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.

中文翻译：

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SLC16A8基因的剪接变体导致人iPS细胞衍生的视网膜色素上皮细胞中的乳酸转运缺陷。

年龄相关性黄斑变性（AMD）是一种致盲性疾病，大多数患者仍无法治愈。由于该疾病影响视网膜中央部位的黄斑，这是灵长类谱系特有的结构，因此研究AMD的病理生理学和制定疗法的啮齿动物模型非常有限。因此，我们的理解主要依赖于遗传研究，该研究强调了许多基因座的风险等位基因。我们正在研究与SLC16A8基因内的风险等位基因相关的代谢失衡的可能含义，该基因编码视网膜色素上皮（RPE）特异性乳酸转运蛋白MCT3及其对视觉的影响。作为第一种方法，我们在这里报告了罕见的SLC16A8跨上皮乳酸运输的缺陷在全基因组关联研究中鉴定的等位基因。我们从队列中唯一携带两份该等位基因的患者中诱导出了多能干细胞（iPSC）。在将iPSC体外分化为RPE细胞及其特性后，我们证明了罕见的等位基因导致SLC16A8基因内含子2的保留，导致缺少MCT3蛋白。我们使用生化分析表明，这些细胞在上皮乳酸盐运输中缺乏。