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J Transl Med. 2019 Oct 1;17(1):330. doi: 10.1186/s12967-019-2080-3.

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

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Department of Physical Chemistry of Drugs, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia.
Department of Ophthalmology, Bambino Gesù IRCCS Children's Hospital, Rome, Italy.
Department of Biomedical and Clinical Sciences "Luigi Sacco", Sacco Hospital, University of Milan, Milan, Italy.
MAGI'S Lab S.R.L., Via Delle Maioliche 57/D, 38068, Rovereto, TN, Italy.
Institute of Ophthalmology, Visual Electrophysiology Service, Fondazione Policlinico Gemelli/UniversitàCattolica del S. Cuore, Rome, Italy.
Neurophthalmology and Neurophysiology Unit, GB Bietti Foundation-IRCCS, Rome, Italy.
Department of Ophthalmology, Orthoptic and Pediatric Ophthalmology, University of Salerno, Salerno, Italy.
Department of Ophthalmology, San Paolo Hospital, University of Milan, Milan, Italy.
Imperial College Ophthalmic Research Unit, Western Eye Hospital, Imperial College Healthcare NHS Trust, London, UK.
Eye Clinic, Department of Neurosciences, Reproductive Sciences and Dentistry, University of Naples Federico II, Naples, Italy.
MAGI Euregio, Bolzano, Italy.
Genius n.o., Trnava, Slovakia.
Department of Ophthalmology, Fondazione IRCCS Cà Granda, Clinica Regina Elena, Milan, Italy.
IRCCS-Ospedale Sacro Cuore Don Calabria, Negrar, VR, Italy.
MAGI'S Lab S.R.L., Via Delle Maioliche 57/D, 38068, Rovereto, TN, Italy.



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. 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.


Here 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.


Thirty-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.


Using this computational approach, we designed a method for estimating BCVA progression in patients with BEST1 variants.


Best disease; Best vitelliform macular dystrophy; Best-corrected visual acuity; Computational structural biology

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