A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness.
Issler N., Afonso S., Weissman I., Jordan K., Cebrian-Serrano A., Meindl K., Dahlke E., Tziridis K., Yan G., Robles-López JM., Tabernero L., Patel V., Kesselheim A., Klootwijk ED., Stanescu HC., Dumitriu S., Iancu D., Tekman M., Mozere M., Jaureguiberry G., Outtandy P., Russell C., Forst A-L., Sterner C., Heinl E-S., Othmen H., Tegtmeier I., Reichold M., Schiessl IM., Limm K., Oefner P., Witzgall R., Fu L., Theilig F., Schilling A., Shuster Biton E., Kalfon L., Fedida A., Arnon-Sheleg E., Ben Izhak O., Magen D., Anikster Y., Schulze H., Ziegler C., Lowe M., Davies B., Böckenhauer D., Kleta R., Falik Zaccai TC., Warth R.
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.