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Defects of CRB2 cause steroid-resistant nephrotic syndrome

 Lwaki Ebarasi  ;  Shazia Ashraf  ;  Arindam Majumdar  ;  Friedhelm Hildebrandt  ;  Moin A. Saleem  ;  Shawn Levy  ;  Erkin Serdaroglu  ;  Ismail Dursun  ;  Michael A. Simpson  ;  Ania Koziell  ;  Humphrey Fang  ;  Virginia Vega-Warner  ;  Werner Pabst  ;  Carolin E. Sadowski  ;  Svjetlana Lovric  ;  Hugh J. McCarthy  ;  Heon Yung Gee  ;  Agnieszka Bierzynska 
 American Journal of Human Genetics, Vol.96(1) : 153-161, 2015 
Journal Title
 American Journal of Human Genetics 
Issue Date
Amino Acid Sequence ; Animals ; Carrier Proteins/genetics* ; Carrier Proteins/metabolism ; Child ; Child, Preschool ; Chromosome Mapping ; Exome ; Genes, Recessive ; Homozygote ; Humans ; Infant ; Kidney Failure, Chronic/etiology ; Kidney Failure, Chronic/genetics ; Membrane Proteins/genetics* ; Membrane Proteins/metabolism ; Molecular Sequence Data ; Mutation ; Nephrotic Syndrome/complications ; Nephrotic Syndrome/genetics* ; Podocytes ; Rats ; Zebrafish/genetics
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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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
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