PUBLICATION
A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness
- Authors
- Issler, N., Afonso, S., Weissman, I., Jordan, K., Cebrian-Serrano, A., Meindl, K., Dahlke, E., Tziridis, K., Yan, G., Robles-López, J.M., Tabernero, L., Patel, V., Kesselheim, A., Klootwijk, E.D., Stanescu, H.C., 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, I.M., 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, T.C., Warth, R.
- ID
- ZDB-PUB-220213-6
- Date
- 2022
- Source
- Journal of the American Society of Nephrology : JASN 33(4): 732-745 (Journal)
- Registered Authors
- Lowe, Martin
- Keywords
- Eps15 homology domain, epithelial transport physiology, genetic renal disease, infertility, megalin, mutation, proximal tubule
- MeSH Terms
-
- Adolescent
- Adult
- Animals
- Child
- Child, Preschool
- Deafness*/genetics
- Endocytosis
- Humans
- Kidney Tubules, Proximal/metabolism
- Low Density Lipoprotein Receptor-Related Protein-2/genetics
- Low Density Lipoprotein Receptor-Related Protein-2/metabolism
- Mice
- Mutation
- Proteinuria/metabolism
- Vesicular Transport Proteins/genetics
- Young Adult
- Zebrafish*/metabolism
- PubMed
- 35149593 Full text @ J. Am. Soc. Nephrol.
Citation
Issler, N., Afonso, S., Weissman, I., Jordan, K., Cebrian-Serrano, A., Meindl, K., Dahlke, E., Tziridis, K., Yan, G., Robles-López, J.M., Tabernero, L., Patel, V., Kesselheim, A., Klootwijk, E.D., Stanescu, H.C., 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, I.M., 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, T.C., Warth, R. (2022) A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness. Journal of the American Society of Nephrology : JASN. 33(4):732-745.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping