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

Ashish K. Solanki, Eugen Widmeier, Ehtesham Arif, Shailza Sharma, Ankana Daga, Pankaj Srivastava, Sang Ho Kwon, Hannah Hugo, Makiko Nakayama, Nina Mann, Amar J. Majmundar, Wei Tan, Heon Yung Gee, Caroline E. Sadowski, Choni Rinat, Rachel Becker-Cohen, Carsten Bergmann, Seymour Rosen, Michael Somers, Shirlee ShrilTobias B. Huber, Shrikant Mane, Friedhelm Hildebrandt, Deepak Nihalani

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalKidney International
DOIs
Publication statusAccepted/In press - 2019 Jan 1

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Podocytes
Nephrotic Syndrome
Diaphragm
Steroids
Chronic Renal Insufficiency
Mutation
Genes
Mutant Proteins
Gene Frequency
Chronic Kidney Failure
Cell Membrane
Population
Therapeutics

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Solanki, A. K., Widmeier, E., Arif, E., Sharma, S., Daga, A., Srivastava, P., ... Nihalani, D. (Accepted/In press). Mutations in KIRREL1, a slit diaphragm component, cause steroid-resistant nephrotic syndrome. Kidney International. https://doi.org/10.1016/j.kint.2019.06.016
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. / Mutations in KIRREL1, a slit diaphragm component, cause steroid-resistant nephrotic syndrome. In: Kidney International. 2019.
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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.",
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Solanki, AK, Widmeier, E, Arif, E, Sharma, S, Daga, A, Srivastava, P, Kwon, SH, Hugo, H, Nakayama, M, Mann, N, Majmundar, AJ, Tan, W, Gee, HY, Sadowski, CE, Rinat, C, Becker-Cohen, R, Bergmann, C, Rosen, S, Somers, M, Shril, S, Huber, TB, Mane, S, Hildebrandt, F & Nihalani, D 2019, 'Mutations in KIRREL1, a slit diaphragm component, cause steroid-resistant nephrotic syndrome', Kidney International. https://doi.org/10.1016/j.kint.2019.06.016

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

In: Kidney International, 01.01.2019.

Research output: Contribution to journalArticle

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T1 - Mutations in KIRREL1, a slit diaphragm component, cause steroid-resistant nephrotic syndrome

AU - Solanki, Ashish K.

AU - Widmeier, Eugen

AU - Arif, Ehtesham

AU - Sharma, Shailza

AU - Daga, Ankana

AU - Srivastava, Pankaj

AU - Kwon, Sang Ho

AU - Hugo, Hannah

AU - Nakayama, Makiko

AU - Mann, Nina

AU - Majmundar, Amar J.

AU - Tan, Wei

AU - Gee, Heon Yung

AU - Sadowski, Caroline E.

AU - Rinat, Choni

AU - Becker-Cohen, Rachel

AU - Bergmann, Carsten

AU - Rosen, Seymour

AU - Somers, Michael

AU - Shril, Shirlee

AU - Huber, Tobias B.

AU - Mane, Shrikant

AU - Hildebrandt, Friedhelm

AU - Nihalani, Deepak

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

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