{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T18:28:56Z","timestamp":1785781736202,"version":"3.56.0"},"reference-count":43,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hacettepe University Scientific Research Projects","award":["#TSA-2021-19011"],"award-info":[{"award-number":["#TSA-2021-19011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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 (DNAH5) mutations in individuals with PCD. Methods: Eight individuals aged 14\u201322 with clinical PCD symptoms and confirmed DNAH5 mutations were included. We analyzed the correlation between DNAH5 abnormalities and preassembly\/chaperone proteins using immunofluorescence labeling. Nasal swabs were double-labeled (DNAH5\u2013\u03b2-tubulin, \u03b2-tubulin\u2013ZMYND10, \u03b2-tubulin\u2013GRP78) and examined via fluorescence microscopy. Serum metabolomics and proteomics were also assessed. Results: The corrected total cell fluorescence (CTCF) levels of DNAH5, 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.<\/jats:p>","DOI":"10.3390\/cells14120916","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T11:53:14Z","timestamp":1750161194000},"page":"916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Molecular Insights into Outer Dynein Arm Defects in Primary Ciliary Dyskinesia: Involvement of ZMYND10 and GRP78"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5931-4408","authenticated-orcid":false,"given":"\u0130lker Levent","family":"Erdem","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, Hacettepe University Faculty of Medicine, 06230 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9713-8732","authenticated-orcid":false,"given":"Zeynep Bengisu","family":"Kaya","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5132-0002","authenticated-orcid":false,"given":"Pergin","family":"Atilla","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Hacettepe University Faculty of Medicine, 06230 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1405-8401","authenticated-orcid":false,"given":"Nagehan","family":"Emiralio\u011flu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Hacettepe University Faculty of Medicine, 06230 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3353-2869","authenticated-orcid":false,"given":"Cemil Can","family":"Eylem","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, 06230 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7337-6215","authenticated-orcid":false,"given":"Emirhan","family":"Nemutlu","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, 06230 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1587-5216","authenticated-orcid":false,"given":"U\u011fur","family":"\u00d6z\u00e7elik","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Hacettepe University Faculty of Medicine, 06230 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6909-7993","authenticated-orcid":false,"given":"Halime Nay\u0131r","family":"B\u00fcy\u00fck\u015fahin","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Hacettepe University Faculty of Medicine, 06230 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2112-1218","authenticated-orcid":false,"given":"Ay\u015fenur","family":"Dani\u015f","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0677-1047","authenticated-orcid":false,"given":"Elif","family":"Karako\u00e7","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Hacettepe University Faculty of Medicine, 06230 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1513\/AnnalsATS.201511-748OC","article-title":"Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents","volume":"13","author":"Leigh","year":"2016","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1378\/chest.13-1704","article-title":"Laterality Defects Other Than Situs Inversus Totalis in Primary Ciliary Dyskinesia","volume":"146","author":"Shapiro","year":"2014","journal-title":"Chest"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1183\/13993003.00209-2016","article-title":"A Longitudinal Study Characterising a Large Adult Primary Ciliary Dyskinesia Population","volume":"48","author":"Shah","year":"2016","journal-title":"Eur. Respir. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2301769","DOI":"10.1183\/13993003.01769-2023","article-title":"Analyses of 1236 Genotyped Primary Ciliary Dyskinesia Individuals Identify Regional Clusters of Distinct DNA Variants and Significant Genotype-Phenotype Correlations","volume":"64","author":"Raidt","year":"2024","journal-title":"Eur. Respir. J."