Laminin β2 variants associated with isolated nephropathy that impact matrix regulation
Laminin β2 variants associated with isolated nephropathy that impact matrix regulation
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DOI：
10.1172/jci.insight.145908
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发表时间：
2021-03-22
期刊：
影响因子：
8
通讯作者：
Harita, Yutaka
中科院分区：
文献类型：
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作者：
Kikkawa, Yamato;Hashimoto, Taeko;Harita, Yutaka
编码层粘连蛋白β（2）的LAMB 2突变可引起皮尔逊综合征，偶尔也会引起轻度肾病，但无肾外异常。已确定的最有害的错义突变主要影响层粘连蛋白β的N末端（2）。另一方面，与孤立性肾病相关的那些分布在整个分子中，并且β（2）LEa-LF-LEb结构域中的变体仅在孤立性肾病病例中发现。在这里，我们报告了与LEa-LF-LEb结构域中的3种LAMB 2变体（p.R469Q、p.G699R和p.R1078C）相关的轻度孤立性肾病的临床特征及其生化特征。尽管Pierson综合征错义突变通常抑制层粘连蛋白β 2的分泌，但3种重组变体的分泌与WT一样有效。然而，β（2）变体丧失了肝素结合的pH依赖性，导致在生理条件下的异常结合。这表明层粘连蛋白β 2与带负电荷分子的结合参与了肾小球基底膜（GBM）的选择性渗透。此外，β（2）变体与其他层粘连蛋白的过度结合似乎导致它们在GBM中的沉积增加。层粘连蛋白β（2）也作为整合素α 4 β（1）的潜在的新型细胞粘附配体。我们的研究结果确定了影响肾小球滤过的层粘连蛋白β（2）变体的生化功能，这可能是LAMB 2异常引起的孤立性肾病的发病机制的基础。
Mutations in LAMB2, encoding laminin beta(2), cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense mutations that have been identified affect primarily the N-terminus of laminin beta(2). On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the beta(2) LEa-LF-LEb domains are exclusively found in cases with isolated nephropathy. Here we report the clinical features of mild isolated nephropathy associated with 3 LAMB2 variants in the LEa-LF-LEb domains (p.R469Q, p.G699R, and p.R1078C) and their biochemical characterization. Although Pierson syndrome missense mutations often inhibit laminin beta(2) secretion, the 3 recombinant variants were secreted as efficiently as WT. However, the beta(2) variants lost pH dependency for heparin binding, resulting in aberrant binding under physiologic conditions. This suggests that the binding of laminin beta(2) to negatively charged molecules is involved in glomerular basement membrane (GBM) permselectivity. Moreover, the excessive binding of the beta(2) variants to other laminins appears to lead to their increased deposition in the GBM. Laminin beta(2) also serves as a potentially novel cell-adhesive ligand for integrin a 4 beta(1.) Our findings define biochemical functions of laminin beta(2) variants influencing glomerular filtration that may underlie the pathogenesis of isolated nephropathy caused by LAMB2 abnormalities.