Mutations in EMP2 cause childhood-onset Nephrotic syndrome

Heon Yung Gee, Shazia Ashraf, Xiaoyang Wan, Virginia Vega-Warner, Julian Esteve-Rudd, Svjetlana Lovric, Humphrey Fang, Toby W. Hurd, Carolin E. Sadowski, Susan J. Allen, Edgar A. Otto, Emine Korkmaz, Joseph Washburn, Shawn Levy, David S. Williams, Sevcan A. Bakkaloglu, Anna Zolotnitskaya, Fatih Ozaltin, Weibin Zhou, Friedhelm Hildebrandt

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91 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)884-890
Number of pages7
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - 2014 Jun 5

Bibliographical note

Funding Information:
The authors thank the families who contributed to this study. We thank David M. Briscoe (Boston Children’s Hospital) for materials and helpful discussion. This research was supported by NIH grants to F.H. (DK076683 and DK086542), E.A.O. (DK090917), W.Z. (DK091405), and D.S.W. (EY07042) and by a Nephcure Foundation grant (to F.H.). F.O. was supported by the European Commission Seventh Framework Programme (EURenOmics, 2012-305608), the Scientific and Technological Research Council of Turkey (TUBITAK 108S417), and the Hacettepe University Infrastructure Project (06A101008 and 011A101003). H.Y.G. is a research fellow of the American Society of Nephrology. W.Z. is a Carl W. Gottschalk Scholar. D.S.W is a Jules and Doris Stein Research to Prevent Blindness Professor. F.H. is an investigator of the Howard Hughes Medical Institute, and Warren E. Grupe is a professor of pediatrics at the Harvard Medical School.

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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