A Splice Variant in <i>SLC16A8</i> 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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2021-01-01
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| author | Laurence Klipfel Marie Cordonnier Léa Thiébault Emmanuelle Clérin Frédéric Blond Géraldine Millet-Puel Saddek Mohand-Saïd Olivier Goureau José-Alain Sahel Emeline F. Nandrot Thierry Léveillard |
| author_facet | Laurence Klipfel Marie Cordonnier Léa Thiébault Emmanuelle Clérin Frédéric Blond Géraldine Millet-Puel Saddek Mohand-Saïd Olivier Goureau José-Alain Sahel Emeline F. Nandrot Thierry Léveillard |
| author_sort | Laurence Klipfel |
| collection | DOAJ |
| 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 <i>SLC16A8</i> 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 <i>SLC16A8</i> 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 <i>SLC16A8</i> gene leading to the absence of MCT3 protein. We show using a biochemical assay that these cells have a deficit in transepithelial lactate transport. |
| first_indexed | 2024-03-09T04:26:55Z |
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| id | doaj.art-8b4b34875552484aad259f5a5bb6ca1c |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T04:26:55Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-8b4b34875552484aad259f5a5bb6ca1c2023-12-03T13:39:08ZengMDPI AGCells2073-44092021-01-0110117910.3390/cells10010179A Splice Variant in <i>SLC16A8</i> Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial CellsLaurence Klipfel0Marie Cordonnier1Léa Thiébault2Emmanuelle Clérin3Frédéric Blond4Géraldine Millet-Puel5Saddek Mohand-Saïd6Olivier Goureau7José-Alain Sahel8Emeline F. Nandrot9Thierry Léveillard10Institut de la Vision, Sorbonne Université, INSERM, CNRS, 17 rue Moreau, F-75012 Paris, FranceInstitut de la Vision, Sorbonne Université, INSERM, CNRS, 17 rue Moreau, F-75012 Paris, FranceInstitut de la Vision, Sorbonne Université, INSERM, CNRS, 17 rue Moreau, F-75012 Paris, FranceInstitut de la Vision, Sorbonne Université, INSERM, CNRS, 17 rue Moreau, F-75012 Paris, FranceInstitut de la Vision, Sorbonne Université, INSERM, CNRS, 17 rue Moreau, F-75012 Paris, FranceInstitut de la Vision, Sorbonne Université, INSERM, CNRS, 17 rue Moreau, F-75012 Paris, FranceCHNO des Quinze-Vingts, INSERM-DGOS CIC 1423, 28 rue de Charenton, F-75012 Paris, FranceInstitut de la Vision, Sorbonne Université, INSERM, CNRS, 17 rue Moreau, F-75012 Paris, FranceInstitut de la Vision, Sorbonne Université, INSERM, CNRS, 17 rue Moreau, F-75012 Paris, FranceInstitut de la Vision, Sorbonne Université, INSERM, CNRS, 17 rue Moreau, F-75012 Paris, FranceInstitut de la Vision, Sorbonne Université, INSERM, CNRS, 17 rue Moreau, F-75012 Paris, FranceAge-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 <i>SLC16A8</i> 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 <i>SLC16A8</i> 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 <i>SLC16A8</i> gene leading to the absence of MCT3 protein. We show using a biochemical assay that these cells have a deficit in transepithelial lactate transport.https://www.mdpi.com/2073-4409/10/1/179retinal pigment epitheliumlactate transportinduced pluripotent stem cellssplicingMCT3age-related macular degeneration |
| spellingShingle | Laurence Klipfel Marie Cordonnier Léa Thiébault Emmanuelle Clérin Frédéric Blond Géraldine Millet-Puel Saddek Mohand-Saïd Olivier Goureau José-Alain Sahel Emeline F. Nandrot Thierry Léveillard A Splice Variant in <i>SLC16A8</i> Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells Cells retinal pigment epithelium lactate transport induced pluripotent stem cells splicing MCT3 age-related macular degeneration |
| title | A Splice Variant in <i>SLC16A8</i> Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells |
| title_full | A Splice Variant in <i>SLC16A8</i> Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells |
| title_fullStr | A Splice Variant in <i>SLC16A8</i> Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells |
| title_full_unstemmed | A Splice Variant in <i>SLC16A8</i> Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells |
| title_short | A Splice Variant in <i>SLC16A8</i> Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells |
| title_sort | splice variant in i slc16a8 i gene leads to lactate transport deficit in human ips cell derived retinal pigment epithelial cells |
| topic | retinal pigment epithelium lactate transport induced pluripotent stem cells splicing MCT3 age-related macular degeneration |
| url | https://www.mdpi.com/2073-4409/10/1/179 |
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