Defects of CRB2 cause steroid-resistant nephrotic syndrome

Am J Hum Genet. 2015 Jan 8;96(1):153-61. doi: 10.1016/j.ajhg.2014.11.014.

Lwaki Ebarasi ¹, Shazia Ashraf ², Agnieszka Bierzynska ³, Heon Yung Gee ², Hugh J McCarthy ³, Svjetlana Lovric ², Carolin E Sadowski ², Werner Pabst ², Virginia Vega-Warner ⁴, Humphrey Fang ², Ania Koziell ⁵, Michael A Simpson ⁶, Ismail Dursun ⁷, Erkin Serdaroglu ⁸, Shawn Levy ⁹, Moin A Saleem ³, Friedhelm Hildebrandt ¹⁰, Arindam Majumdar ¹¹

Affiliations

1 Department of Immunology, Genetics, and Pathology, Uppsala University, 751 85 Uppsala, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden.
2 Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3 Children's and Academic Renal Unit, University of Bristol, Bristol BS1 5NB, UK.
4 Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
5 Department of Experimental Immunobiology, Medical and Molecular Genetics, King's College London, 8th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
6 Medical and Molecular Genetics, King's College London, 8th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
7 Departments of Pediatric Nephrology and Rheumatology, Erciyes University, Kayseri 38039, Turkey.
8 Department of Pediatric Nephrology, Dr. Behcet Uz Children Hospital, Izmir 35210, Turkey.
9 HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
10 Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.
11 Department of Immunology, Genetics, and Pathology, Uppsala University, 751 85 Uppsala, Sweden. Electronic address: arindam.majumdar@igp.uu.se.

PMID: 25557779 DOI: 10.1016/j.ajhg.2014.11.014

Abstract

Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome Sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.

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