stability, activation, gating, selectivity and throughput, and possibly also other features, depending on where the individual mutated amino acid residues are located in the tertiary structure of BEST1. Statistically significant correlations between mean logMAR best-corrected visual acuity (BCVA), age and modulus of computed BEST1 dimerization energies, which reflect variations in the in CaCC stability due to amino acid changes, permitted us to assess the pathogenicity of individual BEST1 variants.ConclusionsUsing this computational approach, we designed a method for estimating BCVA progression in patients with BEST1 variants.

Highlights

Best vitelliform macular dystrophy (BVMD) is an autosomal dominant macular degeneration
Genetic testing revealed 26 different variants in 36 patients who tested positive (63% positivity); 20 variants are already known to be associated with Best disease, and six were novel and associated with BVMD for the first time (Table 1)
We describe the clinical features of probands carrying the other five new variants in Additional files 1, 2

Summary

Introduction

Best vitelliform macular dystrophy (BVMD) is an autosomal dominant macular degeneration. The typical central yellowish yolk-like lesion usually appears in childhood and gradually worsens. Best vitelliform macular dystrophy (BVMD) (OMIM #153700), known as Best’s disease, is an autosomal dominant slowly progressive form of retinal macular degeneration. The typical central yellowish yolk-like lesion due to accumulation of lipofuscin in the retinal pigment epithelium (RPE) usually appears in childhood. The lesion gradually worsens [1] causing progressive macular atrophy or fibrosis and subsequent loss of visual acuity [2]. Five stages of the disease have been described: in the first or pre-vitelliform stage, usually discovered incidentally, subtle RPE alterations of the macula cause no symptoms. Macular fibrosis develops in stage 5 [3]

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