FAT1 mutations cause a glomerulotubular nephropathy
نویسندگان
چکیده
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.
منابع مشابه
Generation and evolution of atubular glomeruli in the progression of renal disorders.
Functional nephrons can be lost through a process of glomerulotubular disconnection. Progressive development of atubular glomeruli seems to play a major role in a number of renal disorders, including glomerular diseases, ascribed to injury to the glomerulotubular junction as a result of proteinuria; however, formation of atubular glomeruli is even more common in tubulointerstitial disorders, su...
متن کاملGlomerulotubular junction abnormalities are associated with proteinuria in type 1 diabetes.
Glomerulotubular junction abnormalities, frequent in proteinuric patients with type 1 diabetes, may contribute to the progressive GFR loss in overt diabetic nephropathy. Glomerulotubular junction abnormalities were examined in patients who have type 1 diabetes with a wide range of albumin excretion rates (AER). Renal biopsies from five normoalbuminuric patients, five microalbuminuric patients, ...
متن کاملFAT1 expression and mutations in adult acute lymphoblastic leukemia
The cadherin gene FAT1, located on chromosome 4q34-35 (ref. 1) within a region frequently deleted in human cancers, encodes a large protein with 34 extracellular cadherin repeats. In solid tumors, aberrant expression of FAT1 was found to be associated with disease progression. Although the gene was originally cloned from a human T-cell acute lymphoblastic leukemia (T-ALL) cell line, FAT1 just r...
متن کاملIntegrative genomic and functional analysis of human oral squamous cell carcinoma cell lines reveals synergistic effects of FAT1 and CASP8 inactivation
Oral squamous cell carcinoma (OSCC) is genetically highly heterogeneous, which contributes to the challenges of treatment. To create an in vitro model that accurately reflects this heterogeneity, we generated a panel of HPV-negative OSCC cell lines. By whole exome sequencing of the lines and matched patient blood samples, we demonstrate that the mutational spectrum of the lines is representativ...
متن کاملAssociation between FAT1 mutation and overall survival in patients with human papillomavirus–negative head and neck squamous cell carcinoma
BACKGROUND The purpose of this study was to characterize the mutation profile of FAT atypical cadherin 1 (FAT1) and determine the prognostic significance of FAT1 mutation for overall survival in patients with human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). METHODS Data were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consor...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 7 شماره
صفحات -
تاریخ انتشار 2016