A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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Issler Naomi, Afonso Sara, Weissman Irith, Jordan Katrin, Cebrian-Serrano Alberto, Meindl Katrin, Dahlke Eileen, Tziridis Konstantin, Yan Guanhua, Robles-López José M, Tabernero Lydia, Patel Vaksha, Kesselheim Anne, Klootwijk Enriko D, Stanescu Horia C, Dumitriu Simona, Iancu Daniela, Tekman Mehmet, Mozere Monika, Jaureguiberry Graciana, Outtandy Priya, Russell Claire, Forst Anna-Lena, Sterner Christina, Heinl Elena-Sofia, Othmen Helga, Tegtmeier Ines, Reichold Markus, Schiessl Ina Maria, Limm Katharina, Oefner Peter, Witzgall Ralph, Fu Lifei, Theilig Franziska, Schilling Achim, Shuster Biton Efrat, Kalfon Limor, Fedida Ayalla, Arnon-Sheleg Elite, Ben Izhak Ofer, Magen Daniella, Anikster Yair, Schulze Holger, Ziegler Christine, Lowe Martin, Davies Benjamin, Böckenhauer Detlef, Kleta Robert, Falik Zaccai Tzipora C, Warth Richard
Аннотация
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.