美国斯克里普斯研究所Martin Friedlander与合作者在新研究中，分析了丝氨酸与脂质代谢在黄斑病变及周围神经病变中的作用。相关论文2019年9月11日在线发表于《新英格兰医学杂志》。

识别具有复杂遗传模式的疾病的机制（例如2型黄斑毛细血管扩张症）是一项挑战。目前已证实黄斑毛细血管扩张2型与丝氨酸代谢变化有相关性。

研究组通过对1例2型黄斑毛细血管扩张症患者及其家族成员的外显子序列分析，确定了一个编码丝氨酸棕榈酰转移酶（SPT）亚单位的SPTLC1变异株。由于影响SPT的突变会导致1型遗传性感觉和自主神经病变（HSAN1），课题组又检查了另外10名HSAN1患者的眼科疾病。对2型黄斑毛细血管扩张症、无HSAN1或影响SPT的致病性变异的患者测定其血清氨基酸和包括脱氧鞘氨脂在内的鞘氨醇水平。

最终确定引起HSAN1的两个变体是2型黄斑毛细血管扩张的病因：在11例HSAN1患者中，9例也同时患有2型黄斑毛细血管扩张。125例2型黄斑毛细血管扩张症患者的循环脱氧鞘氨脂水平比94例正常对照者高84.2%。脱氧鞘氨脂水平与丝氨酸水平呈负相关，比对照组低20.6%。小鼠体内丝氨酸水平降低导致视网膜脱氧鞘氨脂水平升高，诱发视觉功能受损。脱氧鞘氨脂可导致视网膜类器官中感光细胞死亡，但脂质代谢调节因子不会。

总之，由变体SPTLC1或SPTLC2或低丝氨酸水平引起的非典型脱氧鞘氨脂水平升高，是2型黄斑毛细血管扩张症和周围神经病变的危险因素。

附：英文原文

Title: Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy

Author: Marin L. Gantner, Ph.D., Kevin Eade, Ph.D., Martina Wallace, Ph.D., Michal K. Handzlik, Ph.D., Regis Fallon, B.S., Jennifer Trombley, M.S.N., Roberto Bonelli, M.S., Sarah Giles, B.S., Sarah Harkins-Perry, B.S., Tjebo F.C. Heeren, M.D., Lydia Sauer, M.D., Yoichiro Ideguchi, B.S., Michelle Baldini, Lea Scheppke, Ph.D., Michael I. Dorrell, Ph.D., Maki Kitano, B.S., Barbara J. Hart, B.S., Carolyn Cai, B.A., Takayuki Nagasaki, Ph.D., Mehmet G. Badur, Ph.D., Mali Okada, M.D., Sasha M. Woods, Ph.D., Catherine Egan, M.D., Mark Gillies, M.D., Ph.D., Robyn Guymer, M.D., Ph.D., Florian Eichler, M.D., Melanie Bahlo, Ph.D., Marcus Fruttiger, Ph.D., Rando Allikmets, Ph.D., Paul S. Bernstein, M.D., Ph.D., Christian M. Metallo, Ph.D., and Martin Friedlander, M.D., Ph.D.

Issue&Volume: September 11, 2019

Abstract: 

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
Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 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, but not in the presence of regulators of lipid metabolism.

CONCLUSIONS
Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.)