Journal
SCIENCE ADVANCES
Volume 7, Issue 1, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abe1386
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Categories
Funding
- NIH [DK-076683-13, DK007527, T32DK-007726, DK122766]
- Harvard Stem Cell Institute
- American Society of Nephrology Lipps Research Program 2018 Polycystic Kidney Disease Foundation Jared J. Grantham Research Fellowship
- German Research Foundation (DFG) [404527522]
- DFG [403877094]
- KRESCENT Program
- Kidney Foundation of Canada
- Canadian Society of Nephrology
- Canadian Institutes of Health Research
- Leopoldina Fellowship Program, German National Academy of Sciences Leopoldina [LPDS 2015-07]
- Natural Sciences and Engineering Research Council of Canada [RGPIN-2016-06718]
- National Health and Medical Research Council of Australia (NHMRC) [GNT1098654]
- NHMRC Postgraduate Scholarship [GNT1114409]
- Royal Australasian College of Physicians Jacquot Award
- NHMRC [GNT1136085]
- Victorian Government's Operational Infrastructure Support Program
- Stafford Fox Foundation
- Methuselah Foundation
- Organovo Inc.
- National Human Genome Research Institute [UM1HG006504]
- GSP Coordinating Center [U24 HG008956]
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Recessive NOS1AP variants impair CDC42/DIAPH-dependent actin remodeling, causing aberrant organoid glomerulogenesis, and leading to glomerulopathy in both humans and mice.
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 CDC42(Q61L) or the formin DIAPH3. Modeling a NOS1AP patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. Nos1ap(Ex3-/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.
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