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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number330
JournalJournal of Translational Medicine
Volume17
Issue number1
DOIs
Publication statusPublished - Oct 1 2019

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Vitelliform Macular Dystrophy
Computational Biology
Virulence
Amino Acids
Visual Acuity
Chemical activation
Chloride Channels
Molecular mechanics
Retinal Pigments
Dimerization
Penetrance
Retinal Pigment Epithelium
Macular Degeneration
Genetic Testing
Model structures
Mechanics
Computer Simulation
Membrane Proteins
Genes
Throughput

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology. / Frecer, Vladimir; Iarossi, Giancarlo; Salvetti, Anna Paola; Maltese, Paolo Enrico; Delledonne, Giulia; Oldani, Marta; Staurenghi, Giovanni; Falsini, Benedetto; Minnella, Angelo Maria; Ziccardi, Lucia; Magli, Adriano; Colombo, Leonardo; D'Esposito, Fabiana; Miertus, Jan; Viola, Francesco; Attanasio, Marcella; Maggio, Emilia; Bertelli, Matteo.

In: Journal of Translational Medicine, Vol. 17, No. 1, 330, 01.10.2019.

Research output: Contribution to journalArticle

Frecer, V, Iarossi, G, Salvetti, AP, Maltese, PE, Delledonne, G, Oldani, M, Staurenghi, G, Falsini, B, Minnella, AM, Ziccardi, L, Magli, A, Colombo, L, D'Esposito, F, Miertus, J, Viola, F, Attanasio, M, Maggio, E & Bertelli, M 2019, 'Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology', Journal of Translational Medicine, vol. 17, no. 1, 330. https://doi.org/10.1186/s12967-019-2080-3
Frecer, Vladimir ; Iarossi, Giancarlo ; Salvetti, Anna Paola ; Maltese, Paolo Enrico ; Delledonne, Giulia ; Oldani, Marta ; Staurenghi, Giovanni ; Falsini, Benedetto ; Minnella, Angelo Maria ; Ziccardi, Lucia ; Magli, Adriano ; Colombo, Leonardo ; D'Esposito, Fabiana ; Miertus, Jan ; Viola, Francesco ; Attanasio, Marcella ; Maggio, Emilia ; Bertelli, Matteo. / Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology. In: Journal of Translational Medicine. 2019 ; Vol. 17, No. 1.
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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.",
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T1 - Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology

AU - Frecer, Vladimir

AU - Iarossi, Giancarlo

AU - Salvetti, Anna Paola

AU - Maltese, Paolo Enrico

AU - Delledonne, Giulia

AU - Oldani, Marta

AU - Staurenghi, Giovanni

AU - Falsini, Benedetto

AU - Minnella, Angelo Maria

AU - Ziccardi, Lucia

AU - Magli, Adriano

AU - Colombo, Leonardo

AU - D'Esposito, Fabiana

AU - Miertus, Jan

AU - Viola, Francesco

AU - Attanasio, Marcella

AU - Maggio, Emilia

AU - Bertelli, Matteo

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

KW - Best disease

KW - Best vitelliform macular dystrophy

KW - Best-corrected visual acuity

KW - Computational structural biology

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