Nouri Navid, Gussler Bailey Hannon, Stockwell Amy, Truong Tom, Kang Gyeong Jin, Browder Kristen C, Malato Yann, Sene Abdoulaye, Van Everen Sherri, Wykoff Charles C, Brown David, Fu Arthur, Palmer James D, Lima de Carvalho Jose Ronaldo, Ullah Ehsan, Al Rawi Ranya, Chew Emily Y, Zein Wadih M, Guan Bin, McCarthy Mark I, Hofmann Jeffrey W, Chaney Shawnta Y, Jasper Heinrich, Yaspan Brian L
Genentech, Inc., South San Francisco, CA, USA.
Retina Consultants of Texas, Retina Consultants of America, Houston, TX, USA.
NPJ Genom Med. 2024 Oct 28;9(1):50. doi: 10.1038/s41525-024-00442-8.
Age-related macular degeneration (AMD), a complex neurodegenerative disease, is a leading cause of visual impairment worldwide with a strong genetic component. Genetic studies have identified several loci, but few causal genes with functional characterization. Here we highlight multiple lines of evidence which show a causal role in AMD for SLC16A8, which encodes MCT3, a retinal pigment epithelium (RPE) specific lactate transporter. First, in an unbiased, genome-wide analysis of rare coding variants we show multiple SLC16A8 rare variants are associated with AMD risk, corroborating previous borderline significant reports from AMD rare variant studies. Second, we report a novel SLC16A8 mutation in a three-generation family with early onset macular degeneration. Finally, mis-expression in multiple model organisms shows functional and anatomic retinal consequences. This study highlights the important role for SLC16A8 and lactate regulation towards outer retina/RPE health and highlights a potential new therapeutic opportunity for the treatment of AMD.
年龄相关性黄斑变性（AMD）是一种复杂的神经退行性疾病，是全球视力损害的主要原因，具有很强的遗传因素。基因研究已经确定了几个基因座，但具有功能特征的致病基因却很少。在这里，我们强调了多条证据，这些证据表明编码MCT3（一种视网膜色素上皮（RPE）特异性乳酸转运蛋白）的SLC16A8在AMD中起因果作用。首先，在对罕见编码变异进行的无偏全基因组分析中，我们发现多个SLC16A8罕见变异与AMD风险相关，证实了先前AMD罕见变异研究中临界显著的报告。其次，我们在一个患有早发性黄斑变性的三代家族中报告了一种新的SLC16A8突变。最后，在多种模式生物中的错误表达显示出功能性和解剖学上的视网膜后果。这项研究突出了SLC16A8和乳酸调节对外侧视网膜/RPE健康的重要作用，并突出了治疗AMD的潜在新治疗机会。
