TY - JOUR
T1 - Defects of CRB2 cause steroid-resistant nephrotic syndrome
AU - Ebarasi, Lwaki
AU - Ashraf, Shazia
AU - Bierzynska, Agnieszka
AU - Gee, Heon Yung
AU - McCarthy, Hugh J.
AU - Lovric, Svjetlana
AU - Sadowski, Carolin E.
AU - Pabst, Werner
AU - Vega-Warner, Virginia
AU - Fang, Humphrey
AU - Koziell, Ania
AU - Simpson, Michael A.
AU - Dursun, Ismail
AU - Serdaroglu, Erkin
AU - Levy, Shawn
AU - Saleem, Moin A.
AU - Hildebrandt, Friedhelm
AU - Majumdar, Arindam
N1 - Publisher Copyright:
© 2015 The American Society of Human Genetics.
Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2015/1/8
Y1 - 2015/1/8
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2014.11.014
DO - 10.1016/j.ajhg.2014.11.014
M3 - Article
C2 - 25557779
AN - SCOPUS:84920736253
VL - 96
SP - 153
EP - 161
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -