ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

Abstract

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causesend-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.

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

“…Inability to degrade toxic long-chain bases led to decreased viability and slowed growth. Human WT and p.Glu132Gly mutant SGPL1 were found to be able to partially restore dpl1Δ, while p.Arg222Gln, p.Ser346Ile, and p.Tyr416Cys as well as frameshift mutants p.Arg278Glyfs*17 and p.Ser3Lysfs*11 showed no improved growth compared with dpl1Δ ( Figure 2N and Supplemental Figure 7A), consistent with S1P has previously been implicated in the regulation of RHOlike small GTPases (RHOA/RAC1/CDC42), and disruption of RAC1 signaling was previously implicated in the pathogenesis of SRNS (13)(14)(15). We therefore tested whether knockdown of SGPL1 would affect activation of the RHO-like small GTPases.…”

“…Likewise, we did not observe any effect of SGPL1 knockdown on podocyte migration rate, a pathogenic effect that has previously been demonstrated in many monogenic forms of SRNS (Supplemental Figure 11) (13).…”

A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome

“…25 In summary, detection of single-gene causes of SRNS will strongly inform practice, diagnostics, understanding of pathogenesis, and treatment of SRNS for the following reasons: (1) Unnecessary initiation or extension of steroid treatment can be avoided if a single-gene cause of SRNS is found; (2) if causative mutations are detected in a gene of coenzyme Q 10 biosynthesis pathway (COQ2, COQ6, ADCK4, or PDSS2) treatment with coenzyme Q 10 can be attempted 20,24 ; (3) for clinical trials, mutation detection allows etiologic stratification by causative gene in patient cohorts, and thus the small number of patients with a rare disease such as SRNS can be optimally used by stratifying patients according to the etiologic criteria of each causative gene mutation; (4) mutation detection allows definition of correlations between genotype and phenotype as well as between genotype and treatment response; and (5) identification of causative mutations in known single-gene causes of SRNS will help to rapidly define cohorts without mutations, in which additional unknown causative genes can be discovered using whole exome sequencing. 25 …”

“…In the context of discovering and studying novel genes, about 400 of the 1783 families underwent Sanger sequencing for the rare genes PLCE1, LAMB2, SMARCAL1, INF2, COQ6, TRPC6, ITGA3, CUBN, ADCK4, and ARHGDIA. [17][18][19][20][21][22][23][24][25] Disease-causing mutations were detected in 170 families for NPHS2, 93 families for NPHS1, and 78 families for WT1. In an additional 51 families, causative mutations were detected in 1 of the other rare genes, thereby unveiling the causative mutation in a total of 392 families ( Table 1).…”

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

“…Patients with disease-causing mutations in genes encoding enzymes of the coenzyme Q 10 pathway (COQ2, COQ6 and ADCK4) and in the CUBN gene may respond to treatment with coenzyme Q 10 and vitamin B12, respectively. Likewise, patients with ARHGDIA mutations, through modulation of Rac I-mineralocorticoid interactions, could theoretically respond to eplenerone (a mineralocorticoid-receptor antagonist) [36]. As highlighted in Table 2, many syndromic forms of SRNS have associated medical problems that may benefit from early recognition and management.…”