A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness
Creators: name: Issler, Naomi
name: Afonso, Sara
name: Weissman, Irith
name: Jordan, Katrin
name: Cebrian-Serrano, Alberto
name: Meindl, Katrin
name: Dahlke, Eileen
name: Tziridis, Konstantin
name: Yan, Guanhua
name: Robles-López, José M.
name: Tabernero, Lydia
name: Patel, Vaksha
name: Kesselheim, Anne
name: Klootwijk, Enriko D.
name: Stanescu, Horia C.
name: Dumitriu, Simona
name: Iancu, Daniela
name: Tekman, Mehmet
name: Mozere, Monika
name: Jaureguiberry, Graciana
name: Outtandy, Priya
name: Russell, Claire
name: Forst, Anna-Lena
name: Sterner, Christina
name: Heinl, Elena-Sofia
name: Othmen, Helga
name: Tegtmeier, Ines
name: Reichold, Markus
name: Schiessl, Ina Maria
name: Limm, Katharina
name: Oefner, Peter
name: Witzgall, Ralph
name: Fu, Lifei
name: Theilig, Franziska
name: Schilling, Achim
name: Shuster Biton, Efrat
name: Kalfon, Limor
name: Fedida, Ayalla
name: Arnon-Sheleg, Elite
name: Ben Izhak, Ofer
name: Magen, Daniella
name: Anikster, Yair
name: Schulze, Holger
name: Ziegler, Christine
name: Lowe, Martin
name: Davies, Benjamin
name: Böckenhauer, Detlef
name: Kleta, Robert
name: Falik Zaccai, Tzipora C.
name: Warth, Richard
Publisher: name: Universität Regensburg
Year: 2022
Subjects: subject: epithelial transport physiology, infertility, megalin, Eps15 homology domain, proximal tubule, genetic renal disease, mutation
subject: 570 Biowissenschaften, Biologie

description: 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&gt;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.