Homozygous FAT1 frameshift mutation linked to glomerulotubular nephropathy with impaired cell adhesion and Rap1 signaling

Genetic mutations are closely linked to various renal diseases, revealing important molecular mechanisms that contribute to kidney dysfunction. Here, we reported a 35-year-old Chinese female diagnosed of glomerulotubular nephropathy with multiple extra-renal manifestations including ptosis, corneal dystrophy, macular degeneration, right foot syndactyly. Whole-exome sequencing identified a homozygous frameshift variant in FAT1 (NM_005245: c.7444_7445delGT, p.Val2482AsnfsTer16). Further analysis revealed that this mutation caused translation repression of FAT1. RNA sequencing showed dysregulation of cell adhesion and Rap1 signaling pathways, while immunofluorescence staining demonstrated disrupted β-catenin junctions and cytoskeletal abnormalities in patient-derived primary urinary epithelial cells. Pull-down assays indicated that the reduction in activated Rap1 levels was correlated with the observed cellular defects. These findings provide compelling evidence that this loss-of-function homozygous FAT1 variant is causally associated with nephropathy and congenital anomalies, likely through degradation of transcribed mRNA and impaired protein expression. The results emphasize the critical role of FAT1 in renal development and provide new insights into the molecular mechanisms underlying these conditions.