黄斑病变和外周神经病中的丝氨酸和脂质代谢。

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

机构信息

From the Lowy Medical Research Institute (M.L.G., K.E., R.F., J.T., S.G., S.H.-P., Y.I., L. Scheppke, M.I.D., M.K., M. Friedlander), University of California, San Diego (M.W., M.K.H., M. Baldini, M.G.B., C.M.M.), Scripps Research Institute (S.H.-P., Y.I., M.K., M. Friedlander), and Scripps Clinic Medical Group (M. Friedlander), La Jolla, and Point Loma Nazarene University, San Diego (M.I.D.) - all in California; Moran Eye Center, University of Utah, Salt Lake City (L. Sauer, B.J.H., P.S.B.); Moorfields Eye Hospital (T.F.C.H., C.E.) and University College London Institute of Ophthalmology (S.M.W., M. Fruttiger), London; Columbia University, New York (C.C., T.N., R.A.); Walter and Eliza Hall Institute of Medical Research, Parkville, VIC (R.B., M. Bahlo), Royal Victorian Eye and Ear Hospital (M.O.) and University of Melbourne Centre for Eye Research (R.G.), Melbourne, VIC, and the Save Sight Institute, University of Sydney, Sydney (M.G.) - all in Australia; and Massachusetts General Hospital, Boston (F.E.).

出版信息

N Engl J Med. 2019 Oct 10;381(15):1422-1433. doi: 10.1056/NEJMoa1815111. Epub 2019 Sep 11.

DOI:10.1056/NEJMoa1815111

PMID:31509666

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7685488/

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 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 or 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.).

摘要

背景

鉴定具有复杂遗传模式的疾病的机制，如 2 型黄斑毛细血管扩张症，具有挑战性。先前已经确定了 2 型黄斑毛细血管扩张症与丝氨酸代谢改变之间的联系。

方法

通过对 2 型黄斑毛细血管扩张症患者及其家庭成员的外显子组序列分析，我们在编码丝氨酸棕榈酰转移酶（SPT）亚基的基因中发现了一个变异。由于已知影响 SPT 的突变会导致遗传性感觉和自主神经病 1 型（HSAN1），我们检查了另外 10 名患有 HSAN1 的人是否有眼科疾病。我们检测了患有 2 型黄斑毛细血管扩张症但没有 HSAN1 或影响 SPT 的致病性变异的患者的血清氨基酸和神经酰胺水平，包括脱氧神经酰胺水平。我们对丝氨酸水平较低的小鼠进行了特征描述，并测试了脱氧神经酰胺对人视网膜类器官的影响。

结果

鉴定出两个已知导致 HSAN1 的变异为黄斑毛细血管扩张症的致病原因：11 名 HSAN1 患者中有 9 名也患有黄斑毛细血管扩张症。在 125 名没有影响 SPT 的致病性变异的黄斑毛细血管扩张症患者中，循环脱氧神经酰胺水平比 94 名未受影响的对照者高 84.2%。脱氧神经酰胺水平与丝氨酸水平呈负相关，丝氨酸水平比对照组低 20.6%。在小鼠中降低丝氨酸水平会导致视网膜脱氧神经酰胺水平升高，并损害视觉功能。脱氧神经酰胺在视网膜类器官中引起光感受器细胞死亡，但在脂质代谢调节剂存在的情况下不会引起死亡。