Defects of CRB2 cause steroid-resistant nephrotic syndrome

Lwaki Ebarasi; Shazia Ashraf; Agnieszka Bierzynska; Heon Yung Gee; Hugh J. McCarthy; Svjetlana Lovric; Carolin E. Sadowski; Werner Pabst; Virginia Vega-Warner; Humphrey Fang; Ania Koziell; Michael A. Simpson; Ismail Dursun; Erkin Serdaroglu; Shawn Levy; Moin A. Saleem; Friedhelm Hildebrandt; Arindam Majumdar

doi:10.1016/j.ajhg.2014.11.014

Defects of CRB2 cause steroid-resistant nephrotic syndrome

Lwaki Ebarasi, Shazia Ashraf, Agnieszka Bierzynska, Heon Yung Gee, Hugh J. McCarthy, Svjetlana Lovric, Carolin E. Sadowski, Werner Pabst, Virginia Vega-Warner, Humphrey Fang, Ania Koziell, Michael A. Simpson, Ismail Dursun, Erkin Serdaroglu, Shawn Levy, Moin A. Saleem, Friedhelm Hildebrandt, Arindam Majumdar

Department of Pharmacology

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

80 Citations (Scopus)

Abstract

Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.

Original language	English
Pages (from-to)	153-161
Number of pages	9
Journal	American Journal of Human Genetics
Volume	96
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2014.11.014
Publication status	Published - 2015 Jan 8

Bibliographical note

Funding Information:
We would like to acknowledge the late Michelle Winn (Duke University) for initial attempts at finding human CRB2 mutations. We thank Markus Affolter and Hans Georg Belting for the α-Pdxl2 antibody. Special thanks to Lars Holmgren (Karolinska Institute) and Lena Claesson-Welsh (Uppsala University) for their overall support and encouragement. We thank Leslie Steed for clinical samples, Giselbert Hauptmann and Iris Sol for zebrafish care, and Katarina Garpenstrand and Johan Ledin at the SciLife zebrafish, Uppsala University. The authors also thank the families who contributed to this study. This research was supported by grants from the NIH to F.H. (DK076683, DK086542) and by the Nephcure Foundation to F.H. H.Y.G. is supported by the NephCure-ASN Foundation Kidney Research grant. F.H. is an Investigator of the Howard Hughes Medical Institute and the Warren E. Grupe Professor. A.K. is supported by a HEFC Senior Clinical Lectureship. The research was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, Kids Kidney Research, Kidney Research UK, and the British Kidney Patients Association. We would like to acknowledge RADAR, the UK SRNS study group, especially Dr. Larissa Kerecuk for participation and support. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.

Publisher Copyright:
© 2015 The American Society of Human Genetics.

All Science Journal Classification (ASJC) codes

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2014.11.014

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Ebarasi, L., Ashraf, S., Bierzynska, A., Gee, H. Y., McCarthy, H. J., Lovric, S., Sadowski, C. E., Pabst, W., Vega-Warner, V., Fang, H., Koziell, A., Simpson, M. A., Dursun, I., Serdaroglu, E., Levy, S., Saleem, M. A., Hildebrandt, F., & Majumdar, A. (2015). Defects of CRB2 cause steroid-resistant nephrotic syndrome. American Journal of Human Genetics, 96(1), 153-161. https://doi.org/10.1016/j.ajhg.2014.11.014

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title = "Defects of CRB2 cause steroid-resistant nephrotic syndrome",

abstract = "Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.",

author = "Lwaki Ebarasi and Shazia Ashraf and Agnieszka Bierzynska and Gee, {Heon Yung} and McCarthy, {Hugh J.} and Svjetlana Lovric and Sadowski, {Carolin E.} and Werner Pabst and Virginia Vega-Warner and Humphrey Fang and Ania Koziell and Simpson, {Michael A.} and Ismail Dursun and Erkin Serdaroglu and Shawn Levy and Saleem, {Moin A.} and Friedhelm Hildebrandt and Arindam Majumdar",

