Cargando…

Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation

Best Vitelliform Macular dystrophy (BVMD) is the most prevalent of the distinctive retinal dystrophies caused by mutations in the BEST1 gene. This gene, which encodes for a homopentameric calcium-activated ion channel, is crucial for the homeostasis and function of the retinal pigment epithelia (RPE...

Descripción completa

Detalles Bibliográficos
Autores principales: Navinés-Ferrer, Arnau, Ruiz-Nogales, Sheila, Navarro, Rafael, Pomares, Esther
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266689/
https://www.ncbi.nlm.nih.gov/pubmed/35806438
http://dx.doi.org/10.3390/ijms23137432
_version_ 1784743529809969152
author Navinés-Ferrer, Arnau
Ruiz-Nogales, Sheila
Navarro, Rafael
Pomares, Esther
author_facet Navinés-Ferrer, Arnau
Ruiz-Nogales, Sheila
Navarro, Rafael
Pomares, Esther
author_sort Navinés-Ferrer, Arnau
collection PubMed
description Best Vitelliform Macular dystrophy (BVMD) is the most prevalent of the distinctive retinal dystrophies caused by mutations in the BEST1 gene. This gene, which encodes for a homopentameric calcium-activated ion channel, is crucial for the homeostasis and function of the retinal pigment epithelia (RPE), the cell type responsible for recycling the visual pigments generated by photoreceptor cells. In BVMD patients, mutations in this gene induce functional problems in the RPE cell layer with an accumulation of lipofucsin that evolves into cell death and loss of sight. In this work, we employ iPSC-RPE cells derived from a patient with the p.Pro77Ser dominant mutation to determine the correlation between this variant and the ocular phenotype. To this purpose, gene and protein expression and localization are evaluated in iPSC-RPE cells along with functional assays like phagocytosis and anion channel activity. Our cell model shows no differences in gene expression, protein expression/localization, or phagocytosis capacity, but presents an increased chloride entrance, indicating that the p.Pro77Ser variant might be a gain-of-function mutation. We hypothesize that this variant disturbs the neck region of the BEST1 channel, affecting channel function but maintaining cell homeostasis in the short term. This data shed new light on the different phenotypes of dominant mutations in BEST1, and emphasize the importance of understanding its molecular mechanisms. Furthermore, the data widen the knowledge of this pathology and open the door for a better diagnosis and prognosis of the disease.
format Online
Article
Text
id pubmed-9266689
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-92666892022-07-09 Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation Navinés-Ferrer, Arnau Ruiz-Nogales, Sheila Navarro, Rafael Pomares, Esther Int J Mol Sci Article Best Vitelliform Macular dystrophy (BVMD) is the most prevalent of the distinctive retinal dystrophies caused by mutations in the BEST1 gene. This gene, which encodes for a homopentameric calcium-activated ion channel, is crucial for the homeostasis and function of the retinal pigment epithelia (RPE), the cell type responsible for recycling the visual pigments generated by photoreceptor cells. In BVMD patients, mutations in this gene induce functional problems in the RPE cell layer with an accumulation of lipofucsin that evolves into cell death and loss of sight. In this work, we employ iPSC-RPE cells derived from a patient with the p.Pro77Ser dominant mutation to determine the correlation between this variant and the ocular phenotype. To this purpose, gene and protein expression and localization are evaluated in iPSC-RPE cells along with functional assays like phagocytosis and anion channel activity. Our cell model shows no differences in gene expression, protein expression/localization, or phagocytosis capacity, but presents an increased chloride entrance, indicating that the p.Pro77Ser variant might be a gain-of-function mutation. We hypothesize that this variant disturbs the neck region of the BEST1 channel, affecting channel function but maintaining cell homeostasis in the short term. This data shed new light on the different phenotypes of dominant mutations in BEST1, and emphasize the importance of understanding its molecular mechanisms. Furthermore, the data widen the knowledge of this pathology and open the door for a better diagnosis and prognosis of the disease. MDPI 2022-07-04 /pmc/articles/PMC9266689/ /pubmed/35806438 http://dx.doi.org/10.3390/ijms23137432 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Navinés-Ferrer, Arnau
Ruiz-Nogales, Sheila
Navarro, Rafael
Pomares, Esther
Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation
title Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation
title_full Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation
title_fullStr Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation
title_full_unstemmed Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation
title_short Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation
title_sort impaired bestrophin channel activity in an ipsc-rpe model of best vitelliform macular dystrophy (bvmd) from an early onset patient carrying the p77s dominant mutation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266689/
https://www.ncbi.nlm.nih.gov/pubmed/35806438
http://dx.doi.org/10.3390/ijms23137432
work_keys_str_mv AT navinesferrerarnau impairedbestrophinchannelactivityinanipscrpemodelofbestvitelliformmaculardystrophybvmdfromanearlyonsetpatientcarryingthep77sdominantmutation
AT ruiznogalessheila impairedbestrophinchannelactivityinanipscrpemodelofbestvitelliformmaculardystrophybvmdfromanearlyonsetpatientcarryingthep77sdominantmutation
AT navarrorafael impairedbestrophinchannelactivityinanipscrpemodelofbestvitelliformmaculardystrophybvmdfromanearlyonsetpatientcarryingthep77sdominantmutation
AT pomaresesther impairedbestrophinchannelactivityinanipscrpemodelofbestvitelliformmaculardystrophybvmdfromanearlyonsetpatientcarryingthep77sdominantmutation