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Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice

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Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice. / Majmundar, Amar J; Buerger, Florian; Forbes, Thomas A; Klämbt, Verena; Schneider, Ronen; Deutsch, Konstantin; Kitzler, Thomas M; Howden, Sara E; Scurr, Michelle; Tan, Ker Sin; Krzeminski, Mickaël; Widmeier, Eugen; Braun, Daniela A; Lai, Ethan; Ullah, Ihsan; Amar, Ali; Kolb, Amy; Eddy, Kaitlyn; Chen, Chin Heng; Salmanullah, Daanya; Dai, Rufeng; Nakayama, Makiko; Ottlewski, Isabel; Kolvenbach, Caroline M; Onuchic-Whitford, Ana C; Mao, Youying; Mann, Nina; Nabhan, Marwa M; Rosen, Seymour; Forman-Kay, Julie D; Soliman, Neveen A; Heilos, Andreas; Kain, Renate; Aufricht, Christoph; Mane, Shrikant; Lifton, Richard P; Shril, Shirlee; Little, Melissa H; Hildebrandt, Friedhelm.

In: SCI ADV, Vol. 7, No. 1, eabe1386, 01.2021.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Majmundar, AJ, Buerger, F, Forbes, TA, Klämbt, V, Schneider, R, Deutsch, K, Kitzler, TM, Howden, SE, Scurr, M, Tan, KS, Krzeminski, M, Widmeier, E, Braun, DA, Lai, E, Ullah, I, Amar, A, Kolb, A, Eddy, K, Chen, CH, Salmanullah, D, Dai, R, Nakayama, M, Ottlewski, I, Kolvenbach, CM, Onuchic-Whitford, AC, Mao, Y, Mann, N, Nabhan, MM, Rosen, S, Forman-Kay, JD, Soliman, NA, Heilos, A, Kain, R, Aufricht, C, Mane, S, Lifton, RP, Shril, S, Little, MH & Hildebrandt, F 2021, 'Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice', SCI ADV, vol. 7, no. 1, eabe1386. https://doi.org/10.1126/sciadv.abe1386

APA

Majmundar, A. J., Buerger, F., Forbes, T. A., Klämbt, V., Schneider, R., Deutsch, K., Kitzler, T. M., Howden, S. E., Scurr, M., Tan, K. S., Krzeminski, M., Widmeier, E., Braun, D. A., Lai, E., Ullah, I., Amar, A., Kolb, A., Eddy, K., Chen, C. H., ... Hildebrandt, F. (2021). Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice. SCI ADV, 7(1), [eabe1386]. https://doi.org/10.1126/sciadv.abe1386

Vancouver

Majmundar AJ, Buerger F, Forbes TA, Klämbt V, Schneider R, Deutsch K et al. Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice. SCI ADV. 2021 Jan;7(1). eabe1386. https://doi.org/10.1126/sciadv.abe1386

Bibtex

@article{f8acc1d8e0d141129a8200d4b9676536,
title = "Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice",
abstract = "Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive NOS1AP variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) NOS1AP, but not cDNA constructs bearing patient variants, increased active CDC42 and promoted filopodia and podosome formation. Pharmacologic inhibition of CDC42 or its effectors, formin proteins, reduced NOS1AP-induced filopodia formation. NOS1AP knockdown reduced podocyte migration rate (PMR), which was rescued by overexpression of WT Nos1ap but not by constructs bearing patient variants. PMR in NOS1AP knockdown podocytes was also rescued by constitutively active CDC42Q61L or the formin DIAPH3 Modeling a NOS1AP patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. Nos1apEx3-/Ex3- mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis. These findings demonstrate that recessive NOS1AP variants impair CDC42/DIAPH-dependent actin remodeling, cause aberrant organoid glomerulogenesis, and lead to a glomerulopathy in humans and mice.",
keywords = "Actins/genetics, Adaptor Proteins, Signal Transducing/metabolism, Animals, Formins/genetics, Humans, Kidney Diseases/metabolism, Mice, Nephrotic Syndrome/genetics, Podocytes/metabolism",
author = "Majmundar, {Amar J} and Florian Buerger and Forbes, {Thomas A} and Verena Kl{\"a}mbt and Ronen Schneider and Konstantin Deutsch and Kitzler, {Thomas M} and Howden, {Sara E} and Michelle Scurr and Tan, {Ker Sin} and Micka{\"e}l Krzeminski and Eugen Widmeier and Braun, {Daniela A} and Ethan Lai and Ihsan Ullah and Ali Amar and Amy Kolb and Kaitlyn Eddy and Chen, {Chin Heng} and Daanya Salmanullah and Rufeng Dai and Makiko Nakayama and Isabel Ottlewski and Kolvenbach, {Caroline M} and Onuchic-Whitford, {Ana C} and Youying Mao and Nina Mann and Nabhan, {Marwa M} and Seymour Rosen and Forman-Kay, {Julie D} and Soliman, {Neveen A} and Andreas Heilos and Renate Kain and Christoph Aufricht and Shrikant Mane and Lifton, {Richard P} and Shirlee Shril and Little, {Melissa H} and Friedhelm Hildebrandt",
note = "Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).",
year = "2021",
month = jan,
doi = "10.1126/sciadv.abe1386",
language = "English",
volume = "7",
journal = "SCI ADV",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "1",

