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丝氨酸和脂质代谢在黄斑病变和周围神经病变中的作用
Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy


Marin L. Gantner ... 其他 • 2019.10.10
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摘要


背景

对于2型黄斑毛细血管扩张症等遗传模式复杂的疾病,要确定其机制很困难。2型黄斑毛细血管扩张症和丝氨酸代谢改变之间的关联已经被证实。

 

方法

通过1例2型黄斑毛细血管扩张症患者及其家系成员的外显子组序列分析结果,我们发现了编码丝氨酸棕榈酰转移酶(SPT)一个亚基的SPTLC1的一个变异体。由于已知影响SPT的突变会导致1型遗传性感觉和自主神经病变(HSAN1),因此我们检查了另外10例HSAN1患者是否有眼科疾病。我们检测了未患HSAN1,且无影响SPT的致病变异体的2型黄斑毛细血管扩张症患者的血清氨基酸和鞘氨醇碱基水平,包括脱氧鞘脂水平。我们检测了丝氨酸水平低的小鼠的特征,并确定了脱氧鞘脂对人视网膜类器官的效应。

 

结果

已知可导致HSAN1的两种变异体被确定为2型黄斑毛细血管扩张症的致病原因:在11例HSAN1患者中,9例同时患2型黄斑毛细血管扩张症。在无影响SPT的致病性变异体的125例2型黄斑毛细血管扩张症患者中,循环脱氧鞘脂水平比94例未患病对照高84.2%。脱氧鞘脂水平与丝氨酸水平呈负相关,上述患者的丝氨酸水平比对照低20.6%。小鼠丝氨酸水平降低可导致视网膜脱氧鞘脂水平升高和视功能损害。脱氧鞘脂导致视网膜类器官感光细胞死亡,但在脂质代谢调节因子存在的情况下,脱氧鞘脂并未导致视网膜类器官感光细胞死亡。

 

结论

变异SPTLC1SPTLC2或者丝氨酸低水平引起的非典型脱氧鞘脂水平的升高是2型黄斑毛细血管扩张症和周围神经病变的危险因素(由洛伊医学研究所[Lowy Medical Research Institute]等资助)。





作者信息

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.
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.). Address reprint requests to Dr. Friedlander at Lowy Medical Research Institute, 3366 N. Torrey Pines Ct., Suite 300, La Jolla, CA 92037, or at friedlan@scripps.edu.

 

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