Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome

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.

AP-2 complex-mediated endocytosis of Drosophila Crumbs regulates polarity via antagonizing Stardust

“…crb2b mutant zebrafish show defects in the formation of the slit diaphragm as well as in arborization of the foot processes. Furthermore, mutations in human Crb2 are linked to steroid-resistant nephrotic syndrome (Ebarasi et al, 2015), a disease causing kidney failure due to defects in differentiation and function of podocytes. Here, we show that AP-2α mutant garland cells are clearly impaired in Crb endocytosis.…”

Expansion of phenotype and genotypic data in CRB2-related syndrome

“…In a simultaneously published report, sequence variants in CRB2 were also shown to cause steroid resistant nephrotic syndrome (SRNS) with renal histological findings of focal segmental glomerulosclerosis (OMIM 616220) in four families. 2 Studies in Danio rerio demonstrated that the sequence variants associated with apparently isolated SRNS failed to rescue a mutant crb2b phenotype. 2 As crb2b is an orthologous gene to CRB2, these sequence variants were considered pathogenic for the renal abnormalities.…”

“…2 Studies in Danio rerio demonstrated that the sequence variants associated with apparently isolated SRNS failed to rescue a mutant crb2b phenotype. 2 As crb2b is an orthologous gene to CRB2, these sequence variants were considered pathogenic for the renal abnormalities. 2 These patients did not have obvious cerebral or cardiac manifestations.…”

“…2 As crb2b is an orthologous gene to CRB2, these sequence variants were considered pathogenic for the renal abnormalities. 2 These patients did not have obvious cerebral or cardiac manifestations. Both of these reports showed that biallelic, sequence variants predicted to affect function in CRB2 cause phenotypic effects ranging from a severe phenotype manifesting in the second trimester of pregnancy with significant ventriculomegaly and renal failure, to apparently isolated renal disease presenting postnatally.…”

“…Both of these reports showed that biallelic, sequence variants predicted to affect function in CRB2 cause phenotypic effects ranging from a severe phenotype manifesting in the second trimester of pregnancy with significant ventriculomegaly and renal failure, to apparently isolated renal disease presenting postnatally. 1,2 Crb function is important in the organization of epithelia derived from ectoderm during organogenesis and in the maintenance of epithelial cell polarity. 3,4 Expression studies in human tissues demonstrated expression of CRB2 in the fetal eye and fetal cochlea, and in the retinal pigment epithelium, choroid, brain, kidney, heart, placenta and lung.…”