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| Item Type: | Article |
|---|---|
| Title: | Expanding the spectrum of FAT1 nephropathies by novel mutations that affect hippo signaling |
| Creators Name: | Fabretti, F., Tschernoster, N., Erger, F., Hedergott, A., Buescher, A.K., Dafinger, C., Reusch, B., Köntges, V.K., Kohl, S., Bartram, M.P., Weber, L.T., Thiele, H., Altmueller, J., Schermer, B., Beck, B.B. and Habbig, S. |
| Abstract: | INTRODUCTION: Disease-causing mutations in the protocadherin FAT1 have been recently described both in patients with a glomerulotubular nephropathy and in patients with a syndromic nephropathy. METHODS: We identified 4 patients with FAT1-associated disease, performed clinical and genetic characterization, and compared our findings to the previously published patients. Patient-derived primary urinary epithelial cells were analyzed by quantitative polymerase chain reaction (qPCR) and immunoblotting to identify possible alterations in Hippo signaling. RESULTS: Here we expand the spectrum of FAT1-associated disease with the identification of novel FAT1 mutations in 4 patients from 3 families (homozygous truncating variants in 3, compound heterozygous missense variants in 1 patient). All patients show an ophthalmologic phenotype together with heterogeneous renal phenotypes ranging from normal renal function to early-onset end-stage kidney failure. Molecular analysis of primary urine-derived urinary renal epithelial cells revealed alterations in the Hippo signaling cascade with a decreased phosphorylation of both the core kinase MST and the downstream effector YAP. Consistently, we found a transcriptional upregulation of bona fide YAP target genes. CONCLUSION: A comprehensive review of the here identified patients and those previously published indicates a highly diverse phenotype in patients with missense mutations but a more uniform and better recognizable phenotype in the patients with truncating mutations. Altered Hippo signaling and de-repressed YAP activity might be novel contributing factors to the pathomechanism in FAT1-associated renal disease. |
| Keywords: | Children, Genetic Kidney Disease, Hippo Signaling, Podocyte, TAZ, YAP |
| Source: | Kidney International Reports |
| ISSN: | 2468-0249 |
| Publisher: | Elsevier |
| Volume: | 6 |
| Number: | 5 |
| Page Range: | 1368-1378 |
| Date: | May 2021 |
| Official Publication: | https://doi.org/10.1016/j.ekir.2021.01.023 |
| PubMed: | View item in PubMed |
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