A missense mutation in Ehd1 associated with defective spermatogenesis and male infertility
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 E...
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| Format: | Article |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1240558/full |
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| author | Katrin Meindl Naomi Issler Naomi Issler Sara Afonso Sara Afonso Alberto Cebrian-Serrano Alberto Cebrian-Serrano Alberto Cebrian-Serrano Karin Müller Christina Sterner Helga Othmen Helga Othmen Ines Tegtmeier Ralph Witzgall Enriko Klootwijk Benjamin Davies Benjamin Davies Robert Kleta Richard Warth |
| author_facet | Katrin Meindl Naomi Issler Naomi Issler Sara Afonso Sara Afonso Alberto Cebrian-Serrano Alberto Cebrian-Serrano Alberto Cebrian-Serrano Karin Müller Christina Sterner Helga Othmen Helga Othmen Ines Tegtmeier Ralph Witzgall Enriko Klootwijk Benjamin Davies Benjamin Davies Robert Kleta Richard Warth |
| author_sort | Katrin Meindl |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T18:44:19Z |
| format | Article |
| id | doaj.art-fd42d22c6ae24e04acdfb7eeea4fccc3 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-03-11T18:44:19Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-fd42d22c6ae24e04acdfb7eeea4fccc32023-10-12T06:54:21ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-10-011110.3389/fcell.2023.12405581240558A missense mutation in Ehd1 associated with defective spermatogenesis and male infertilityKatrin Meindl0Naomi Issler1Naomi Issler2Sara Afonso3Sara Afonso4Alberto Cebrian-Serrano5Alberto Cebrian-Serrano6Alberto Cebrian-Serrano7Karin Müller8Christina Sterner9Helga Othmen10Helga Othmen11Ines Tegtmeier12Ralph Witzgall13Enriko Klootwijk14Benjamin Davies15Benjamin Davies16Robert Kleta17Richard Warth18Medical Cell Biology, University Regensburg, Regensburg, GermanyDepartment of Renal Medicine, University College London, London, United KingdomPediatric Nephrology Unit and Research Lab, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, IsraelMedical Cell Biology, University Regensburg, Regensburg, GermanyInstitute of Cellular and Molecular Physiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyWellcome Centre for Human Genetics, University Oxford, Oxford, United KingdomHelmholtz Zentrum München, Institute of Diabetes and Obesity, Munich, GermanyGerman Center for Diabetes Research (DZD), Neuherberg, GermanyLeibniz Institute for Zoo- und Wildlife Research, Berlin, GermanyMedical Cell Biology, University Regensburg, Regensburg, GermanyMedical Cell Biology, University Regensburg, Regensburg, GermanyMolecular and Cellular Anatomy, University Regensburg, Regensburg, GermanyMedical Cell Biology, University Regensburg, Regensburg, GermanyMolecular and Cellular Anatomy, University Regensburg, Regensburg, GermanyDepartment of Renal Medicine, University College London, London, United KingdomWellcome Centre for Human Genetics, University Oxford, Oxford, United Kingdom0Genetic Modification Service, The Francis Crick Institute, London, United KingdomDepartment of Renal Medicine, University College London, London, United KingdomMedical Cell Biology, University Regensburg, Regensburg, GermanyNormal 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.https://www.frontiersin.org/articles/10.3389/fcell.2023.1240558/fulltestisendocytosisretromergenetic diseasespermciliogenesis |
| spellingShingle | Katrin Meindl Naomi Issler Naomi Issler Sara Afonso Sara Afonso Alberto Cebrian-Serrano Alberto Cebrian-Serrano Alberto Cebrian-Serrano Karin Müller Christina Sterner Helga Othmen Helga Othmen Ines Tegtmeier Ralph Witzgall Enriko Klootwijk Benjamin Davies Benjamin Davies Robert Kleta Richard Warth A missense mutation in Ehd1 associated with defective spermatogenesis and male infertility Frontiers in Cell and Developmental Biology testis endocytosis retromer genetic disease sperm ciliogenesis |
| title | A missense mutation in Ehd1 associated with defective spermatogenesis and male infertility |
| title_full | A missense mutation in Ehd1 associated with defective spermatogenesis and male infertility |
| title_fullStr | A missense mutation in Ehd1 associated with defective spermatogenesis and male infertility |
| title_full_unstemmed | A missense mutation in Ehd1 associated with defective spermatogenesis and male infertility |
| title_short | A missense mutation in Ehd1 associated with defective spermatogenesis and male infertility |
| title_sort | missense mutation in ehd1 associated with defective spermatogenesis and male infertility |
| topic | testis endocytosis retromer genetic disease sperm ciliogenesis |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1240558/full |
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