A novel NPHS2 mutation (c.865A > G) identified in a Chinese family with steroid-resistant nephrotic syndrome alters subcellular localization of nephrin
A novel NPHS2 mutation (c.865A > G) identified in a Chinese family with steroid-resistant nephrotic syndrome alters subcellular localization of nephrin
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在一个患有类固醇抵抗性肾病综合征的中国家族中发现的一种新的 NPHS2 突变 (c.865A > G) 改变了去氧肾上腺素的亚细胞定位
DOI：
10.1007/s13258-022-01220-5
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发表时间：
2022
期刊：
影响因子：
2.1
通讯作者：
Yongxin Ma
中科院分区：
文献类型：
--
作者：
Na Wu;Yingchuan Zhu;Wenhao Jiang;Yue Song;Lan Yin;Yi;D. Tao;Yunqiang Liu;Yongxin Ma
NPHS2是2型肾病综合征(MIM 600995)的致病基因，临床上常表现为激素抵抗型肾病综合征(SRNS)。NPHS2基因编码一种狭缝隔膜(SD)相关蛋白podocin。这项研究报告了一个患有SRNS的中国家庭中一个新的致病突变NPHS2。我们还研究了该家族变异的致病机制。招募了一个患有SRNS的中国家庭。进行外显子全序列测定以筛选致病突变。采用Sanger测序对结果进行验证。体外功能实验包括免疫印迹、免疫共沉淀和双重免疫荧光染色，以探讨突变的致病机制。在这个家系中，发现了NPHS2的复合杂合突变(c.467dupT和c.865A >； G)，并与该病分离。母系基因c.865A >； G是一个新的变异，导致氨基酸替换(p.K289E)。体外功能分析表明，c.467dupT(p.L156FfsX11)突变体失去了与neparin的相互作用。K289E和L156FfsX11突变体的质膜定位均显著减弱。此外，podocin突变体的异常分布也改变了neparin的细胞膜定位。我们报告了一个由NPHS2复合杂合突变(c.467dupT和c.865A >； G)引起的SRNS家系。NPHS2中的C.865A >； G(p.K289E)是一种与SRNS相关的新的致病变异。该家族的这两个变异体不仅影响了podocin的正常细胞膜定位，而且还改变了SD的主要结构蛋白newitin的细胞膜定位。
NPHS2 is the causative gene of nephrotic syndrome type 2 (MIM 600995) which often clinically manifests as steroid-resistant nephrotic syndrome (SRNS). The NPHS2 gene encodes a slit diaphragm (SD) associated protein podocin. This study reported a novel disease-causing mutation of NPHS2 in a Chinese family with SRNS. We also investigated the pathogenic mechanism of the variants in this family. A Chinese family with SRNS was recruited. Whole exome sequencing was performed to screen for disease-causing mutation. Sanger sequencing was used to confirm the results. In vitro functional experiments including immunoblotting, co‐immunoprecipitation and double immunofluorescence staining were performed to explore the pathogenic mechanisms of mutations. In this family, compound heterozygous mutations of NPHS2 (c.467dupT and c.865A > G) were identified and segregated with the disease. The maternal c.865A > G was a novel variant, leading to amino acid substitution (p.K289E). In vitro functional assays indicated that c.467dupT (p.L156FfsX11) mutant lost interaction with nephrin. Both K289E and L156FfsX11 mutants showed sharply diminished plasma membrane localization. Furthermore, abnormal distribution of podocin mutants also altered the cell membrane localization of nephrin. We reported a family with SRNS caused by compound heterozygous mutations of NPHS2 (c.467dupT and c.865A > G). c.865A > G (p.K289E) in NPHS2 was a novel causative variant associated with SRNS. Both variants in this family not only affected the normal cell membrane localization of podocin, but also altered the cell membrane localization of nephrin which is the major architectural protein of SD.
DOI：
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发表时间：
1999-11
期刊：
Journal of the American Society of Nephrology : JASN
影响因子：
--
作者：
K. Tryggvason
通讯作者：
K. Tryggvason
影响因子：
13.6
作者：
Hinkes, Bernward;Vlangos, Christopher;Hildebrandt, Friedhelm
通讯作者：
Hildebrandt, Friedhelm
影响因子：
19.6
作者：
Holzman, LB;St John, PL;Abrahamson, DR
通讯作者：
Abrahamson, DR