Mutations in EMP2 Cause Childhood-Onset Nephrotic Syndrome

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• 作者：Heon Yung Gee¹ ; ¹³ ; Shazia Ashraf¹ ; ¹³ ; Xiaoyang Wan² ; Virginia Vega-Warner² ; Julian Esteve-Rudd³ ; Svjetlana Lovric¹ ; Humphrey Fang¹ ; Toby W. Hurd⁴ ; Carolin E. Sadowski¹ ; Susan J. Allen² ; Edgar A. Otto² ; Emine Korkmaz⁵ ; Joseph Washburn⁶ ; Shawn Levy⁷ ; David S. Williams³ ; Sevcan A. Bakkaloglu⁸ ; Anna Zolotnitskaya⁹ ; Fatih Ozaltin⁵ ; ¹⁰ ; ¹¹ ; Weibin Zhou² ; Friedhelm Hildebrandt¹ ; ¹² ; ^{friedhelm.hildebrandt@childrens.harvard.edu" class="auth_mail}
• 刊名：The American Journal of Human Genetics
• 出版年：5 June 2014
• 年：2014
• 卷：94
• 期：6
• 页码：884-890
• 全文大小：2331 K

文摘

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.