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 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

SUBMITTER: Majmundar AJ 

PROVIDER: S-EPMC10763988 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature