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 Y. Zolotnitskaya, Fatih Ozaltin, Weibin Zhou, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

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Abstract

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 (US)
Pages (from-to)884-890
Number of pages7
JournalAmerican Journal of Human Genetics
Volume94
Issue number6
DOIs
StatePublished - Jun 5 2014
Externally publishedYes

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Nephrotic Syndrome
Membrane Proteins
Steroids
Mutation
Kidney Glomerulus
Exome
Podocytes
Pericardial Effusion
Multiplex Polymerase Chain Reaction
Zebrafish
Chronic Kidney Failure
Endothelial Cells
Cell Proliferation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Gee, H. Y., Ashraf, S., Wan, X., Vega-Warner, V., Esteve-Rudd, J., Lovric, S., ... Hildebrandt, F. (2014). Mutations in EMP2 cause childhood-onset Nephrotic syndrome. American Journal of Human Genetics, 94(6), 884-890. https://doi.org/10.1016/j.ajhg.2014.04.010

Mutations in EMP2 cause childhood-onset Nephrotic syndrome. / Gee, Heon Yung; Ashraf, Shazia; Wan, Xiaoyang; Vega-Warner, Virginia; Esteve-Rudd, Julian; Lovric, Svjetlana; Fang, Humphrey; Hurd, Toby W.; Sadowski, Carolin E.; Allen, Susan J.; Otto, Edgar A.; Korkmaz, Emine; Washburn, Joseph; Levy, Shawn; Williams, David S.; Bakkaloglu, Sevcan A.; Zolotnitskaya, Anna Y.; Ozaltin, Fatih; Zhou, Weibin; Hildebrandt, Friedhelm.

In: American Journal of Human Genetics, Vol. 94, No. 6, 05.06.2014, p. 884-890.

Research output: Contribution to journalArticle

Gee, HY, Ashraf, S, Wan, X, Vega-Warner, V, Esteve-Rudd, J, Lovric, S, Fang, H, Hurd, TW, Sadowski, CE, Allen, SJ, Otto, EA, Korkmaz, E, Washburn, J, Levy, S, Williams, DS, Bakkaloglu, SA, Zolotnitskaya, AY, Ozaltin, F, Zhou, W & Hildebrandt, F 2014, 'Mutations in EMP2 cause childhood-onset Nephrotic syndrome', American Journal of Human Genetics, vol. 94, no. 6, pp. 884-890. https://doi.org/10.1016/j.ajhg.2014.04.010
Gee HY, Ashraf S, Wan X, Vega-Warner V, Esteve-Rudd J, Lovric S et al. Mutations in EMP2 cause childhood-onset Nephrotic syndrome. American Journal of Human Genetics. 2014 Jun 5;94(6):884-890. https://doi.org/10.1016/j.ajhg.2014.04.010
Gee, Heon Yung ; Ashraf, Shazia ; Wan, Xiaoyang ; Vega-Warner, Virginia ; Esteve-Rudd, Julian ; Lovric, Svjetlana ; Fang, Humphrey ; Hurd, Toby W. ; Sadowski, Carolin E. ; Allen, Susan J. ; Otto, Edgar A. ; Korkmaz, Emine ; Washburn, Joseph ; Levy, Shawn ; Williams, David S. ; Bakkaloglu, Sevcan A. ; Zolotnitskaya, Anna Y. ; Ozaltin, Fatih ; Zhou, Weibin ; Hildebrandt, Friedhelm. / Mutations in EMP2 cause childhood-onset Nephrotic syndrome. In: American Journal of Human Genetics. 2014 ; Vol. 94, No. 6. pp. 884-890.
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