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在早期发病的黄斑变性中,CFH的哈普洛缺陷和补充变化

Rayne R Lim¹, Sharlene Shirali¹, Jessica Rowlan¹

¹Department of Ophthalmology, University of Washington, Seattle, Washington, United States.

Investigative ophthalmology & visual science

|April 29, 2024

概括

一种新的补充因子H (CFH) 变体导致早期发病的黄斑中毒症 (EOMD) 减少了CFH和因子H类蛋白1 (FHL-1). 这导致视网膜细胞的补充活性增加,支持CFH在EOMD中的脱.

科学领域:

眼科医生眼科眼科
免疫学免疫学免疫学
遗传学是一个遗传学.

背景情况:

补剂失调与与年龄相关的黄斑变性 (AMD) 和早期发病的黄斑干燥症 (EOMD) 有关.
补充因子H (CFH) 的遗传变异与AMD风险有关.
CFH和H型蛋白1 (FHL-1) 表达对视网膜色素表皮 (RPE) 中局部补充活性的影响尚未完全理解.

研究的目的:

为了调查新型CFH变异在EOMD病变发生中的作用.
评估这种变体对CFH和FHL-1表达和患者衍生的RPE细胞中的局部补充活性的影响.

主要方法:

产生的诱导多能干细胞 (iPSC) 衍生RPE细胞来自一个具有新型CFH变异的家族.
通过C3b分解试验评估CFH和FHL-1辅因子活性.
测量了膜攻击复合体 (MAC) 的形成和补充元件和调节物的定量表达,使用qPCR,西斑和免疫染色.
利用CRISPR/Cas9基因编辑来创建同位素控制的RPE细胞 (cEOMD).

主要成果:

鉴定到的CFH变体 (c.351-2A>G) 在EOMD iPSC RPE细胞中导致CFH和FHL-1表达显著减少 (∼50%).
在压力下,EOMD RPE细胞显示MAC沉积增加和补体调节者的表达升高.
克里斯普尔/卡斯9校正恢复了CFH/FHL-1表达,并使替代途径补充活性正常化.

结论:

一种新的CFH变异导致EOMD中CFH和FHL-1表达减少.
这种减少导致RPE细胞中局部补充活性增加.
这些研究结果支持CFH哈普洛缺陷作为EOMD病原发生的一个因素.

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