ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

TLDR

Nephrotic syndrome is classified as steroid‑sensitive or steroid‑resistant, with the latter progressing to end‑stage kidney disease and whose underlying mechanisms remain largely unknown despite genetic evidence of many single‑gene causes. The study aimed to identify the genetic lesion responsible for steroid‑resistant nephrotic syndrome. By combining homozygosity mapping and whole‑exome sequencing, the authors discovered an ARHGDIA mutation that disrupts its interaction with RHO GTPases, elevates RAC1/CDC42 activity, increases podocyte migration, and reproduces the disease phenotype in zebrafish, with RAC1 inhibitors reversing the migration defect. The ARHGDIA mutation constitutes a single‑gene cause of SRNS, implicating RAC1/CDC42‑mediated RHO GTPase signaling as a pathogenic driver and demonstrating that RAC1 inhibition can partially ameliorate the associated defects.

Abstract

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.