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Laurence Klipfel, Mélanie Var, Marie Cordonnier, Saddek Mohand-Saïd, Olivier Goureau, Thierry D. Leveillard; Impact of lactate transport deficit in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):793.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related macular degeneration (AMD) is the principal cause of irreversible visual impairment in the elderly in industrialized countries. In AMD, one of the prominent accepted hypotheses proposes that degeneration results from a defect in photoreceptor outer segment shedding by the retinal pigmented epithelium (RPE). Genome wide association studies (GWAS) have led to the identification of 34 susceptibility loci, encompassing genes such as complement factor H (CFH) or ARMS2/HTRA1. The lactate transporter SLC16A8 gene is the only AMD susceptibility gene that is pointing directly to a dysfunction of photoreceptors. The recent identification of an AMD risk allele (rs8135665T) and a candidate causal splicing mutation (rs77968014G) in the lactate transporter gene led us to produce iPS cells from skin biopsies of patients carrying these risk alleles (both homozygous and heterozygous genotypes).
We have characterized the RPE status of the iPS-derived RPE cell lines, and verified the presence of the two lactate transporters, MCT1 (SLC16A1) and MCT3 (SLC163A8), which facilitate the transepithelial transport of lactate from the retina to the choroid, the presence of markers of RPE cells (OTX2, RPE65, MITF, BEST1 and MERTK), and the absence of markers of stem cells (POU5F1 and LIN28A). We have also quantified the lactate transport using the fluorescent probe BCECF (2’,7’-bis-(carboxyethyl)-5(6)-carboxyfluorescein) in the iPS-derived RPE cells carrying the risk allele.
Interestingly, there is a reduced expression of SLC16A8 in iPS-derived RPE cell lines carrying one copy of the risk allele at rs8135665 (C/T). Whereas the 420/490 nm ratio increase reflects intracellular acidification in control cell lines (C/C), there is no measurable lactate transport in the heterozygous iPS-derived RPE cell lines.
Looking for splicing deficit in the SLC16A8 gene in iPS-derived RPE cells carrying the risk allele will enable us to address the role of a risk allele at the SLC16A8 locus, in order to analyze the impact of lactate transport deficit in AMD. Testing for a correlation between vitreous lactate concentration and the number of copies of the risk allele SLC16A8 (rs8135665T) in AMD patients could later address vitreous lactate as a biomarker of AMD independently of the SLC16A8 risk allele.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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