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A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness
Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review
DOI
- https://doi.org/10.1681/ASN.2021101312
Forlagets udgivne version
- Naomi Issler, University College London ,
- Sara Afonso, University of Regensburg ,
- Irith Weissman, Western Galilee Medical Center of Nahariya ,
- Katrin Jordan, University of Regensburg ,
- Alberto Cebrian-Serrano, University of Oxford ,
- Katrin Meindl, University of Regensburg ,
- Eileen Dahlke, Kiel University ,
- Konstantin Tziridis, Friedrich-Alexander University Erlangen-Nürnberg ,
- Guanhua Yan, University of Manchester ,
- José M Robles-López, University of Manchester ,
- Lydia Tabernero, University of Manchester ,
- Vaksha Patel, University College London ,
- Anne Kesselheim, University College London ,
- Enriko D Klootwijk, University College London ,
- Horia C Stanescu, University College London ,
- Simona Dumitriu, University College London ,
- Daniela Iancu, University College London ,
- Mehmet Tekman, University College London ,
- Monika Mozere, University College London ,
- Graciana Jaureguiberry, University College London ,
- Priya Outtandy, University College London ,
- Claire Russell, Royal Veterinary College University of London ,
- Anna-Lena Forst, University of Regensburg ,
- Christina Sterner, University of Regensburg ,
- Elena-Sofia Heinl, University of Regensburg ,
- Helga Othmen, University of Regensburg ,
- Ines Tegtmeier, University of Regensburg ,
- Markus Reichold, University of Regensburg ,
- Ina Maria Schiessl
- Katharina Limm, University of Regensburg ,
- Peter Oefner, University of Regensburg ,
- Ralph Witzgall, University of Regensburg ,
- Lifei Fu, University of Regensburg ,
- Franziska Theilig, Kiel University ,
- Achim Schilling, Friedrich-Alexander University Erlangen-Nürnberg ,
- Efrat Shuster Biton, Western Galilee Medical Center of Nahariya ,
- Limor Kalfon, Western Galilee Medical Center of Nahariya ,
- Ayalla Fedida, Western Galilee Medical Center of Nahariya ,
- Elite Arnon-Sheleg, Western Galilee Medical Center of Nahariya ,
- Ofer Ben Izhak, Radboud University Nijmegen ,
- Daniella Magen, Syddansk Universitet ,
- Yair Anikster, Sheba Medical Center at Tel Hashomer ,
- Holger Schulze, Friedrich-Alexander University Erlangen-Nürnberg ,
- Christine Ziegler, University of Regensburg ,
- Martin Lowe, University of Manchester ,
- Benjamin Davies, University College London ,
- Detlef Böckenhauer, University College London ,
- Robert Kleta, University College London ,
- Tzipora C Falik Zaccai, Bar-Ilan University ,
- Richard Warth, University of Regensburg
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 Ehd1R398W/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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Journal of the American Society of Nephrology : JASN |
| Vol/bind | 33 |
| Nummer | 4 |
| Sider (fra-til) | 732-745 |
| Antal sider | 14 |
| ISSN | 1046-6673 |
| DOI | |
| Status | Udgivet - apr. 2022 |
| Eksternt udgivet | Ja |
Bibliografisk note
Copyright © 2022 by the American Society of Nephrology.
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