A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness

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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish
Pages (from-to)732-745
Number of pages14
JournalJournal of the American Society of Nephrology : JASN
Issue number4
StatePublished - Apr 2022

Bibliographical note

Publisher Copyright:
Copyright ß 2022 by the American Society of Nephrology


D. Bockenhauer and R. Kleta were supported by the Mitchell Charitable Trust, Kids Kidney Research, Kidney Research UK, the Lowe Syndrome Trust, and the Grocers’ Charity. R. Kleta was supported by the David and Elaine Potter Charitable Foundation. R. Kleta, D. Bo€ckenhauer, E.D. Klootwijk, and H.C. Stanescu were supported by St Peter’s Trust for Kidney, Bladder, and Prostate Research. D. Bockenhauer was supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital/Institute of Child Health. R. Warth was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) (387509280, SFB 1350). M. Lowe and J.M. Robles-López were supported by the Lowe Syndrome Trust (MU/ML/2016) and the Erasmus program, respectively. B. Davies and A. Cebrian-Serrano were supported by the Wellcome Trust (203141/Z/16/Z). E. Arnon-Sheleg reports other interests or relationships with General Electric. D. Bo€ckenhauer reports consultancy with Advicenne, Avrobio, Otsuka, and Sanofi; honoraria from Advicenne and Recordati; associate editor for Pediatric Nephrology and Nephrology Dialysis Transplantation; and editorial board for JASN. B. Davies reports advisory or leadership role with the International Society of Transgenic Technologies. N. Issler reports advisory or leadership role with University College London. A. Kesselheim reports employment with University College London and Oxford Gene Technology. E. Klootwijk reports patents or royalties with New Zealand Pharmaceuticals. D. Magen reports consultancy with Alny-lam Pharmaceuticals; research funding from Alnylam Pharmaceuticals; and honoraria from Alnylam Pharmaceuticals. P. Oefner reports ownership interest with PDL BioPharma Inc.; editorial board of BioTechniques, BioMed Research International (Oncology Section), and Metabolites; and communicating editor of Human Mutation. I.M. Schiessl reports research funding with Aarhus University Research Foundation and Novo Nordisk Foundation; advisory or leadership role with American Physiological Society’s Epithelial Transport Group; and member of the American Physiological Society. R. Warth reports editorial board of JASN and Pflu€gers Archive; and member of the German Society of Nephrology and the German Physiological Society. All remaining authors have nothing to disclose.

FundersFunder number
D. Bo€ckenhauer
David and Elaine Potter Charitable Foundation
Mitchell Charitable Trust
Alnylam Pharmaceuticals
Wellcome Trust203141/Z/16/Z
NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
Kidney Research UK
Lowe Syndrome Trust
Deutsche ForschungsgemeinschaftSFB 1350, 387509280, MU/ML/2016


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