A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness

Issler, Naomi; Afonso, Sara; Weissman, Irith; Jordan, Katrin; Cebrián-Serrano, Alberto; Meindl, Katrin; Dahlke, Eileen; Tziridis, Konstantin; Yan, Guanhua; Robles-López, José M; Tabernero, Lydia; Patel, Vaksha; Kesselheim, Anne; Klootwijk, Enriko; Stanescu, Horia; Dumitriu, Simona; Iancu, Daniela; Tekman, Mehmet; Mozere, Monika; Jaureguiberry, Graciana; Outtandy, Priya; Russell, Claire; Forst, A. W.; Sterner, Christina; Heinl, Elena-Sofia; Othmen, Helga; Tegtmeier, Ines; Reichold, Markus; Schießl, Ina Maria; Limm, Katharina; Oefner, Peter J.; Witzgall, Ralph; Fu, Lifei; Theilig, Franziska; Schilling, Achim; Biton, Efrat Shuster; Kalfon, Limor; Fedida, Ayalla; Arnon-Sheleg, Elite; Izhak, Ofer Ben; Magen, Daniella; Anikster, Yair; Schulze, Holger; Ziegler, Christine; Lowe, Martin; Davies, Benjamin; Böckenhauer, Detlef; Kleta, Robert; Zaccai, Tzipora C. Falik; Warth, Richard

doi:10.1681/asn.2021101312

Cited by 10 publications

(25 citation statements)

References 36 publications

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“…8,32 Indeed, the observed redistribution of NHE3 to intracellular compartments observed in ClC-5 KO mice and OK cells was previously attributed to reduced exocytosis or recycling. 6,36 Similarly, endocytic recycling has been implicated as the cause of tubular proteinuria in patients with mutations in EHD1 37 and may also underlie the reduced uptake of filtered proteins in Lowe syndrome. 38,39 Instead, we find that the rate of endosome maturation profoundly affects the efficiency of apical endocytic traffic in PT cells.…”

Section: Discussionmentioning

confidence: 99%

Impaired Endosome Maturation Mediates Tubular Proteinuria in Dent Disease Cell Culture and Mouse Models

Shipman

Baty

Long

et al. 2023

JASN

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Significance Statement Loss of function of the 2Cl−/H+ antiporter ClC-5 in Dent disease causes an unknown impairment in endocytic traffic, leading to tubular proteinuria. The authors integrated data from biochemical and quantitative imaging studies in proximal tubule cells into a mathematical model to determine that loss of ClC-5 impairs endosome acidification and delays early endosome maturation in proximal tubule cells, resulting in reduced megalin recycling, surface expression, and half-life. Studies in a Dent mouse model also revealed subsegment-specific differences in the effects of ClC-5 knockout on proximal tubule subsegments. The approach provides a template to dissect the effects of mutations or perturbations that alter tubular recovery of filtered proteins from the level of individual cells to the entire proximal tubule axis. Background Loss of function of the 2Cl−/H+ antiporter ClC-5 in Dent disease impairs the uptake of filtered proteins by the kidney proximal tubule, resulting in tubular proteinuria. Reduced posttranslational stability of megalin and cubilin, the receptors that bind to and recover filtered proteins, is believed to underlie the tubular defect. How loss of ClC-5 leads to reduced receptor expression remains unknown. Methods We used biochemical and quantitative imaging data to adapt a mathematical model of megalin traffic in ClC-5 knockout and control cells. Studies in ClC-5 knockout mice were performed to describe the effect of ClC-5 knockout on megalin traffic in the S1 segment and along the proximal tubule axis. Results The model predicts that ClC-5 knockout cells have reduced rates of exit from early endosomes, resulting in decreased megalin recycling, surface expression, and half-life. Early endosomes had lower [Cl−] and higher pH. We observed more profound effects in ClC-5 knockout cells expressing the pathogenic ClC-5E211G mutant. Alterations in the cellular distribution of megalin in ClC-5 knockout mice were consistent with delayed endosome maturation and reduced recycling. Greater reductions in megalin expression were observed in the proximal tubule S2 cells compared with S1, with consequences to the profile of protein retrieval along the proximal tubule axis. Conclusions Delayed early endosome maturation due to impaired acidification and reduced [Cl−] accumulation is the primary mediator of reduced proximal tubule receptor expression and tubular proteinuria in Dent disease. Rapid endosome maturation in proximal tubule cells is critical for the efficient recovery of filtered proteins.

