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Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
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2015 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 96, no 1, 153-161 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 96, no 1, 153-161 p.
National Category
Medical Genetics
URN: urn:nbn:se:uu:diva-247168DOI: 10.1016/j.ajhg.2014.11.014ISI: 000347707800012PubMedID: 25557779OAI: oai:DiVA.org:uu-247168DiVA: diva2:795387
Available from: 2015-03-16 Created: 2015-03-13 Last updated: 2015-03-16Bibliographically approved

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