Mutations in EMP2 Cause Childhood-Onset Nephrotic Syndrome
Mutations in EMP2 Cause Childhood-Onset Nephrotic Syndrome
复制标题
DOI：
10.1016/j.ajhg.2014.04.010
复制
发表时间：
2014-06-05
影响因子：
9.8
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
--
作者：
Gee, Heon Yung;Ashraf, Shazia;Hildebrandt, Friedhelm
肾病综合征（NS）是一组遗传异质性疾病，分为激素敏感型NS（SSNS）和激素耐药型NS（SRNS）。SRNS不可避免地导致终末期肾病，并且没有治愈性治疗。到目前为止，超过24个基因的突变已被描述在孟德尔形式的SRNS;然而，没有孟德尔形式的SSNS已被描述。为了鉴定SSNS的遗传形式，我们进行了纯合性作图、全外显子组测序和多重PCR，然后进行下一代测序。因此，我们检测到EMP 2（上皮膜蛋白2）的双等位基因突变在三个无关的家庭SRNS或SSNS影响的四个人。我们发现，EMP 2只局限于肾小球在肾脏。在斑马鱼中敲低emp 2导致心包积液，支持突变的EMP 2在人类NS中的致病作用。在细胞水平上，我们发现在足细胞和内皮细胞中敲低EMP 2导致CAVEOLIN-1的量增加和细胞增殖减少。因此，我们的数据确定EMP 2突变导致隐性孟德尔形式的SSNS。
Nephrotic syndrome (NS) is a genetically heterogeneous group of diseases that are divided into steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS). SRNS inevitably leads to end-stage kidney disease, and no curative treatment is available. To date, mutations in more than 24 genes have been described in Mendelian forms of SRNS; however, no Mendelian form of SSNS has been described. To identify a genetic form of SSNS, we performed homozygosity mapping, whole-exome sequencing, and multiplex PCR followed by next-generation sequencing. We thereby detected biallelic mutations in EMP2 (epithelial membrane protein 2) in four individuals from three unrelated families affected by SRNS or SSNS. We showed that EMP2 exclusively localized to glomeruli in the kidney. Knockdown of emp2 in zebrafish resulted in pericardial effusion, supporting the pathogenic role of mutated EMP2 in human NS. At the cellular level, we showed that knockdown of EMP2 in podocytes and endothelial cells resulted in an increased amount of CAVEOLIN-1 and decreased cell proliferation. Our data therefore identify EMP2 mutations as causing a recessive Mendelian form of SSNS.