Expanding the Spectrum of FAT1 Nephropathies by Novel Mutations That Affect Hippo Signaling

Francesca Fabretti; Nikolai Tschernoster; Florian Erger; Andrea Hedergott; Anja K Buescher; Claudia Dafinger; Bjoern Reusch; Vincent K Köntges; Stefan Kohl; Malte P Bartram; Lutz Thorsten Weber; Holger Thiele; Janine Altmueller; Bernhard Schermer; Bodo B Beck; Sandra Habbig

doi:10.1016/j.ekir.2021.01.023

Expanding the Spectrum of FAT1 Nephropathies by Novel Mutations That Affect Hippo Signaling

Kidney Int Rep. 2021 Jan 29;6(5):1368-1378. doi: 10.1016/j.ekir.2021.01.023. eCollection 2021 May.

Authors

Francesca Fabretti^{1

2

3}, Nikolai Tschernoster^{4

5}, Florian Erger⁴, Andrea Hedergott⁶, Anja K Buescher⁷, Claudia Dafinger^{1

8}, Bjoern Reusch⁴, Vincent K Köntges^{1

2

3}, Stefan Kohl⁸, Malte P Bartram^{1

2}, Lutz Thorsten Weber⁸, Holger Thiele⁵, Janine Altmueller⁵, Bernhard Schermer^{1

2

3}, Bodo B Beck⁴, Sandra Habbig⁸

Affiliations

¹ Department II of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
² Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
³ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
⁴ Institute of Human Genetics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
⁵ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
⁶ Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
⁷ Children's Hospital, Pediatrics II, University of Duisburg-Essen, Essen, Germany.
⁸ Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

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: Hippo signaling; TAZ; YAP; children; genetic kidney disease; podocyte.