SLC16A8 is a causal contributor to age-related macular degeneration risk.

IF 4.7 2区 医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2024-10-28 DOI:10.1038/s41525-024-00442-8
Navid Nouri, Bailey Hannon Gussler, Amy Stockwell, Tom Truong, Gyeong Jin Kang, Kristen C Browder, Yann Malato, Abdoulaye Sene, Sherri Van Everen, Charles C Wykoff, David Brown, Arthur Fu, James D Palmer, Jose Ronaldo Lima de Carvalho, Ehsan Ullah, Ranya Al Rawi, Emily Y Chew, Wadih M Zein, Bin Guan, Mark I McCarthy, Jeffrey W Hofmann, Shawnta Y Chaney, Heinrich Jasper, Brian L Yaspan
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Abstract

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.

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SLC16A8 是老年性黄斑变性风险的成因之一。
老年性黄斑变性(AMD)是一种复杂的神经退行性疾病,是导致全球视力损伤的主要原因之一,其中有很大的遗传因素。遗传学研究发现了几个基因位点,但具有功能特征的致病基因却很少。在此,我们强调了多个证据,这些证据显示 SLC16A8 在老年性痴呆中的因果作用,SLC16A8 编码 MCT3,MCT3 是视网膜色素上皮(RPE)特异性乳酸转运体。首先,在一项无偏见的全基因组罕见编码变异分析中,我们发现多个 SLC16A8 罕见变异与 AMD 风险有关,这证实了之前 AMD 罕见变异研究中的边缘显著性报告。其次,我们报告了一个三代同堂的早发性黄斑变性家族中的新型 SLC16A8 突变。最后,SLC16A8 在多种模式生物中的错误表达显示了功能性和解剖性视网膜后果。这项研究强调了 SLC16A8 和乳酸调节对外部视网膜/RPE 健康的重要作用,并强调了治疗黄斑变性的潜在新疗法机会。
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来源期刊
NPJ Genomic Medicine
NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
1.90%
发文量
67
审稿时长
17 weeks
期刊介绍: npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.
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