Molecular Insights into Outer Dynein Arm Defects in Primary Ciliary Dyskinesia: Involvement of ZMYND10 and GRP78
Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by recurrent sinopulmonary infections due to motile cilia defects. The disease is genetically heterogeneous, with abnormalities in structural ciliary proteins. Zinc finger MYND-type containing 10 (ZMYND10) is essen...
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2025-06-01
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| author | İlker Levent Erdem Zeynep Bengisu Kaya Pergin Atilla Nagehan Emiralioğlu Cemil Can Eylem Emirhan Nemutlu Uğur Özçelik Halime Nayır Büyükşahin Ayşenur Daniş Elif Karakoç |
| author_facet | İlker Levent Erdem Zeynep Bengisu Kaya Pergin Atilla Nagehan Emiralioğlu Cemil Can Eylem Emirhan Nemutlu Uğur Özçelik Halime Nayır Büyükşahin Ayşenur Daniş Elif Karakoç |
| author_sort | İlker Levent Erdem |
| collection | DOAJ |
| description | Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by recurrent sinopulmonary infections due to motile cilia defects. The disease is genetically heterogeneous, with abnormalities in structural ciliary proteins. Zinc finger MYND-type containing 10 (ZMYND10) is essential for the assembly of outer dynein arms (ODA), with chaperones like Glucose-regulated protein 78 (GRP78) facilitating protein folding. This study investigates ZMYND10 and Dynein axonemal heavy chain 5 <i>(DNAH5</i>) mutations in individuals with PCD. Methods: Eight individuals aged 14–22 with clinical PCD symptoms and confirmed <i>DNAH5</i> mutations were included. We analyzed the correlation between <i>DNAH5</i> abnormalities and preassembly/chaperone proteins using immunofluorescence labeling. Nasal swabs were double-labeled (<i>DNAH5</i>–β-tubulin, β-tubulin–ZMYND10, β-tubulin–GRP78) and examined via fluorescence microscopy. Serum metabolomics and proteomics were also assessed. Results: The corrected total cell fluorescence (CTCF) levels of <i>DNAH5</i>, ZMYND10, and GRP78 were significantly different between PCD individuals and controls. Metabolomic analysis showed reduced valine, leucine, and isoleucine biosynthesis, with increased malate and triacylglycerol biosynthesis, malate-aspartate and glycerol phosphate shuttles, and arginine/proline metabolism, suggesting mitochondrial and ER stress. Conclusions: The altered expression of DNAH5, ZMYND10, and GRP78, along with metabolic shifts, points to a complex link between ciliary dysfunction and cellular stress in PCD. Further studies are needed to clarify the underlying mechanisms. |
| format | Article |
| id | doaj-art-ba9decc187fb42b0b650826ea4a5ef86 |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| spelling | doaj-art-ba9decc187fb42b0b650826ea4a5ef862025-08-20T03:27:00ZengMDPI AGCells2073-44092025-06-01141291610.3390/cells14120916Molecular Insights into Outer Dynein Arm Defects in Primary Ciliary Dyskinesia: Involvement of ZMYND10 and GRP78İlker Levent Erdem0Zeynep Bengisu Kaya1Pergin Atilla2Nagehan Emiralioğlu3Cemil Can Eylem4Emirhan Nemutlu5Uğur Özçelik6Halime Nayır Büyükşahin7Ayşenur Daniş8Elif Karakoç9Department of Histology and Embryology, Hacettepe University Faculty of Medicine, 06230 Ankara, TurkeyDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USADepartment of Histology and Embryology, Hacettepe University Faculty of Medicine, 06230 Ankara, TurkeyDepartment of Pediatric Pulmonology, Hacettepe University Faculty of Medicine, 06230 Ankara, TurkeyDepartment of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, 06230 Ankara, TurkeyDepartment of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, 06230 Ankara, TurkeyDepartment of Pediatric Pulmonology, Hacettepe University Faculty of Medicine, 06230 Ankara, TurkeyDepartment of Pediatric Pulmonology, Hacettepe University Faculty of Medicine, 06230 Ankara, TurkeyDepartment of Pediatrics, University at Buffalo, Buffalo, NY 14203, USADepartment of Histology and Embryology, Hacettepe University Faculty of Medicine, 06230 Ankara, TurkeyBackground: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by recurrent sinopulmonary infections due to motile cilia defects. The disease is genetically heterogeneous, with abnormalities in structural ciliary proteins. Zinc finger MYND-type containing 10 (ZMYND10) is essential for the assembly of outer dynein arms (ODA), with chaperones like Glucose-regulated protein 78 (GRP78) facilitating protein folding. This study investigates ZMYND10 and Dynein axonemal heavy chain 5 <i>(DNAH5</i>) mutations in individuals with PCD. Methods: Eight individuals aged 14–22 with clinical PCD symptoms and confirmed <i>DNAH5</i> mutations were included. We analyzed the correlation between <i>DNAH5</i> abnormalities and preassembly/chaperone proteins using immunofluorescence labeling. Nasal swabs were double-labeled (<i>DNAH5</i>–β-tubulin, β-tubulin–ZMYND10, β-tubulin–GRP78) and examined via fluorescence microscopy. Serum metabolomics and proteomics were also assessed. Results: The corrected total cell fluorescence (CTCF) levels of <i>DNAH5</i>, ZMYND10, and GRP78 were significantly different between PCD individuals and controls. Metabolomic analysis showed reduced valine, leucine, and isoleucine biosynthesis, with increased malate and triacylglycerol biosynthesis, malate-aspartate and glycerol phosphate shuttles, and arginine/proline metabolism, suggesting mitochondrial and ER stress. Conclusions: The altered expression of DNAH5, ZMYND10, and GRP78, along with metabolic shifts, points to a complex link between ciliary dysfunction and cellular stress in PCD. Further studies are needed to clarify the underlying mechanisms.https://www.mdpi.com/2073-4409/14/12/916PCDciliopathyODADNAH5ZMYND10GRP78 |
| spellingShingle | İlker Levent Erdem Zeynep Bengisu Kaya Pergin Atilla Nagehan Emiralioğlu Cemil Can Eylem Emirhan Nemutlu Uğur Özçelik Halime Nayır Büyükşahin Ayşenur Daniş Elif Karakoç Molecular Insights into Outer Dynein Arm Defects in Primary Ciliary Dyskinesia: Involvement of ZMYND10 and GRP78 Cells PCD ciliopathy ODA DNAH5 ZMYND10 GRP78 |
| title | Molecular Insights into Outer Dynein Arm Defects in Primary Ciliary Dyskinesia: Involvement of ZMYND10 and GRP78 |
| title_full | Molecular Insights into Outer Dynein Arm Defects in Primary Ciliary Dyskinesia: Involvement of ZMYND10 and GRP78 |
| title_fullStr | Molecular Insights into Outer Dynein Arm Defects in Primary Ciliary Dyskinesia: Involvement of ZMYND10 and GRP78 |
| title_full_unstemmed | Molecular Insights into Outer Dynein Arm Defects in Primary Ciliary Dyskinesia: Involvement of ZMYND10 and GRP78 |
| title_short | Molecular Insights into Outer Dynein Arm Defects in Primary Ciliary Dyskinesia: Involvement of ZMYND10 and GRP78 |
| title_sort | molecular insights into outer dynein arm defects in primary ciliary dyskinesia involvement of zmynd10 and grp78 |
| topic | PCD ciliopathy ODA DNAH5 ZMYND10 GRP78 |
| url | https://www.mdpi.com/2073-4409/14/12/916 |
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