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 identified 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.

Donnai-Barrow 综合征 (DBS) 是一种常染色体隐性遗传疾病，其特征是多种病理，包括前脑和眼睛畸形，以及肾近端小管的吸收缺陷。DBS 的根本原因是LRP2突变，编码多功能内吞受体巨蛋白。在这里，我们鉴定了 LRP2 的独特错义突变R3192Q在受影响的家庭中，这可能提供对肾近端小管和 DBS 受影响的其他组织中受体功能障碍的分子原因的新见解。使用源自患者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 无法正确释放溶酶体中的配体和配体诱导的受体衰变。因此，突变受体异常靶向溶酶体进行分解代谢，在该受影响家族中存在配体的情况下基本上消耗巨蛋白。