Journal article

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

Amar J Majmundar, Florian Buerger, Thomas A Forbes, Verena Klambt, Ronen Schneider, Konstantin Deutsch, Thomas M Kitzler, Sara E Howden, Michelle Scurr, Ker Sin Tan, Mickael Krzeminski, Eugen Widmeier, Daniela A Braun, Ethan Lai, Ihsan Ullah, Ali Amar, Amy Kolb, Kaitlyn Eddy, Chin Heng Chen, Daanya Salmanullah Show all



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 Mode..

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Awarded by NIH

Awarded by German Research Foundation (DFG)

Awarded by DFG

Awarded by Leopoldina Fellowship Program, German National Academy of Sciences Leopoldina

Awarded by Natural Sciences and Engineering Research Council of Canada

Awarded by National Health and Medical Research Council of Australia (NHMRC)

Awarded by NHMRC Postgraduate Scholarship

Awarded by NHMRC

Awarded by National Human Genome Research Institute

Awarded by GSP Coordinating Center

Funding Acknowledgements

F.H. is the William E. Harmon Professor of Pediatrics. This research is supported by a grant from the NIH to F.H. (DK-076683-13). A.J.M. was supported by an NIH 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. F.B. was supported by a fellowship grant (404527522) from the German Research Foundation (DFG). V.K. is supported by a DFG fellowship grant (403877094). T.M.K. was supported by a Post-doctoral Fellowship award from the KRESCENT Program, a national kidney research training partnership of the Kidney Foundation of Canada, the Canadian Society of Nephrology, and the Canadian Institutes of Health Research. E.W. was supported by the Leopoldina Fellowship Program, German National Academy of Sciences Leopoldina (LPDS 2015-07). A.C.O.-W. acknowledges support from NIH T32 (DK007527) and F32 (DK122766) Ruth L. Kirschstein National Research Service Awards. J.D.F.-K. acknowledges funding from the Natural Sciences and Engineering Research Council of Canada (#RGPIN-2016-06718). Organoid work was funded by the National Health and Medical Research Council of Australia (NHMRC) (GNT1098654). T.A.F. is supported by an NHMRC Postgraduate Scholarship (GNT1114409) and a Royal Australasian College of Physicians Jacquot Award. M.H.L. is an NHMRC Senior Principal Research Fellow (GNT1136085). MCRI is supported by the Victorian Government's Operational Infrastructure Support Program. The MCRI iPSC gene editing facility is supported by the Stafford Fox Foundation. We acknowledge the support of the Methuselah Foundation and Organovo Inc. for the Novogen MMX bioprinter. The Yale Center for Mendelian Genomics (UM1HG006504) is funded by the National Human Genome Research Institute. The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.