Recessive <i>NOS1AP</i> 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 <i>NOS1AP</i> variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) <i>NOS1AP</i>, 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. <i>NOS1AP</i> knockdown reduced podocyte migration rate (PMR), which was rescued by overexpression of WT <i>Nos1ap</i> but not by constructs bearing patient variants. PMR in <i>NOS1AP</i> knockdown podocytes was also rescued by constitutively active <i>CDC42^Q61L</i> or the formin <i>DIAPH3</i> Modeling a <i>NOS1AP</i> patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. <i>Nos1ap^Ex3-/Ex3-</i> mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis. These findings demonstrate that recessive <i>NOS1AP</i> variants impair CDC42/DIAPH-dependent actin remodeling, cause aberrant organoid glomerulogenesis, and lead to a glomerulopathy in humans and mice.