Homozygous FAT1 Frameshift Mutation Causes Glomerulotubular Nephropathy and Congenital Anomalies via Dysregulated Cell Adhesion and Rap1 Signaling

Background: Chronic kidney disease(CKD) is increasingly recognized as a significant public burden, affecting over 10% of adults worldwide. While hereditary kidney diseases are a primary cause of CKD, genetic factors can also affected progression of kidney diseases. Advances in whole-exome sequencing (WES) have revolutionized the molecular diagnostics of hereditary kidney diseases in both pediatric and adult populations, enhancing diagnostic accuracy and facilitating the discovery of novel genotype-phenotype correlations. Methods: Here, we report a 35-year-old Chinese female with microscopic hematuria, proteinuria, and a complex syndrome including ptosis, corneal dystrophy, macular degeneration, right feet syndactyly, and glomerulotubular nephropathy. Whole-exome sequencing (WES) and homozygosity mapping identified a homozygous frameshift mutation in FAT1 (NM_005245: c.7444_7445delGT, p.Val2482fs). Further analysis revealed that this mutation caused translational repression of FAT1. Results: 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 a reduction in activated Rap1 levels, correlating with the observed cellular defects. These findings provide compelling evidence that the homozygous FAT1 frameshift mutation is causally associated with nephropathy and congenital anomalies, likely through degradation of transcribed mRNA and impaired protein expression. Conclusion: The results emphasize the critical role of FAT1 in renal development and provide new insights into the molecular mechanisms underlying these conditions.