Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy

作者：Marin L. Gantner, Kevin Eade, Martina Wallace, Michal K. Handzlik, Regis Fallon, Jennifer Trombley, Roberto Bonelli, Sarah Giles, Sarah Harkins‐Perry, Tjebo Heeren, Lydia Sauer, Yoichiro Ideguchi, M Baldini, Lea Scheppke, Michael I. Dorrell, Maki Kitano, Barbara Hart, Carolyn Cai, Takayuki Nagasaki, Mehmet G. Badur, Mali Okada, Sasha M. Woods, Catherine Egan, Mark C. Gillies, Robyn H. Guymer, Florian Eichler, Melanie Bahlo, Marcus Fruttiger, Rando Allikmets, Paul S. Bernstein, Christian M. Metallo, Martin Friedlander · 发表于：New England Journal of Medicine · 年份：2019 · DOI：10.1056/nejmoa1815111 · 被引用次数：261 · 研究领域：Sphingolipid Metabolism and Signaling、Biomedical Research and Pathophysiology、Glaucoma and retinal disorders

BACKGROUND: Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS: encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS: Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids,...