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Section: Discussionmentioning

confidence: 99%

Impaired Endosome Maturation Mediates Tubular Proteinuria in Dent Disease Cell Culture and Mouse Models

Shipman

Baty

Long

et al. 2023

JASN

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“…A role in caveolar uptake is unlikely considering the caveolin proteins are not expressed in the proximal tubule in vivo ( Zhuang et al, 2011 ), consistent with a more likely role for Pacsin2 in clathrin-dependent endocytosis. Of note, a recent study has shown that mutation of the PACSIN2 binding partner EHD1, which is involved in endocytic recycling ( Naslavsky and Caplan, 2011 ), causes a rare tubular disorder characterised by low molecular weight proteinuria due to defective endocytic traffic ( Issler et al, 2022 ). Thus, it remains possible that Pacsin2 contributes to both endocytic uptake and recycling within the proximal tubule.…”

Section: Discussionmentioning

confidence: 99%

Pacsin2 is required for endocytosis in the zebrafish pronephric tubule

et al. 2022

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Endocytosis mediates the cellular uptake of numerous molecules from the extracellular space and is a fundamentally important process. In the renal proximal tubule, the scavenger receptor megalin and its co-receptor cubilin mediate endocytosis of low molecular weight proteins from the renal filtrate. However, the extent to which megalin endocytosis relies on different components of the trafficking machinery remains relatively poorly defined in vivo. In this study, we identify a functional requirement for the F-BAR protein pacsin2 in endocytosis in the renal proximal tubule of zebrafish larvae. Pacsin2 is expressed throughout development and in all zebrafish tissues, similar to the mammalian orthologue. Within renal tubular epithelial cells, pacsin2 is enriched at the apical pole where it is localised to endocytic structures. Loss of pacsin2 results in reduced endocytosis within the proximal tubule, which is accompanied by a reduction in the abundance of megalin and endocytic organelles. Our results indicate that pacsin2 is required for efficient endocytosis in the proximal tubule, where it likely cooperates with other trafficking machinery to maintain endocytic uptake and recycling of megalin.

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“…Recently, we identified a homozygous missense mutation in the gene encoding the EHD1 protein in patients with low-molecular-weight proteinuria (0.7–2.1 g/d) and high-frequency hearing loss ( Issler et al, 2022 ). To gain further insights into the pathophysiology of the mutant EHD1 protein, we established a knockin mouse model carrying the respective mutation (p.R398W) in the mouse Ehd1 gene.…”

Section: Introductionmentioning

confidence: 99%

A missense mutation in Ehd1 associated with defective spermatogenesis and male infertility

Meindl,

Issler,

Afonso

et al. 2023

Front. Cell Dev. Biol.

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Normal function of the C-terminal Eps15 homology domain-containing protein 1 (EHD1) has previously been associated with endocytic vesicle trafficking, shaping of intracellular membranes, and ciliogenesis. We recently identified an autosomal recessive missense mutation c.1192C>T (p.R398W) of EHD1 in patients who had low molecular weight proteinuria (0.7–2.1 g/d) and high-frequency hearing loss. It was already known from Ehd1 knockout mice that inactivation of Ehd1 can lead to male infertility. However, the exact role of the EHD1 protein and its p.R398W mutant during spermatogenesis remained still unclear. Here, we report the testicular phenotype of a knockin mouse model carrying the p.R398W mutation in the EHD1 protein. Male homozygous knockin mice were infertile, whereas the mutation had no effect on female fertility. Testes and epididymes were significantly reduced in size and weight. The testicular epithelium appeared profoundly damaged and had a disorganized architecture. The composition of developing cell types was altered. Malformed acrosomes covered underdeveloped and misshaped sperm heads. In the sperm tail, midpieces were largely missing indicating disturbed assembly of the sperm tail. Defective structures, i.e., nuclei, acrosomes, and sperm tail midpieces, were observed in large vacuoles scattered throughout the epithelium. Interestingly, cilia formation itself did not appear to be affected, as the axoneme and other parts of the sperm tails except the midpieces appeared to be intact. In wildtype mice, EHD1 co-localized with acrosomal granules on round spermatids, suggesting a role of the EHD1 protein during acrosomal development. Wildtype EHD1 also co-localized with the VPS35 component of the retromer complex, whereas the p.R398W mutant did not. The testicular pathologies appeared very early during the first spermatogenic wave in young mice (starting at 14 dpp) and tubular destruction worsened with age. Taken together, EHD1 plays an important and probably multifaceted role in spermatogenesis in mice. Therefore, EHD1 may also be a hitherto underestimated infertility gene in humans.

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A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness

Cited by 10 publications

References 36 publications

Impaired Endosome Maturation Mediates Tubular Proteinuria in Dent Disease Cell Culture and Mouse Models

Impaired Endosome Maturation Mediates Tubular Proteinuria in Dent Disease Cell Culture and Mouse Models

Pacsin2 is required for endocytosis in the zebrafish pronephric tubule

A missense mutation in Ehd1 associated with defective spermatogenesis and male infertility

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