Universität zu Köln

Fabretti, Francesca, Tschernoster, Nikolai, Erger, Florian, Hedergott, Andrea ORCID: 0000-0002-6398-3919, Buescher, Anja K., Dafinger, Claudia, Reusch, Bjoern, Koentges, Vincent K., Kohl, Stefan, Bartram, Malte P., Weber, Lutz Thorsten, Thiele, Holger, Altmueller, Janine, Schermer, Bernhard, Beck, Bodo B. and Habbig, Sandra (2021). Expanding the Spectrum of FAT1 Nephropathies by Novel Mutations That Affect Hippo Signaling. Kidney Int. Rep., 6 (5). S. 1368 - 1379. NEW YORK: ELSEVIER SCIENCE INC. ISSN 2468-0249

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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 charac-terization, 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 heteroge-neous 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fabretti, Francesca UNSPECIFIED UNSPECIFIED UNSPECIFIED Tschernoster, Nikolai UNSPECIFIED UNSPECIFIED UNSPECIFIED Erger, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Hedergott, Andrea UNSPECIFIED orcid.org/0000-0002-6398-3919 UNSPECIFIED Buescher, Anja K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dafinger, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Reusch, Bjoern UNSPECIFIED UNSPECIFIED UNSPECIFIED Koentges, Vincent K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kohl, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartram, Malte P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Lutz Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Schermer, Bernhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Beck, Bodo B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Habbig, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-575202
DOI:	10.1016/j.ekir.2021.01.023
Journal or Publication Title:	Kidney Int. Rep.
Volume:	6
Number:	5
Page Range:	S. 1368 - 1379
Date:	2021
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	2468-0249
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CADHERIN ACTS; DISEASE; PROTEIN; PODOCYTES; GENOMICS; NEPHRIN; KIDNEY; GENE Multiple languages Urology & Nephrology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/57520