A Missense LAMB2 Mutation Causes Congenital Nephrotic Syndrome by Impairing Laminin Secretion
A Missense LAMB2 Mutation Causes Congenital Nephrotic Syndrome by Impairing Laminin Secretion
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DOI：
10.1681/asn.2010060632
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发表时间：
2011-05-01
影响因子：
13.6
通讯作者：
Miner, Jeffrey H.
中科院分区：
文献类型：
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作者：
Chen, Ying Maggie;Kikkawa, Yamato;Miner, Jeffrey H.
层粘连蛋白β 2是层粘连蛋白-521的组分，层粘连蛋白-521是肾小球基底膜（GBM）的重要成分。层粘连蛋白β 2（LAMB 2）的突变导致皮尔逊综合征，这是一种严重的先天性肾病综合征，伴有眼部和神经系统缺陷。相比之下，具有LAMB 2错义突变（如R246 Q）的患者可以具有不太严重的肾外缺陷，但仍然表现出先天性肾病综合征。为了研究LAMB 2中的这种错义突变如何引起蛋白尿，我们产生了三种转基因小鼠品系，其中R246 Q突变的大鼠层粘连蛋白β 2取代了GBM中的野生型小鼠层粘连蛋白β 2。这些转基因小鼠比非转基因Lamb 2缺陷的同窝小鼠发生的蛋白尿严重得多;蛋白尿水平与R246 Q-LAMB 2表达呈负相关。在蛋白尿发作时，与裂膈和足突相关的蛋白质的表达和定位是正常的，并且没有明显的超微结构异常。低转基因表达者在3个月时出现严重蛋白尿、足突消失、GBM增厚和肾衰竭，而高转基因表达者在9个月时仅出现轻度蛋白尿。体外研究表明，R246 Q突变导致层粘连蛋白分泌受损。综上所述，这些结果表明，R246 Q突变导致肾病综合征的损害分泌层粘连蛋白-521从足细胞到GBM;然而，增加表达的突变蛋白能够克服这种分泌缺陷，提高肾小球渗透选择性。
Laminin beta 2 is a component of laminin-521, which is an important constituent of the glomerular basement membrane (GBM). Null mutations in laminin beta 2 (LAMB2) cause Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects. In contrast, patients with LAMB2 missense mutations, such as R246Q, can have less severe extrarenal defects but still exhibit congenital nephrotic syndrome. To investigate how such missense mutations in LAMB2 cause proteinuria, we generated three transgenic lines of mice in which R246Q-mutant rat laminin beta 2 replaced the wild-type mouse laminin beta 2 in the GBM. These transgenic mice developed much less severe proteinuria than their nontransgenic Lamb2-deficient littermates; the level of proteinuria correlated inversely with R246Q-LAMB2 expression. At the onset of proteinuria, expression and localization of proteins associated with the slit diaphragm and foot processes were normal, and there were no obvious ultrastructural abnormalities. Low transgene expressors developed heavy proteinuria, foot process effacement, GBM thickening, and renal failure by 3 months, but high expressors developed only mild proteinuria by 9 months. In vitro studies demonstrated that the R246Q mutation results in impaired secretion of laminin. Taken together, these results suggest that the R246Q mutation causes nephrotic syndrome by impairing secretion of laminin-521 from podocytes into the GBM; however, increased expression of the mutant protein is able to overcome this secretion defect and improve glomerular permselectivity.