Altered expression of Crb2 in podocytes expands a variation of CRB2 mutations in steroid-resistant nephrotic syndrome

Abstract

These findings demonstrate that Crb2 abnormalities caused by these mutations are the mechanism of steroid-resistant NS. Although CRB2 mutations previously found in SRNS patients have been clustered within the extracellular tenth EGF-like domain of this protein, the present results expand the variation of CRB2 mutations that cause SRNS.

Long‐term clinicopathologic observation in a case of steroid‐resistant nephrotic syndrome caused by a novel Crumbs homolog 2 mutation

“…It is currently recommended to perform genetic testing for SRNS in children with early‐onset SRNS . Indeed, genetic testing for SRNS was performed at a relatively earlier time from detection in recently reported cases of CRB2 ‐related SRNS . In our patient, it was impossible to conduct such testing at that time of our initial presentation.…”

“…Thus, the implication of clinical genetic testing in SRNS is increasing. Recent advances in high‐throughput sequencing for clinical genetic testing have revealed novel disease‐causing genes, such as CRB2 for early‐onset SRNS . The CRB2 gene contains 15 epidermal growth factor (EGF)‐like domains and three laminin‐like domains, and its product Crb, a key protein in CRB complexes that are crucial for biological development of epithelial cells including podocytes .…”

“…The CRB2 gene contains 15 epidermal growth factor (EGF)‐like domains and three laminin‐like domains, and its product Crb, a key protein in CRB complexes that are crucial for biological development of epithelial cells including podocytes . So far, only five children with SRNS due to identified CRB2 mutations exhibiting histologically confirmed FSGS (four showed FSGS and the remaining one did not undergo renal biopsy) have been reported . Although the CRB2 mutation in these SRNS patients is reported to occur predominantly in the 10th EGF‐like domain, details regarding the long‐term outcome as well as the genotype–phenotype correlation of these patients remain largely unclear.…”

“…A newly identified vertebral Crumbs (CRB) protein family has been reported to regulate epithelial cell polarity . Among the CRB family proteins, Crumbs homolog 2 (CRB2) is reportedly expressed on glomerular podocytes and CRB2 mutations cause both early‐onset steroid‐resistant nephrotic syndrome (SRNS), histologically exhibiting focal segmental glomerular sclerosis (FSGS) (OMIM 616220) and CRB2 ‐related syndrome characterized by foetal hydrocephalus, retinal abnormality, and congenital nephrosis that mimics Finnish type nephrosis (OMIM 219730) . Since CRB2 is required for epithelial apical‐basal differentiation, loss of CRB2 function causes podocyte alterations leading to the above mentioned diseases mimicking ciliopathy However, detailed information regarding the genotype–phenotype correlations of this disease is still lacking.…”

“…Since CRB2 is required for epithelial apical‐basal differentiation, loss of CRB2 function causes podocyte alterations leading to the above mentioned diseases mimicking ciliopathy However, detailed information regarding the genotype–phenotype correlations of this disease is still lacking. To our current knowledge, only five paediatric cases of SRNS without extrarenal signs caused by CRB2 mutations have been reported to date . However, the long‐term clinicopathological outcome of SRNS caused by the CRB2 mutation remains unclear.…”