Issler, Naomi and Afonso, Sara and Weissman, Irith and Jordan, Katrin and Cebrian-Serrano, Alberto and Meindl, Katrin and Dahlke, Eileen and Tziridis, Konstantin and Yan, Guanhua and Robles-Lopez, Jose M. and Tabernero, Lydia and Patel, Vaksha and Kesselheim, Anne and Klootwijk, Enriko D. and Stanescu, Horia C. and Dumitriu, Simona and Iancu, Daniela and Tekman, Mehmet and Mozere, Monika and Jaureguiberry, Graciana and Outtandy, Priya and Russell, Claire and Forst, Anna-Lena and Sterner, Christina and Heinl, Elena-Sofia and Othmen, Helga and Tegtmeier, Ines and Reichold, Markus and Schiessl, Ina Maria and Limm, Katharina and Oefner, Peter and Witzgall, Ralph and Fu, Lifei and Theilig, Franziska and Schilling, Achim and Biton, Efrat Shuster and Kalfon, Limor and Fedida, Ayalla and Arnon-Sheleg, Elite and Ben Izhak, Ofer and Magen, Daniella and Anikster, Yair and Schulze, Holger and Ziegler, Christine and Lowe, Martin and Davies, Benjamin and Boeckenhauer, Detlef and Kleta, Robert and Zaccai, Tzipora C. Falik and Warth, Richard (2022) A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 33 (4). pp. 732-745. ISSN 1046-6673, 1533-3450
Full text not available from this repository. (Request a copy)Abstract
Background The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of EHD1 in human tissues, in particular in the kidney, was unknown.Methods Genetic techniques were used in patients with tubular proteinuria and deafness to identify the disease-causing gene. Diagnostic and functional studies were performed in patients and disease models to investigate the pathophysiology.Results We identified six individuals (5-33 years) with proteinuria and a high-frequency hearing deficit associated with the homozygous missense variant c.1192C > T (p.R398W) in EHD1. Proteinuria (0.7-2.1 g/d) consisted predominantly of low molecular weight proteins, reflecting impaired renal proximal tubular endocytosis of filtered proteins. Ehd1 knockout and Ehd1(R398W/R398W) knockin mice also showed a high frequency hearing deficit and impaired receptor-mediated endocytosis in proximal tubules, and a zebrafish model showed impaired ability to reabsorb low molecular weight dextran. Interestingly, ciliogenesis appeared unaffected in patients and mouse models. In silico structural analysis predicted a destabilizing effect of the R398W variant and possible inference with nucleotide binding leading to impaired EHD1 oligomerization and membrane remodeling ability.Conclusions A homozygous missense variant of EHD1 causes a previously unrecognized autosomal recessive disorder characterized by sensorineural deafness and tubular proteinuria. Recessive EHD1 variants should be considered in individuals with hearing impairment, especially if tubular proteinuria is noted.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RECEPTOR; MEGALIN; EHD1; MEMBRANE; CUBILIN; TRAFFICKING; MICAL-L1; epithelial transport physiology; infertility; megalin; Eps15 homology domain; proximal tubule; genetic renal disease; mutation |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Richard Warth Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Molekulare und zelluläre Anatomie > Prof. Dr. Ralph Witzgall |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Feb 2024 09:39 |
| Last Modified: | 14 Feb 2024 09:39 |
| URI: | https://pred.uni-regensburg.de/id/eprint/57359 |
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