Predisposition to relapsing nephrotic syndrome by a nephrin mutation that interferes with assembly of functioning microdomains
Predisposition to relapsing nephrotic syndrome by a nephrin mutation that interferes with assembly of functioning microdomains
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DOI：
10.1093/hmg/ddp232
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发表时间：
2009-08-15
影响因子：
3.5
通讯作者：
Iijima, Kazumoto
中科院分区：
文献类型：
--
作者：
Shono, Akemi;Tsukaguchi, Hiroyasu;Iijima, Kazumoto
微小病变（MCD）是肾病综合征（NS）最常见的病因，其特征仅在于足细胞的微小形态学改变。MCD的一个亚型是由肾配蛋白突变引起的，肾配蛋白是裂膈（SD）的主要成分。特发性MCD是一种复杂的性状，其中涉及遗传和免疫因素的相互作用。然而，致病机制仍不清楚。在这里，我们研究了家族性NS的分子基础，其特点是频繁复发和组织学变化极小。我们先前的突变分析显示，两名患病儿童是肾配蛋白变体C265R和V822M的复合杂合子（Kidney Int.，2008年）。当异源表达时，这些变体表现出正常的代谢半衰期和筏结合。C265 R表现出大量的ER滞留，反映了细胞内运输缺陷。相比之下，V822M能够到达质膜，但在侧向扩散以及在细胞表面的运输方面受到限制。V822M的聚集未能引起最大的酪氨酸磷酸化和肌动蛋白重组，表明无法组装成功能膜微区。我们的研究结果表明，C265 R和V822 M组成了一个功能失调的SD复合物，由于其混合缺陷，包括减少细胞表面靶向和无效的组装信号微域。有缺陷的SD可能赋予对免疫原性刺激的易感性并易于复发表型。
Minimal-change disease (MCD) is the most common cause of nephrotic syndrome (NS) and is characterized only by minor morphological alterations in podocytes. A subtype of MCD arises from mutations in nephrin, a major component of the slit diaphragm (SD). Idiopathic MCD is a complex trait where interactions of genetic and immunological factors are implicated. However, the pathogenic mechanisms remain unclear. Here we studied the molecular basis for familial NS characterized by frequent relapses and minimal-change histology. Our previous mutational analysis revealed that the two affected children were compound heterozygotes for nephrin variants C265R and V822M (Kidney Int., 2008). When heterologously expressed, these variants exhibited normal metabolic half-life and raft binding. C265R exhibited substantial ER retention, reflecting an intracellular trafficking defect. In contrast, V822M was able to reach the plasma membrane, but was restricted in lateral diffusion as well as trafficking at the cell surface. Clustering of V822M failed to evoke a maximum tyrosine-phosphorylation and actin reorganization, suggesting the inability to assemble into functioning membrane microdomains. Our results suggest that C265R and V822M compose a dysfunctional SD complex due to their mixed defects comprising reduced cell surface targeting and ineffective assembly of signaling microdomains. The defective SD likely confers a susceptibility to immunogenic stimuli and predisposes to a relapsing phenotype.