Novel Homozygous FAT1 Mutation Causes glomerulotubular nephropathy in Asian adult

Introduction: Although sequence variants in FAT1 have been identified in patients with distinct renal disease, definitive proof of causality in human disease is meager. Methods: A 35-year-old Chinese female with microscopic hematuria and proteinuria underwent a renal biopsy to identify the underlying cause. Whole-exome sequencing (WES) with homozygosity mapping revealed genetic factors, and patient-derived primary urinary epithelial cells confirmed the renal agenesis phenotype. RNA sequencing, immunofluorescence staining, and immunoblotting were used to explore the mechanisms involved. Results: The patient, whose parents are cousins, exhibited a syndrome featuring ptosis, corneal dystrophy, macular degeneration and right feet syndactyly, with glomerulotubular nephropathy. A homozygous frameshift mutation in FAT1 (NM_005245: c.7444_7445delGT) was identified. Structural prediction, immunohistochemistry, and Western blot analyses confirmed that the mutation caused translational repression of FAT1. RNA-seq analysis revealed significant dysregulation of cell adhesion and the Rap1 signaling pathway. Immunofluorescence showed a marked loss of intercellular β-catenin junctions and cytoskeletal disruption in patient-derived primary urinary epithelial cells. Pull-down assays demonstrated that these effects were associated with a reduction in activated Rap1 levels. Conclusion: This study presents compelling evidence that the homozygous FAT1 frameshift mutation (c.7444_7445delGT, p.Val2482fs) is causally associated with nephropathy and congenital anomalies. The mutation likely leads to the degradation of transcribed mRNA, which in turn impairs protein expression. These findings underscore the critical role of FAT1 in renal development and offer new insights into the molecular mechanisms underlying these conditions.