Characterization of a Novel Nitric Oxide Synthase 1 Adaptor Protein Isoform in Kidney Development

Abstract

The pathogenic roles of NOS1AP have predominantly been attributed to the canonical isoform, which encodes an N-terminal phosphotyrosine-binding (PTB) domain and a C-terminal PDZ-binding motif. However, in addition to the canonical isoform, previous studies have identified alternative isoforms arising from intergenic splicing. This splicing results in a distinct protein of unknown function, NOS1APc. The biological role of NOS1APc has not been previously characterized. This work demonstrates that NOS1APc is highly expressed in the developing kidney, particularly in Nephrin-positive cells within the glomeruli. Mutant mice deficient in NOS1APc exhibited proteinuria, podocyte foot process effacement, and increased glomerular basement membrane thickness. Notably, these phenotypes resemble those observed in mice lacking all NOS1AP isoforms, implicating NOS1APc as a critical mediator of kidney function. These findings suggest that kidney defects and associated pathologies linked to human NOS1AP mutations may primarily arise due to the loss of NOS1APc.