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A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells

Age-related macular degeneration (AMD) is a blinding disease for which most of the patients remain untreatable. Since the disease affects the macula at the center of the retina, a structure specific to the primate lineage, rodent models to study the pathophysiology of AMD and to develop therapies ar...

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Autores principales: Klipfel, Laurence, Cordonnier, Marie, Thiébault, Léa, Clérin, Emmanuelle, Blond, Frédéric, Millet-Puel, Géraldine, Mohand-Saïd, Saddek, Goureau, Olivier, Sahel, José-Alain, Nandrot, Emeline F., Léveillard, Thierry
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831140/
https://www.ncbi.nlm.nih.gov/pubmed/33477551
http://dx.doi.org/10.3390/cells10010179
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author Klipfel, Laurence
Cordonnier, Marie
Thiébault, Léa
Clérin, Emmanuelle
Blond, Frédéric
Millet-Puel, Géraldine
Mohand-Saïd, Saddek
Goureau, Olivier
Sahel, José-Alain
Nandrot, Emeline F.
Léveillard, Thierry
author_facet Klipfel, Laurence
Cordonnier, Marie
Thiébault, Léa
Clérin, Emmanuelle
Blond, Frédéric
Millet-Puel, Géraldine
Mohand-Saïd, Saddek
Goureau, Olivier
Sahel, José-Alain
Nandrot, Emeline F.
Léveillard, Thierry
author_sort Klipfel, Laurence
collection PubMed
description Age-related macular degeneration (AMD) is a blinding disease for which most of the patients remain untreatable. Since the disease affects the macula at the center of the retina, a structure specific to the primate lineage, rodent models to study the pathophysiology of AMD and to develop therapies are very limited. Consequently, our understanding relies mostly on genetic studies highlighting risk alleles at many loci. We are studying the possible implication of a metabolic imbalance associated with risk alleles within the SLC16A8 gene that encodes for a retinal pigment epithelium (RPE)-specific lactate transporter MCT3 and its consequences for vision. As a first approach, we report here the deficit in transepithelial lactate transport of a rare SLC16A8 allele identified during a genome-wide association study. We produced induced pluripotent stem cells (iPSCs) from the unique patient in our cohort that carries two copies of this allele. After in vitro differentiation of the iPSCs into RPE cells and their characterization, we demonstrate that the rare allele results in the retention of intron 2 of the SLC16A8 gene leading to the absence of MCT3 protein. We show using a biochemical assay that these cells have a deficit in transepithelial lactate transport.
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spelling pubmed-78311402021-01-26 A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells Klipfel, Laurence Cordonnier, Marie Thiébault, Léa Clérin, Emmanuelle Blond, Frédéric Millet-Puel, Géraldine Mohand-Saïd, Saddek Goureau, Olivier Sahel, José-Alain Nandrot, Emeline F. Léveillard, Thierry Cells Article Age-related macular degeneration (AMD) is a blinding disease for which most of the patients remain untreatable. Since the disease affects the macula at the center of the retina, a structure specific to the primate lineage, rodent models to study the pathophysiology of AMD and to develop therapies are very limited. Consequently, our understanding relies mostly on genetic studies highlighting risk alleles at many loci. We are studying the possible implication of a metabolic imbalance associated with risk alleles within the SLC16A8 gene that encodes for a retinal pigment epithelium (RPE)-specific lactate transporter MCT3 and its consequences for vision. As a first approach, we report here the deficit in transepithelial lactate transport of a rare SLC16A8 allele identified during a genome-wide association study. We produced induced pluripotent stem cells (iPSCs) from the unique patient in our cohort that carries two copies of this allele. After in vitro differentiation of the iPSCs into RPE cells and their characterization, we demonstrate that the rare allele results in the retention of intron 2 of the SLC16A8 gene leading to the absence of MCT3 protein. We show using a biochemical assay that these cells have a deficit in transepithelial lactate transport. MDPI 2021-01-18 /pmc/articles/PMC7831140/ /pubmed/33477551 http://dx.doi.org/10.3390/cells10010179 Text en © 2021 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Klipfel, Laurence
Cordonnier, Marie
Thiébault, Léa
Clérin, Emmanuelle
Blond, Frédéric
Millet-Puel, Géraldine
Mohand-Saïd, Saddek
Goureau, Olivier
Sahel, José-Alain
Nandrot, Emeline F.
Léveillard, Thierry
A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells
title A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells
title_full A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells
title_fullStr A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells
title_full_unstemmed A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells
title_short A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells
title_sort splice variant in slc16a8 gene leads to lactate transport deficit in human ips cell-derived retinal pigment epithelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831140/
https://www.ncbi.nlm.nih.gov/pubmed/33477551
http://dx.doi.org/10.3390/cells10010179
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