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wu, R., Li, H., Wu, P., Yang, Q., Wan, X., and Wu, Y. (2025). Lrrc56 Deletion Causes Primary Ciliary Dyskinesia in Mice Characterized by Dynein Arms Defects. Biol. Open, 14.","DOI":"10.1242\/bio.061846"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"19","DOI":"10.5152\/TurkThoracJ.2017.16049","article-title":"Quality of Life Questionnaire for Turkish Patients with Primary Ciliary Dyskinesia","volume":"18","author":"Emiralioglu","year":"2017","journal-title":"Turk. Thorac. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1083\/jcb.200504008","article-title":"Proteomic Analysis of a Eukaryotic Cilium","volume":"170","author":"Witman","year":"2005","journal-title":"J. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1055\/s-0035-1546748","article-title":"Primary Ciliary Dyskinesia","volume":"36","author":"Zariwala","year":"2015","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/S2213-2600(19)30374-1","article-title":"Primary Ciliary Dyskinesia in the Genomics Age","volume":"8","author":"Lucas","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_10","unstructured":"Michael, H., and Ross, W.P. (2016). Histology, a Text and Atlas with Correlated Cell and Molecular Biology, Lippincott Williams & Wilkins. [7th ed.]."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ishikawa, T. (2017). Axoneme Structure from Motile Cilia. Cold Spring Harb. Perspect. Biol., 9.","DOI":"10.1101\/cshperspect.a028076"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/j.cell.2019.09.030","article-title":"Structure of the Decorated Ciliary Doublet Microtubule","volume":"179","author":"Ma","year":"2019","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yang, W., Chen, L., Guo, J., Shi, F., Yang, Q., Xie, L., Lu, D., Li, Y., Luo, J., and Wang, L. (2022). Multiomics Analysis of a Dnah5-Mutated Pcd Organoid Model Revealed the Key Role of the Tgf-Beta\/Bmp and Notch Pathways in Epithelial Differentiation and the Immune Response in Dnah5-Mutated Patients. Cells, 11.","DOI":"10.3390\/cells11244013"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s13023-025-03596-5","article-title":"Genetic Spectrum and Genotype-Phenotype Correlations in Dnah5-Mutated Primary Ciliary Dyskinesia: A Systematic Review","volume":"20","author":"Dong","year":"2025","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1055\/s-0041-1733940","article-title":"Novel Pathogenic Dnah5 Variants in Primary Ciliary Dyskinesia: Association with Visceral Heterotaxia and Neonatal Cholestasis","volume":"12","author":"Lin","year":"2023","journal-title":"J. Pediatr. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/cm.970290304","article-title":"22s Axonemal Dynein Is Preassembled and Functional Prior to Being Transported to and Attached on the Axonemes","volume":"29","author":"Fok","year":"1994","journal-title":"Cell Motil. Cytoskelet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1091\/mbc.9.9.2337","article-title":"The Role of Preassembled Cytoplasmic Complexes in Assembly of Flagellar Dynein Subunits","volume":"9","author":"Fowkes","year":"1998","journal-title":"Mol. Biol. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1083\/jcb.200802025","article-title":"Oda16 Aids Axonemal Outer Row Dynein Assembly through an Interaction with the Intraflagellar Transport Machinery","volume":"183","author":"Ahmed","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nature07471","article-title":"Ktu\/Pf13 Is Required for Cytoplasmic Pre-Assembly of Axonemal Dyneins","volume":"456","author":"Omran","year":"2008","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/ng.1106","article-title":"Mutations in Axonemal Dynein Assembly Factor Dnaaf3 Cause Primary Ciliary Dyskinesia","volume":"44","author":"Mitchison","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cho, K.J., Noh, S.H., Han, S.M., Choi, W.I., Kim, H.Y., Yu, S., Lee, J.S., Rim, J.H., Lee, M.G., and Hildebrandt, F. (2018). Zmynd10 Stabilizes Intermediate Chain Proteins in the Cytoplasmic Pre-Assembly of Dynein Arms. