Abstract
Background
Steroid-resistant nephrotic syndrome (SRNS) is a genetically heterogeneous disorder for which more than 25 single-gene hereditary causes have been identified.
Methods
Whole exome sequencing was performed in a 3-year-old girl with SRNS. We analyzed the expression of Crb2 and slit diaphragm molecules in the patient’s glomeruli, and compared it with that of controls or other nephrotic patients.
Results
Whole-exome analysis identified novel compound heterozygous mutations in exons 10 and 12 of CRB2 (p.Trp1086ArgfsX64 and p.Asn1184Thr, each from different parents; Asn1184 within extracellular 15th EGF repeat domain). Renal pathology showed focal segmental glomerulosclerosis with effaced podocyte foot processes in a small area, with significantly decreased Crb2 expression. Molecules critical for slit diaphragm were well-expressed in this patient’s podocytes. Crb2 expression was not altered in the other patients with congenital nephrotic syndrome with NPHS1 mutations.
Conclusions
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.
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Acknowledgments
The authors thank Dr. Masaki Nishimura (Shiga University of Medical Science) for providing Crb2 plasmid constructs.
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Informed consent for DNA analysis was obtained from the parents. The study was performed with approval from the Ethics Committee of the University of Tokyo.
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The authors declare that they have no conflicts of interest.
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Tomohiro Udagawa and Tohaku Jo contributed equally to this work
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Udagawa, T., Jo, T., Yanagihara, T. et al. Altered expression of Crb2 in podocytes expands a variation of CRB2 mutations in steroid-resistant nephrotic syndrome. Pediatr Nephrol 32, 801–809 (2017). https://doi.org/10.1007/s00467-016-3549-4
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DOI: https://doi.org/10.1007/s00467-016-3549-4