Defects of CRB2 cause steroid-resistant nephrotic syndrome

Lwaki Ebarasi, Shazia Ashraf, Agnieszka Bierzynska, Heon Yung Gee, Hugh J. McCarthy, Svjetlana Lovric, Carolin E. Sadowski, Werner Pabst, Virginia Vega-Warner, Humphrey Fang, Ania Koziell, Michael A. Simpson, Ismail Dursun, Erkin Serdaroglu, Shawn Levy, Moin A. Saleem, Friedhelm Hildebrandt, Arindam Majumdar

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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.

Original languageEnglish
Pages (from-to)153-161
Number of pages9
JournalAmerican Journal of Human Genetics
Volume96
Issue number1
DOIs
Publication statusPublished - 2015 Jan 8

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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  • Cite this

    Ebarasi, L., Ashraf, S., Bierzynska, A., Gee, H. Y., McCarthy, H. J., Lovric, S., Sadowski, C. E., Pabst, W., Vega-Warner, V., Fang, H., Koziell, A., Simpson, M. A., Dursun, I., Serdaroglu, E., Levy, S., Saleem, M. A., Hildebrandt, F., & Majumdar, A. (2015). Defects of CRB2 cause steroid-resistant nephrotic syndrome. American Journal of Human Genetics, 96(1), 153-161. https://doi.org/10.1016/j.ajhg.2014.11.014