FAT1 mutations cause a glomerulotubular nephropathy

Abstract

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.

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.…”

Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome

“…We next examined the effect of AVIL on the PMR, which represents a relevant intermediate cellular phenotype in many forms of monogenic SRNS (8,10,12). We used the IncuCyte ZOOM video microscopy system, which monitors cell migration in real time.…”

“…In addition, actin remodeling has also been implicated in NS (9). Defects in actin remodeling may be part of the reason why a defect in the podocyte migration rate (PMR) in cell culture has been established as a reliable intermediate phenotype in monogenic forms of SRNS (8,(10)(11)(12).…”

Fat-like cadherins in cell migration—leading from both the front and the back

“…This finding has been accompanied by the discoveries that mutations in human fat1 cause a lethal kidney disease and an increased susceptibility to bipolar disorder [10–12], and that FAT1 levels are altered in a wide range of cancers [8,13]. Given that defects in cell motility may underlie many of these conditions, there is growing interest in understanding how these massive proteins affect a cell’s migratory ability.…”

“…Altogether, these data suggested that Fat1 plays two roles in epithelial cell migration: polarizing the tissue in the direction of movement, and stimulating the formation of the leading edge protrusions though Ena/VASP-mediated F-actin assembly. Building from this work, Fat1 and Fat2 have since been shown to promote the migration of numerous cell types in vitro [12,14,16–20]. …”