note = "Funding Information: We would like to acknowledge the late Michelle Winn (Duke University) for initial attempts at finding human CRB2 mutations. We thank Markus Affolter and Hans Georg Belting for the α-Pdxl2 antibody. Special thanks to Lars Holmgren (Karolinska Institute) and Lena Claesson-Welsh (Uppsala University) for their overall support and encouragement. We thank Leslie Steed for clinical samples, Giselbert Hauptmann and Iris Sol for zebrafish care, and Katarina Garpenstrand and Johan Ledin at the SciLife zebrafish, Uppsala University. The authors also thank the families who contributed to this study. This research was supported by grants from the NIH to F.H. (DK076683, DK086542) and by the Nephcure Foundation to F.H. H.Y.G. is supported by the NephCure-ASN Foundation Kidney Research grant. F.H. is an Investigator of the Howard Hughes Medical Institute and the Warren E. Grupe Professor. A.K. is supported by a HEFC Senior Clinical Lectureship. The research was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London, Kids Kidney Research, Kidney Research UK, and the British Kidney Patients Association. We would like to acknowledge RADAR, the UK SRNS study group, especially Dr. Larissa Kerecuk for participation and support. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Publisher Copyright: {\textcopyright} 2015 The American Society of Human Genetics.",

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doi = "10.1016/j.ajhg.2014.11.014",

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Ebarasi, L, Ashraf, S, Bierzynska, A, Gee, HY, McCarthy, HJ, Lovric, S, Sadowski, CE, Pabst, W, Vega-Warner, V, Fang, H, Koziell, A, Simpson, MA, Dursun, I, Serdaroglu, E, Levy, S, Saleem, MA, Hildebrandt, F & Majumdar, A 2015, 'Defects of CRB2 cause steroid-resistant nephrotic syndrome', American Journal of Human Genetics, vol. 96, no. 1, pp. 153-161. https://doi.org/10.1016/j.ajhg.2014.11.014

TY - JOUR

T1 - Defects of CRB2 cause steroid-resistant nephrotic syndrome

AU - Ebarasi, Lwaki

AU - Ashraf, Shazia

AU - Bierzynska, Agnieszka

AU - Gee, Heon Yung

AU - McCarthy, Hugh J.

AU - Lovric, Svjetlana

AU - Sadowski, Carolin E.

AU - Pabst, Werner

AU - Vega-Warner, Virginia

AU - Fang, Humphrey

AU - Koziell, Ania

AU - Simpson, Michael A.

AU - Dursun, Ismail

AU - Serdaroglu, Erkin

AU - Levy, Shawn

AU - Saleem, Moin A.

AU - Hildebrandt, Friedhelm

AU - Majumdar, Arindam

N1 - Funding Information: We would like to acknowledge the late Michelle Winn (Duke University) for initial attempts at finding human CRB2 mutations. We thank Markus Affolter and Hans Georg Belting for the α-Pdxl2 antibody. Special thanks to Lars Holmgren (Karolinska Institute) and Lena Claesson-Welsh (Uppsala University) for their overall support and encouragement. We thank Leslie Steed for clinical samples, Giselbert Hauptmann and Iris Sol for zebrafish care, and Katarina Garpenstrand and Johan Ledin at the SciLife zebrafish, Uppsala University. The authors also thank the families who contributed to this study. This research was supported by grants from the NIH to F.H. (DK076683, DK086542) and by the Nephcure Foundation to F.H. H.Y.G. is supported by the NephCure-ASN Foundation Kidney Research grant. F.H. is an Investigator of the Howard Hughes Medical Institute and the Warren E. Grupe Professor. A.K. is supported by a HEFC Senior Clinical Lectureship. The research was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, Kids Kidney Research, Kidney Research UK, and the British Kidney Patients Association. We would like to acknowledge RADAR, the UK SRNS study group, especially Dr. Larissa Kerecuk for participation and support. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Publisher Copyright: © 2015 The American Society of Human Genetics.

PY - 2015/1/8

Y1 - 2015/1/8

N2 - Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.

AB - Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.

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Defects of CRB2 cause steroid-resistant nephrotic syndrome

Abstract

Bibliographical note

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