Induced pluripotent stem cell -based disease modeling identi fies ligand-induced decay of see commentary megalin as a cause of Donnai-Barrow
Induced pluripotent stem cell -based disease modeling identi fies ligand-induced decay of see commentary megalin as a cause of Donnai-Barrow
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DOI：
10.1016/j.kint.2020.02.021
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发表时间：
2020-07-01
影响因子：
19.6
通讯作者：
Willnow, Thomas E.
中科院分区：
文献类型：
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作者：
Flemming, Julia;Marczenke, Maike;Willnow, Thomas E.
唐奈-巴罗综合征 (DBS) 是一种常染色体隐性遗传疾病，其特征为多种病理，包括前脑和眼睛畸形以及肾近端小管吸收缺陷。 DBS 的根本原因是编码多功能内吞受体巨蛋白的 LRP2 突变。在这里，我们在受影响的家族中鉴定出了 LRP2 的独特错义突变 R3192Q，这可能为 DBS 影响的肾近曲小管和其他组织中受体功能障碍的分子原因提供新的见解。使用患者来源的诱导多能干细胞系，我们生成了神经上皮细胞和肾细胞类型作为该疾病的模型。使用这些细胞模型，我们记录了巨蛋白 R3192Q 无法在溶酶体中正确释放配体和配体诱导的受体衰变。因此，突变受体异常地靶向溶酶体进行分解代谢，在该受影响的家族中在配体存在的情况下基本上耗尽了巨蛋白。
Donnai-Barrow syndrome (DBS) is an autosomal-recessive disorder characterized by multiple pathologies including malformation of forebrain and eyes, as well as resorption defects of the kidney proximal tubule. The underlying cause of DBS are mutations in LRP2 , encoding the multifunctional endocytic receptor megalin. Here, we identi fied a unique missense mutation R3192Q of LRP2 in an affected family that may provide novel insights into the molecular causes of receptor dysfunction in the kidney proximal tubule and other tissues affected in DBS. Using patient -derived induced pluripotent stem cell lines we generated neuroepithelial and kidney cell types as models of the disease. Using these cell models, we documented the inability of megalin R3192Q to properly discharge ligand and ligand-induced receptor decay in lysosomes. Thus, mutant receptors are aberrantly targeted to lysosomes for catabolism, essentially depleting megalin in the presence of ligand in this affected family.