Mutations in EMP2 cause childhood-onset nephrotic syndrome

Am J Hum Genet. 2014 Jun 5;94(6):884-90. doi: 10.1016/j.ajhg.2014.04.010.

Heon Yung Gee ¹, Shazia Ashraf ¹, Xiaoyang Wan ², Virginia Vega-Warner ², Julian Esteve-Rudd ³, Svjetlana Lovric ¹, Humphrey Fang ¹, Toby W Hurd ⁴, Carolin E Sadowski ¹, Susan J Allen ², Edgar A Otto ², Emine Korkmaz ⁵, Joseph Washburn ⁶, Shawn Levy ⁷, David S Williams ³, Sevcan A Bakkaloglu ⁸, Anna Zolotnitskaya ⁹, Fatih Ozaltin ¹⁰, Weibin Zhou ², Friedhelm Hildebrandt ¹¹

Affiliations

1 Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
2 Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
3 Jules Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
4 Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
5 Nephrogenetics Laboratory, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.
6 Biomedical Research Core Facilities, University of Michigan, Ann Arbor, MI 48109, USA.
7 HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
8 Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara 06570, Turkey.
9 New York Medical College, Valhalla, NY 10595, USA.
10 Nephrogenetics Laboratory, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey; Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey; Center for Biobanking and Genomics, Hacettepe University, Ankara 06100, Turkey.
11 Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: [email protected].

PMID: 24814193 DOI: 10.1016/j.ajhg.2014.04.010

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.

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