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

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...

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Bibliographic Details
Published in:	Kidney international Vol. 96; no. 4; p. 883
Main Authors:	Solanki, Ashish K, Widmeier, Eugen, Arif, Ehtesham, Sharma, Shailza, Daga, Ankana, Srivastava, Pankaj, Kwon, Sang-Ho, Hugo, Hannah, Nakayama, Makiko, Mann, Nina, Majmundar, Amar J, Tan, Wei, Gee, Heon Yung, Sadowski, Caroline E, Rinat, Choni, Becker-Cohen, Rachel, Bergmann, Carsten, Rosen, Seymour, Somers, Michael, Shril, Shirlee, Huber, Tobias B, Mane, Shrikant, Hildebrandt, Friedhelm, Nihalani, Deepak
Format:	Journal Article
Language:	English
Published:	United States 01-10-2019
Subjects:	Adolescent Age of Onset Cell Line Child Child, Preschool Consanguinity Disease Progression DNA Mutational Analysis 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 KIRREL1 steroid-resistant nephrotic syndrome minimal change disease focal segmental glomerulosclerosis
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Summary:	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.
ISSN:	1523-1755
DOI:	10.1016/j.kint.2019.06.016