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A founder mutation in EHD1 presents with tubular proteinuria and deafness

Russell, Claire; Issler, Naomi; Afonso, Sara; Ziegler, Christine; Weissman, Irith; Dumitriu, Simona; Lowe, Martin; Jordan, Katrin; Iancu, Daniela; Davies, Benjamin; Cebrian-Serrano, Alberto; Tekman, Mehmet; Böckenhauer, Detlef; Warth, Richard; Kleta, Robert; Zaccai, Tzipora C. Falik; Meindl, Katrin; Stanescu, Horia C.; Dahlke, Eileen; Klootwijk, Enriko D.; Tziridis, Konstantin; Yan, Guanhua; Kesselheim, Anne; Patel, Vaksha; Robles-López, José M.; Tabernero, Lydia; Schulze, Holger; Mozere, Monika; Anikster, Yair; Magen, Daniella; Jaureguiberry, Graciana; Ben Izhak, Ofer; Arnon-Sheleg, Elite; Outtandy, Priya; Fedida, Ayalla; Forst, Anna-Lena; Kalfon, Limor; Sterner, Christina; Biton, Efrat Shuster; Heinl, Elena-Sofia; Othmen, Helga; Tegtmeier, Ines; Reichold, Markus; Schiessl, Ina Maria; Limm, Katharina; Oefner, Peter; Witzgall, Ralph; Fu, Lifei; Theilig, Franziska; Schilling, Achim


Claire Russell

Naomi Issler

Sara Afonso

Christine Ziegler

Irith Weissman

Simona Dumitriu

Martin Lowe

Katrin Jordan

Daniela Iancu

Benjamin Davies

Alberto Cebrian-Serrano

Mehmet Tekman

Detlef Böckenhauer

Richard Warth

Robert Kleta

Tzipora C. Falik Zaccai

Katrin Meindl

Horia C. Stanescu

Eileen Dahlke

Enriko D. Klootwijk

Konstantin Tziridis

Guanhua Yan

Anne Kesselheim

Vaksha Patel

José M. Robles-López

Lydia Tabernero

Holger Schulze

Monika Mozere

Yair Anikster

Daniella Magen

Graciana Jaureguiberry

Ofer Ben Izhak

Elite Arnon-Sheleg

Priya Outtandy

Ayalla Fedida

Anna-Lena Forst

Limor Kalfon

Christina Sterner

Efrat Shuster Biton

Elena-Sofia Heinl

Helga Othmen

Ines Tegtmeier

Markus Reichold

Ina Maria Schiessl

Katharina Limm

Peter Oefner

Ralph Witzgall

Lifei Fu

Franziska Theilig

Achim Schilling


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 the kidney, was unknown.
Genetic techniques were used in patients with tubular proteinuria and deafness to identify the diseasecausing
gene. Diagnostic and functional studies were performed in patients and disease models to
investigate the pathophysiology.
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.
A previously unrecognized autosomal recessive disorder characterized by sensorineural deafness and
tubular proteinuria is caused by a homozygous missense variant in EHD1. Recessive EHD1 variants
should be considered in individuals with hearing impairment, especially if tubular proteinuria is noted.


Russell, C., Issler, N., Afonso, S., Ziegler, C., Weissman, . I., Dumitriu, S., …Schilling, A. (in press). A founder mutation in EHD1 presents with tubular proteinuria and deafness. Journal of the American Society of Nephrology,

Journal Article Type Article
Acceptance Date Dec 17, 2021
Online Publication Date Jan 14, 2022
Deposit Date Jan 14, 2022
Publicly Available Date Dec 17, 2022
Print ISSN 1046-6673
Publisher American Society of Nephrology
Peer Reviewed Peer Reviewed
Keywords Epithelial transport physiology, Infertility, Megalin, Eps15 Homology Domain, proximal tubule, genetic renal disease
Public URL


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