贝斯特罗芬1基因突变导致患者干细胞来源的视网膜色素上皮细胞中氯离子传导缺陷。
BESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE.
作者信息
Moshfegh Yasmin, Velez Gabriel, Li Yao, Bassuk Alexander G, Mahajan Vinit B, Tsang Stephen H
机构信息
Barbara & Donald Jonas Laboratory of Regenerative Medicine, and Bernard & Shirlee Brown Glaucoma Laboratory, Department of Pathology & Cell Biology, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY 10032, USA.
出版信息
Hum Mol Genet. 2016 Jul 1;25(13):2672-2680. doi: 10.1093/hmg/ddw126. Epub 2016 May 18.
Bestrophin1 (BEST1) is expressed in human retinal pigment epithelium (RPE) and mutations in the BEST1 gene commonly cause retinal dysfunction and macular degeneration. BEST1 is presumed to assemble into a calcium-activated chloride channel and be involved in chloride transport but there is no direct evidence in live human RPE cells to support this idea. To test whether BEST1 functions as a chloride channel in living tissue, BEST1-mutant RPE (R218H, L234P, A243T) were generated from patient-derived induced pluripotent stem cells and compared with wild-type RPE in a retinal environment, using a biosensor that visualizes calcium-induced chloride ion flux in the cell. Calcium stimulation elicited chloride ion export in normal RPE but not in RPE derived from three patients with BEST1 mutations. These data, along with three-dimensional modeling, provide evidence that BEST1 assembles into a key calcium-sensing chloride channel in human RPE.
最佳rophin1（BEST1）在人类视网膜色素上皮（RPE）中表达，BEST1基因的突变通常会导致视网膜功能障碍和黄斑变性。BEST1被推测组装成钙激活氯离子通道并参与氯离子转运，但在活的人类RPE细胞中没有直接证据支持这一观点。为了测试BEST1在活组织中是否作为氯离子通道发挥作用，从患者来源的诱导多能干细胞中产生了BEST1突变型RPE（R218H、L234P、A243T），并在视网膜环境中与野生型RPE进行比较，使用一种生物传感器来可视化细胞中钙诱导的氯离子通量。钙刺激在正常RPE中引发氯离子外流，但在三名患有BEST1突变的患者来源的RPE中未引发。这些数据，连同三维建模，提供了证据表明BEST1在人类RPE中组装成一个关键的钙敏感氯离子通道。
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