Steroid-resistant nephrotic syndrome is a frequent cause of chronic kidney disease almost inevitably progressing to end-stage renal disease. More than 58 monogenic causes of SRNS have been discovered and majority of known steroid-resistant nephrotic syndrome causing genes are predominantly expressed in glomerular podocytes, placing them at the center of disease pathogenesis. Herein, we describe two unrelated families with steroid-resistant nephrotic syndrome with homozygous mutations in the KIRREL1 gene. One mutation showed high frequency in the European population (minor allele frequency 0.0011) and this patient achieved complete remission following treatment, but later progressed to chronic kidney disease. We found that mutant KIRREL1 proteins failed to localize to the podocyte cell membrane, indicating defective trafficking and impaired podocytes function. Thus, the KIRREL1 gene product has an important role in modulating the integrity of the slit diaphragm and maintaining glomerular filtration function.
Bibliographical noteFunding Information:
This research was supported by grants from the National Institutes of Health ( DK076683 [to FH], RO1 2R01DK087956-06A1 [to DN] ), the Yale Center for Mendelian Genomics ( U54HG006504 ), and Boston Children's Hospital ( T32-DK007726-33 [to NM] ) and Ben J. Lipps Research Fellowship from the American Society of Nephrology (to AKS). TBH was supported for this study by the Deutsche Forschungsgemeinschaft ( CRC1140 ), the Bundesministerium für Bildung und Forschung ( 01GM1518C ), and the European Research Council ( 616891 ). EW was supported by the German National Academy of Sciences Leopoldina ( LPDS-2015-07 ). AJM was supported by a National Institutes of Health Training Grant ( T32DK-007726 ), by the 2017 Post-doctoral Fellowship Grant from the Harvard Stem Cell Institute , and by the American Society of Nephrology Lipps Research Program 2018 Polycystic Kidney Disease Foundation Jared J. Grantham Research Fellowship.
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