FAT1 mutations cause a glomerulotubular nephropathy.

Area of Science:

• Genetics
• Nephrology
• Cell Biology

Background:

• Steroid-resistant nephrotic syndrome (SRNS) accounts for 15% of chronic kidney disease (CKD).
• Distinct genetic causes of SRNS are continually being identified, highlighting the complexity of glomerular and tubular kidney diseases.

Purpose of the Study:

• To identify the genetic basis of a distinct renal disease characterized by SRNS, tubular ectasia, and hematuria in four families.
• To elucidate the functional role of the identified gene, FAT1, in kidney development and disease pathogenesis.

Main Methods:

• Genetic analysis of affected families to identify causative mutations.
• In vitro studies using fibroblasts and podocytes to assess FAT1 function, including cell adhesion and migration assays.
• In vivo studies using mouse models with podocyte-specific Fat1 deletion.
• In vivo studies using zebrafish models with fat1 knockdown.

Main Results:

• Recessive mutations in FAT1 were identified as the cause of a novel SRNS entity with tubular ectasia, hematuria, and neurological involvement.
• Loss of FAT1 impaired fibroblast and podocyte adhesion and migration, with partial rescue by RAC1/CDC42 activators.
• Podocyte-specific Fat1 deletion in mice led to glomerular filtration barrier defects and foot process effacement.
• Fat1 knockdown in renal tubular cells and zebrafish pronephros caused migration defects and cysts, respectively, with partial rescue by RAC1/CDC42 activators.

Conclusions:

• FAT1 mutations cause a distinct hereditary kidney disease combining SRNS and tubulopathy.
• FAT1 plays a crucial role in podocyte and tubular cell migration and function, partly through regulation of RAC1/CDC42.
• These findings expand the understanding of SRNS pathogenesis and identify FAT1 as a key player in kidney development and disease.