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

Sci Adv. 2021 Jan 1;7(1):eabe1386. doi: 10.1126/sciadv.abe1386.

Amar J Majmundar ¹, Florian Buerger ¹, Thomas A Forbes ² ³ ⁴, Verena Klämbt ¹, Ronen Schneider ¹, Konstantin Deutsch ¹, Thomas M Kitzler ¹ ⁵, Sara E Howden ² ³, Michelle Scurr ², Ker Sin Tan ², Mickaël Krzeminski ⁶, Eugen Widmeier ¹, Daniela A Braun ¹, Ethan Lai ¹, Ihsan Ullah ¹, Ali Amar ¹, Amy Kolb ¹, Kaitlyn Eddy ¹, Chin Heng Chen ¹, Daanya Salmanullah ¹, Rufeng Dai ¹, Makiko Nakayama ¹, Isabel Ottlewski ¹, Caroline M Kolvenbach ¹, Ana C Onuchic-Whitford ¹ ⁷, Youying Mao ¹, Nina Mann ¹, Marwa M Nabhan ⁸, Seymour Rosen ⁹, Julie D Forman-Kay ⁶ ¹⁰, Neveen A Soliman ⁸, Andreas Heilos ¹¹, Renate Kain ¹², Christoph Aufricht ¹¹, Shrikant Mane ¹³, Richard P Lifton ¹³ ¹⁴, Shirlee Shril ¹, Melissa H Little ² ³, Friedhelm Hildebrandt ¹⁵

Affiliations

1 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
2 Kidney Development, Disease and Regeneration Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
3 Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
4 Department of Nephrology, Royal Children's Hospital, Parkville, Victoria, Australia.
5 The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
6 Molecular Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.
7 Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
8 Department of Pediatrics, Center for Pediatric Nephrology and Transplantation, Kasr Al Ainy Medical School, Cairo University, Cairo, Egypt.
9 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
10 Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
11 Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
12 Department of Pathology, Medical University of Vienna, Vienna, Austria.
13 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
14 Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
15 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].

PMID: 33523862 DOI: 10.1126/sciadv.abe1386

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 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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