Department of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
JCI Insight. 2021 Mar 22;6(6):145908. doi: 10.1172/jci.insight.145908.
Mutations in LAMB2, encoding laminin β2, 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 β2. On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the β2 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 β2 secretion, the 3 recombinant variants were secreted as efficiently as WT. However, the β2 variants lost pH dependency for heparin binding, resulting in aberrant binding under physiologic conditions. This suggests that the binding of laminin β2 to negatively charged molecules is involved in glomerular basement membrane (GBM) permselectivity. Moreover, the excessive binding of the β2 variants to other laminins appears to lead to their increased deposition in the GBM. Laminin β2 also serves as a potentially novel cell-adhesive ligand for integrin α4β1. Our findings define biochemical functions of laminin β2 variants influencing glomerular filtration that may underlie the pathogenesis of isolated nephropathy caused by LAMB2 abnormalities.
LAMB2 基因突变导致皮尔逊综合征，偶尔也会导致较轻微的肾病，而无肾脏外异常。已鉴定的最具破坏性的错义突变主要影响层粘连蛋白β2 的 N 端。另一方面，与孤立性肾病相关的突变分布在整个分子中，而仅在孤立性肾病中发现β2 LEa-LF-LEb 结构域中的变异。在这里，我们报告了与 LEa-LF-LEb 结构域中的 3 个 LAMB2 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。尽管皮尔逊综合征的错义突变通常会抑制层粘连蛋白β2 的分泌，但这 3 种重组变体的分泌效率与 WT 相当。然而，β2 变体失去了对肝素结合的 pH 依赖性，导致在生理条件下发生异常结合。这表明层粘连蛋白β2 与带负电荷分子的结合参与了肾小球基底膜（GBM）的选择性通透性。此外，β2 变体与其他层粘连蛋白的过度结合似乎导致其在 GBM 中的沉积增加。层粘连蛋白β2 还作为整合素α4β1 的潜在新型细胞黏附配体。我们的研究结果定义了影响肾小球滤过的层粘连蛋白β2 变体的生化功能，这可能是由 LAMB2 异常引起的孤立性肾病发病机制的基础。
