1. Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice
- Author
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Majmundar, AJ, Buerger, F, Forbes, TA, Klambt, V, Schneider, R, Deutsch, K, Kitzler, TM, Howden, SE, Scurr, M, Tan, KS, Krzeminski, M, Widmeier, E, Braun, DA, Lai, E, Ullah, I, Amar, A, Kolb, A, Eddy, K, Chen, CH, Salmanullah, D, Dai, R, Nakayama, M, Ottlewski, I, Kolvenbach, CM, Onuchic-Whitford, AC, Mao, Y, Mann, N, Nabhan, MM, Rosen, S, Forman-Kay, JD, Soliman, NA, Heilos, A, Kain, R, Aufricht, C, Mane, S, Lifton, RP, Shril, S, Little, MH, Hildebrandt, F, Majmundar, AJ, Buerger, F, Forbes, TA, Klambt, V, Schneider, R, Deutsch, K, Kitzler, TM, Howden, SE, Scurr, M, Tan, KS, Krzeminski, M, Widmeier, E, Braun, DA, Lai, E, Ullah, I, Amar, A, Kolb, A, Eddy, K, Chen, CH, Salmanullah, D, Dai, R, Nakayama, M, Ottlewski, I, Kolvenbach, CM, Onuchic-Whitford, AC, Mao, Y, Mann, N, Nabhan, MM, Rosen, S, Forman-Kay, JD, Soliman, NA, Heilos, A, Kain, R, Aufricht, C, Mane, S, Lifton, RP, Shril, S, Little, MH, and Hildebrandt, F
- 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 CDC42Q61L or the formin DIAPH3 Modeling a NOS1AP patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. Nos1apEx3-/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.
- Published
- 2021