TY - JOUR
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
Y1 - 2019
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
KW - Best disease
KW - Best vitelliform macular dystrophy
KW - Best-corrected visual acuity
KW - Computational structural biology
UR - http://hdl.handle.net/10807/150921
U2 - 10.1186/s12967-019-2080-3
DO - 10.1186/s12967-019-2080-3
M3 - Article
SN - 1479-5876
VL - 17
SP - 330
EP - 344
JO - Journal of Translational Medicine
JF - Journal of Translational Medicine
ER -