Mutations in KIRREL1, a slit diaphragm component, cause steroid-resistant nephrotic syndrome

Kidney Int. 2019 Oct;96(4):883-889. doi: 10.1016/j.kint.2019.06.016.

Ashish K Solanki ¹, Eugen Widmeier ², Ehtesham Arif ¹, Shailza Sharma ¹, Ankana Daga ³, Pankaj Srivastava ¹, Sang-Ho Kwon ⁴, Hannah Hugo ³, Makiko Nakayama ³, Nina Mann ³, Amar J Majmundar ³, Wei Tan ³, Heon Yung Gee ⁵, Caroline E Sadowski ³, Choni Rinat ⁶, Rachel Becker-Cohen ⁶, Carsten Bergmann ⁷, Seymour Rosen ⁸, Michael Somers ³, Shirlee Shril ³, Tobias B Huber ⁹, Shrikant Mane ¹⁰, Friedhelm Hildebrandt ¹¹, Deepak Nihalani ¹²

Affiliations

1 Department of Medicine, Nephrology Division, Medical University of South Carolina, Charleston, South Carolina, USA.
2 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
3 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
4 Department of Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, USA.
5 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Pharmacology, Brain Korea 21 Program for Leading Universities & Students (PLUS) Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
6 Division of Pediatric Nephrology, Shaare Zedek Medical Center, The Hadassah-Hebrew University School of Medicine, Jerusalem, Israel.
7 Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
8 Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
9 Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; III Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Biological Signalling Studies (BIOSS) Center for Biological Signaling Studies, Albert-Ludwigs-University, Freiburg, Germany.
10 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
11 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.
12 Department of Medicine, Nephrology Division, Medical University of South Carolina, Charleston, South Carolina, USA. Electronic address: nihalani@musc.edu.

PMID: 31472902 DOI: 10.1016/j.kint.2019.06.016

Abstract

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.

Keywords

KIRREL1; focal segmental glomerulosclerosis; minimal change disease; steroid-resistant nephrotic syndrome.

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