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Basic Research
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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, José M. Robles-López, Lydia Tabernero, Vaksha Patel, Anne Kesselheim, Enriko D. Klootwijk, Horia C. Stanescu, Simona Dumitriu, Daniela Iancu, Mehmet Tekman, Monika Mozere, Graciana Jaureguiberry, Priya 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 Böckenhauer, Robert Kleta, Tzipora C. Falik Zaccai and Richard Warth
JASN April 2022, 33 (4) 732-745; DOI: https://doi.org/10.1681/ASN.2021101312
Naomi Issler
1Department of Renal Medicine, University College London, London, United Kingdom
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Sara Afonso
2Medical Cell Biology, University of Regensburg, Regensburg, Germany
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Irith Weissman
3Pediatric Nephrology, Galilee Medical Center, Nahraia, Israel
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Katrin Jordan
2Medical Cell Biology, University of Regensburg, Regensburg, Germany
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Alberto Cebrian-Serrano
4Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
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Katrin Meindl
2Medical Cell Biology, University of Regensburg, Regensburg, Germany
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Eileen Dahlke
5Institute of Anatomy, University of Kiel, Kiel, Germany
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Konstantin Tziridis
6Ear, Nose, and Throat Clinic, University Hospital Erlangen, Erlangen, Germany
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Guanhua Yan
7Division of Molecular and Cellular Function, University of Manchester, United Kingdom
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José M. Robles-López
7Division of Molecular and Cellular Function, University of Manchester, United Kingdom
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Lydia Tabernero
7Division of Molecular and Cellular Function, University of Manchester, United Kingdom
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Vaksha Patel
1Department of Renal Medicine, University College London, London, United Kingdom
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Anne Kesselheim
1Department of Renal Medicine, University College London, London, United Kingdom
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Enriko D. Klootwijk
1Department of Renal Medicine, University College London, London, United Kingdom
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Horia C. Stanescu
1Department of Renal Medicine, University College London, London, United Kingdom
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Simona Dumitriu
1Department of Renal Medicine, University College London, London, United Kingdom
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Daniela Iancu
1Department of Renal Medicine, University College London, London, United Kingdom
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Mehmet Tekman
1Department of Renal Medicine, University College London, London, United Kingdom
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Monika Mozere
1Department of Renal Medicine, University College London, London, United Kingdom
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Graciana Jaureguiberry
1Department of Renal Medicine, University College London, London, United Kingdom
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Priya Outtandy
1Department of Renal Medicine, University College London, London, United Kingdom
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Claire Russell
8Royal Veterinary College, London, United Kingdom
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Anna-Lena Forst
2Medical Cell Biology, University of Regensburg, Regensburg, Germany
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Christina Sterner
2Medical Cell Biology, University of Regensburg, Regensburg, Germany
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Elena-Sofia Heinl
2Medical Cell Biology, University of Regensburg, Regensburg, Germany
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Helga Othmen
2Medical Cell Biology, University of Regensburg, Regensburg, Germany
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Ines Tegtmeier
2Medical Cell Biology, University of Regensburg, Regensburg, Germany
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Markus Reichold
2Medical Cell Biology, University of Regensburg, Regensburg, Germany
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Ina Maria Schiessl
9Institute of Physiology, University of Regensburg, Regensburg, Germany
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Katharina Limm
10Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
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Peter Oefner
10Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
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Ralph Witzgall
11Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany
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Lifei Fu
12Structural Biology, University of Regensburg, Regensburg, Germany
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Franziska Theilig
5Institute of Anatomy, University of Kiel, Kiel, Germany
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Achim Schilling
6Ear, Nose, and Throat Clinic, University Hospital Erlangen, Erlangen, Germany
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Efrat Shuster Biton
13Institute of Human Genetics, Galilee Medical Center, Nahraia, Israel
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Limor Kalfon
13Institute of Human Genetics, Galilee Medical Center, Nahraia, Israel
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Ayalla Fedida
13Institute of Human Genetics, Galilee Medical Center, Nahraia, Israel
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Elite Arnon-Sheleg
14Galilee Medical Center, Nahariya, Israel
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Ofer Ben Izhak
15Department of Pathology, Rambam Health Care Campus, Technion Faculty of Medicine, Haifa, Israel
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Daniella Magen
16Pediatric Nephrology Institute, Rambam Health Care Campus, Technion Faculty of Medicine, Haifa, Israel
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Yair Anikster
17Sheba Medical Center, Tel Aviv, Israel
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Holger Schulze
6Ear, Nose, and Throat Clinic, University Hospital Erlangen, Erlangen, Germany
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Christine Ziegler
12Structural Biology, University of Regensburg, Regensburg, Germany
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Martin Lowe
7Division of Molecular and Cellular Function, University of Manchester, United Kingdom
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Benjamin Davies
4Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
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Detlef Böckenhauer
1Department of Renal Medicine, University College London, London, United Kingdom
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Robert Kleta
1Department of Renal Medicine, University College London, London, United Kingdom
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Tzipora C. Falik Zaccai
18The Azrieli Faculty of Medicine, Bar Ilan, Safed, Israel
19Institute of Human Genetics, Galilee Medical Center, Nahraia, Israel
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Richard Warth
2Medical Cell Biology, University of Regensburg, Regensburg, Germany
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Significance Statement

Renal tubular protein reabsorption has been of interest in the kidney community, and despite recognition of numerous associated inherited diseases, the detailed molecular basis remains poorly understood. We identified a missense mutation in EHD1 in six patients with tubular proteinuria and sensorineural hearing deficit, identifying the gene as a critical component of the renal protein reabsorption machinery and of inner ear function. EHD1, a key player in vesicular dynamics, has previously been associated with early ciliogenesis. However, no obvious defect of ciliogenesis was found in the kidneys of the patients nor in knockin and knockout mice. These data may contribute to a better understanding of the functional relevance of EHD1 in human tissues, particularly in the kidney and inner ear.

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 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.

  • epithelial transport physiology
  • infertility
  • megalin
  • Eps15 homology domain
  • proximal tubule
  • genetic renal disease
  • mutation
  • Copyright © 2022 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 33 (4)
Journal of the American Society of Nephrology
Vol. 33, Issue 4
April 2022
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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, José M. Robles-López, Lydia Tabernero, Vaksha Patel, Anne Kesselheim, Enriko D. Klootwijk, Horia C. Stanescu, Simona Dumitriu, Daniela Iancu, Mehmet Tekman, Monika Mozere, Graciana Jaureguiberry, Priya 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 Böckenhauer, Robert Kleta, Tzipora C. Falik Zaccai, Richard Warth
JASN Apr 2022, 33 (4) 732-745; DOI: 10.1681/ASN.2021101312

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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, José M. Robles-López, Lydia Tabernero, Vaksha Patel, Anne Kesselheim, Enriko D. Klootwijk, Horia C. Stanescu, Simona Dumitriu, Daniela Iancu, Mehmet Tekman, Monika Mozere, Graciana Jaureguiberry, Priya 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 Böckenhauer, Robert Kleta, Tzipora C. Falik Zaccai, Richard Warth
JASN Apr 2022, 33 (4) 732-745; DOI: 10.1681/ASN.2021101312
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Keywords

  • epithelial transport physiology
  • infertility
  • megalin
  • Eps15 homology domain
  • proximal tubule
  • genetic renal disease
  • mutation

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