}

RIS

TY - JOUR

T1 - Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice

AU - Majmundar, Amar J

AU - Buerger, Florian

AU - Forbes, Thomas A

AU - Klämbt, Verena

AU - Schneider, Ronen

AU - Deutsch, Konstantin

AU - Kitzler, Thomas M

AU - Howden, Sara E

AU - Scurr, Michelle

AU - Tan, Ker Sin

AU - Krzeminski, Mickaël

AU - Widmeier, Eugen

AU - Braun, Daniela A

AU - Lai, Ethan

AU - Ullah, Ihsan

AU - Amar, Ali

AU - Kolb, Amy

AU - Eddy, Kaitlyn

AU - Chen, Chin Heng

AU - Salmanullah, Daanya

AU - Dai, Rufeng

AU - Nakayama, Makiko

AU - Ottlewski, Isabel

AU - Kolvenbach, Caroline M

AU - Onuchic-Whitford, Ana C

AU - Mao, Youying

AU - Mann, Nina

AU - Nabhan, Marwa M

AU - Rosen, Seymour

AU - Forman-Kay, Julie D

AU - Soliman, Neveen A

AU - Heilos, Andreas

AU - Kain, Renate

AU - Aufricht, Christoph

AU - Mane, Shrikant

AU - Lifton, Richard P

AU - Shril, Shirlee

AU - Little, Melissa H

AU - Hildebrandt, Friedhelm

N1 - Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

PY - 2021/1

Y1 - 2021/1

N2 - Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive NOS1AP variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) NOS1AP, but not cDNA constructs bearing patient variants, increased active CDC42 and promoted filopodia and podosome formation. Pharmacologic inhibition of CDC42 or its effectors, formin proteins, reduced NOS1AP-induced filopodia formation. NOS1AP knockdown reduced podocyte migration rate (PMR), which was rescued by overexpression of WT Nos1ap but not by constructs bearing patient variants. PMR in NOS1AP knockdown podocytes was also rescued by constitutively active CDC42Q61L or the formin DIAPH3 Modeling a NOS1AP patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. Nos1apEx3-/Ex3- mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis. These findings demonstrate that recessive NOS1AP variants impair CDC42/DIAPH-dependent actin remodeling, cause aberrant organoid glomerulogenesis, and lead to a glomerulopathy in humans and mice.

AB - Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive NOS1AP variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) NOS1AP, but not cDNA constructs bearing patient variants, increased active CDC42 and promoted filopodia and podosome formation. Pharmacologic inhibition of CDC42 or its effectors, formin proteins, reduced NOS1AP-induced filopodia formation. NOS1AP knockdown reduced podocyte migration rate (PMR), which was rescued by overexpression of WT Nos1ap but not by constructs bearing patient variants. PMR in NOS1AP knockdown podocytes was also rescued by constitutively active CDC42Q61L or the formin DIAPH3 Modeling a NOS1AP patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. Nos1apEx3-/Ex3- mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis. These findings demonstrate that recessive NOS1AP variants impair CDC42/DIAPH-dependent actin remodeling, cause aberrant organoid glomerulogenesis, and lead to a glomerulopathy in humans and mice.

KW - Actins/genetics

KW - Adaptor Proteins, Signal Transducing/metabolism

KW - Animals

KW - Formins/genetics

KW - Humans

KW - Kidney Diseases/metabolism

KW - Mice

KW - Nephrotic Syndrome/genetics

KW - Podocytes/metabolism

U2 - 10.1126/sciadv.abe1386

DO - 10.1126/sciadv.abe1386

M3 - SCORING: Journal article

C2 - 33523862

VL - 7

JO - SCI ADV

JF - SCI ADV

SN - 2375-2548

IS - 1

M1 - eabe1386

ER -