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 Shril; Tobias B. Huber; Shrikant Mane; Friedhelm Hildebrandt; Deepak Nihalani

doi:10.1016/j.kint.2019.06.016

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

Department of Pharmacology

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

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 language	English
Pages (from-to)	883-889
Number of pages	7
Journal	Kidney International
Volume	96
Issue number	4
DOIs	https://doi.org/10.1016/j.kint.2019.06.016
Publication status	Published - 2019 Oct

Bibliographical note

Funding 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.

Publisher Copyright:
© 2019 International Society of Nephrology

All Science Journal Classification (ASJC) codes

Nephrology

Access to Document

10.1016/j.kint.2019.06.016

Cite this

Solanki, A. K., Widmeier, E., Arif, E., Sharma, S., Daga, A., Srivastava, P., Kwon, S. H., Hugo, H., Nakayama, M., Mann, N., Majmundar, A. J., Tan, W., Gee, H. Y., Sadowski, C. E., Rinat, C., Becker-Cohen, R., Bergmann, C., Rosen, S., Somers, M., ... Nihalani, D. (2019). Mutations in KIRREL1, a slit diaphragm component, cause steroid-resistant nephrotic syndrome. Kidney International, 96(4), 883-889. https://doi.org/10.1016/j.kint.2019.06.016

@article{64f36c1fb390449ba2eeb9ded6d1c784,

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

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.",

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

note = "Funding 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 f{\"u}r 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. Publisher Copyright: {\textcopyright} 2019 International Society of Nephrology",

year = "2019",

month = oct,

doi = "10.1016/j.kint.2019.06.016",

language = "English",

volume = "96",

pages = "883--889",

journal = "Kidney International",

issn = "0085-2538",

publisher = "Nature Publishing Group",

number = "4",

}

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, vol. 96, no. 4, pp. 883-889. https://doi.org/10.1016/j.kint.2019.06.016

TY - JOUR

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

N1 - Funding 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. Publisher Copyright: © 2019 International Society of Nephrology

PY - 2019/10

Y1 - 2019/10

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85071285678&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071285678&partnerID=8YFLogxK

U2 - 10.1016/j.kint.2019.06.016

DO - 10.1016/j.kint.2019.06.016

M3 - Article

C2 - 31472902

AN - SCOPUS:85071285678

SN - 0085-2538

VL - 96

SP - 883

EP - 889

JO - Kidney International

JF - Kidney International

IS - 4

ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this