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. Epub 2019 Jul 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Age of Onset
  • Cell Line
  • Child
  • Child, Preschool
  • Consanguinity
  • DNA Mutational Analysis
  • Disease Progression
  • Drug Resistance / genetics*
  • Exome Sequencing
  • Female
  • Follow-Up Studies
  • Gene Frequency
  • Glomerular Basement Membrane / pathology
  • Glomerular Basement Membrane / ultrastructure
  • Glucocorticoids / pharmacology*
  • Glucocorticoids / therapeutic use
  • Homozygote
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Microscopy, Electron, Transmission
  • Mutation
  • Nephrotic Syndrome / drug therapy
  • Nephrotic Syndrome / genetics*
  • Nephrotic Syndrome / pathology
  • Pedigree
  • Podocytes
  • Renal Insufficiency, Chronic / genetics*
  • Renal Insufficiency, Chronic / pathology


  • Glucocorticoids
  • KIRREL1 protein, human
  • Kirrel1 protein, mouse
  • Membrane Proteins
  • nephrin