Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology
Abstract Background 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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-10-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s12967-019-2080-3 |
| _version_ | 1818260251361673216 |
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| author | Vladimir Frecer Giancarlo Iarossi Anna Paola Salvetti Paolo Enrico Maltese Giulia Delledonne Marta Oldani Giovanni Staurenghi Benedetto Falsini Angelo Maria Minnella Lucia Ziccardi Adriano Magli Leonardo Colombo Fabiana D’Esposito Jan Miertus Francesco Viola Marcella Attanasio Emilia Maggio Matteo Bertelli |
| author_facet | Vladimir Frecer Giancarlo Iarossi Anna Paola Salvetti Paolo Enrico Maltese Giulia Delledonne Marta Oldani Giovanni Staurenghi Benedetto Falsini Angelo Maria Minnella Lucia Ziccardi Adriano Magli Leonardo Colombo Fabiana D’Esposito Jan Miertus Francesco Viola Marcella Attanasio Emilia Maggio Matteo Bertelli |
| author_sort | Vladimir Frecer |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions Using this computational approach, we designed a method for estimating BCVA progression in patients with BEST1 variants. |
| first_indexed | 2024-12-12T18:28:22Z |
| format | Article |
| id | doaj.art-b9eea62ce8b64120b262c67a06437420 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-12T18:28:22Z |
| publishDate | 2019-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-b9eea62ce8b64120b262c67a064374202022-12-22T00:15:58ZengBMCJournal of Translational Medicine1479-58762019-10-0117111510.1186/s12967-019-2080-3Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biologyVladimir Frecer0Giancarlo Iarossi1Anna Paola Salvetti2Paolo Enrico Maltese3Giulia Delledonne4Marta Oldani5Giovanni Staurenghi6Benedetto Falsini7Angelo Maria Minnella8Lucia Ziccardi9Adriano Magli10Leonardo Colombo11Fabiana D’Esposito12Jan Miertus13Francesco Viola14Marcella Attanasio15Emilia Maggio16Matteo Bertelli17Department of Physical Chemistry of Drugs, Faculty of Pharmacy, Comenius University in BratislavaDepartment of Ophthalmology, Bambino Gesù IRCCS Children’s HospitalDepartment of Biomedical and Clinical Sciences “Luigi Sacco”, Sacco Hospital, University of MilanMAGI’S Lab S.R.L.Department of Biomedical and Clinical Sciences “Luigi Sacco”, Sacco Hospital, University of MilanDepartment of Biomedical and Clinical Sciences “Luigi Sacco”, Sacco Hospital, University of MilanDepartment of Biomedical and Clinical Sciences “Luigi Sacco”, Sacco Hospital, University of MilanInstitute of Ophthalmology, Visual Electrophysiology Service, Fondazione Policlinico Gemelli/UniversitàCattolica del S. CuoreInstitute of Ophthalmology, Visual Electrophysiology Service, Fondazione Policlinico Gemelli/UniversitàCattolica del S. CuoreNeurophthalmology and Neurophysiology Unit, GB Bietti Foundation-IRCCSDepartment of Ophthalmology, Orthoptic and Pediatric Ophthalmology, University of SalernoDepartment of Ophthalmology, San Paolo Hospital, University of MilanImperial College Ophthalmic Research Unit, Western Eye Hospital, Imperial College Healthcare NHS TrustGenius n.o.Department of Ophthalmology, Fondazione IRCCS Cà Granda, Clinica Regina ElenaIRCCS-Ospedale Sacro Cuore Don CalabriaIRCCS-Ospedale Sacro Cuore Don CalabriaMAGI’S Lab S.R.L.Abstract Background 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. Methods 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. Results 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. Conclusions Using this computational approach, we designed a method for estimating BCVA progression in patients with BEST1 variants.http://link.springer.com/article/10.1186/s12967-019-2080-3Best vitelliform macular dystrophyBest diseaseBest-corrected visual acuityComputational structural biology |
| spellingShingle | Vladimir Frecer Giancarlo Iarossi Anna Paola Salvetti Paolo Enrico Maltese Giulia Delledonne Marta Oldani Giovanni Staurenghi Benedetto Falsini Angelo Maria Minnella Lucia Ziccardi Adriano Magli Leonardo Colombo Fabiana D’Esposito Jan Miertus Francesco Viola Marcella Attanasio Emilia Maggio Matteo Bertelli Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology Journal of Translational Medicine Best vitelliform macular dystrophy Best disease Best-corrected visual acuity Computational structural biology |
| title | Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology |
| title_full | Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology |
| title_fullStr | Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology |
| title_full_unstemmed | Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology |
| title_short | Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology |
| title_sort | pathogenicity of new best1 variants identified in italian patients with best vitelliform macular dystrophy assessed by computational structural biology |
| topic | Best vitelliform macular dystrophy Best disease Best-corrected visual acuity Computational structural biology |
| url | http://link.springer.com/article/10.1186/s12967-019-2080-3 |
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