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007316"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.ajhg.2012.08.022","article-title":"Whole-Exome Capture and Sequencing Identifies Heatr2 Mutation as a Cause of Primary Ciliary Dyskinesia","volume":"91","author":"Horani","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1038\/ng.2707","article-title":"Dyx1c1 Is Required for Axonemal Dynein Assembly and Ciliary Motility","volume":"45","author":"Tarkar","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.ajhg.2013.06.007","article-title":"Zmynd10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with Lrrc6","volume":"93","author":"Zariwala","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.ajhg.2012.10.003","article-title":"Loss-of-Function Mutations in Lrrc6, a Gene Essential for Proper Axonemal Assembly of Inner and Outer Dynein Arms, Cause Primary Ciliary Dyskinesia","volume":"91","author":"Kott","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Horani, A., Ferkol, T.W., Shoseyov, D., Wasserman, M.G., Oren, Y.S., Kerem, B., Amirav, I., Cohen-Cymberknoh, M., Dutcher, S.K., and Brody, S.L. (2013). Lrrc6 Mutation Causes Primary Ciliary Dyskinesia with Dynein Arm Defects. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059436"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.lfs.2019.04.022","article-title":"Grp78: A Cell\u2019s Response to Stress","volume":"226","author":"Ibrahim","year":"2019","journal-title":"Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14799731251314872","DOI":"10.1177\/14799731251314872","article-title":"Active Cycle of Breathing Technique Versus Oscillating Positive Expiratory Pressure Therapy: Effect on Lung Function in Children with Primary Ciliary Dyskinesia; a Feasibility Study","volume":"22","author":"Fashho","year":"2025","journal-title":"Chronic Respir. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Karakoc, E., Hjeij, R., Kaya, Z.B., Emiralioglu, N., Ademhan Tural, D., Atilla, P., Ozcelik, U., and Omran, H. (2025). Diagnostic Role of Immunofluorescence Analysis in Primary Ciliary Dyskinesia-Suspected Individuals. J. Clin. Med., 14.","DOI":"10.3390\/jcm14061941"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Pereira, R., Barbosa, T., Gales, L., Oliveira, E., Santos, R., Oliveira, J., and Sousa, M. (2019). Clinical and Genetic Analysis of Children with Kartagener Syndrome. Cells, 8.","DOI":"10.3390\/cells8080900"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wilken, A., Hoben, I.M., Wolter, A., Loges, N.T., Olbrich, H., Aprea, I., Dworniczak, B., Raidt, J., and Omran, H. (2024). Primary Ciliary Dyskinesia Associated Disease-Causing Variants in Ccdc39 and Ccdc40 Cause Axonemal Absence of Inner Dynein Arm Heavy Chains Dnah1, Dnah6, and Dnah7. Cells, 13.","DOI":"10.3390\/cells13141200"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ccm.2021.11.008","article-title":"Diagnosis of Primary Ciliary Dyskinesia","volume":"43","author":"Goutaki","year":"2022","journal-title":"Clin. Chest Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wang, L., Zhao, X., Liang, H., Zhang, L., Li, C., Li, D., Meng, X., Meng, F., and Gao, M. (2021). Novel Compound Heterozygous Mutations of Dnah5 Identified in a Pediatric Patient with Kartagener Syndrome: Case Report and Literature Review. BMC Pulm. Med., 21.","DOI":"10.1186\/s12890-021-01586-4"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e002686","DOI":"10.1161\/CIRCGEN.119.002686","article-title":"Randomization of Left-Right Asymmetry and Congenital Heart Defects: The Role of Dnah5 in Humans and Mice","volume":"12","author":"Wallmeier","year":"2019","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Al-Mutairi, D.A., Alsabah, B.H., Pennekamp, P., and Omran, H. (2024). Novel Pathogenic Variants of Dnah5 Associated with Clinical and Genetic Spectra of Primary Ciliary Dyskinesia in an Arab Population. Front. Genet., 15.","DOI":"10.3389\/fgene.2024.1396797"},{"key":"ref_36","first-page":"18","article-title":"Genetics and Biology of Primary Ciliary Dyskinesia","volume":"18","author":"Horani","year":"2016","journal-title":"Paediatr. Respir. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1164\/rccm.201607-1351OC","article-title":"Accuracy of Immunofluorescence in the Diagnosis of Primary Ciliary Dyskinesia","volume":"196","author":"Shoemark","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_38","unstructured":"Erdem, I.L., Dani\u015f, A., Nayir B\u00fcy\u00fck\u015fahin, H., Emiralio\u011flu, N., Kaya, Z.B., \u00d6z\u00e7elik, U., Atilla, P., and Bilgi\u00e7, E. (2022, January 26\u201328). A Histolog\u0131cal Approach to a Pat\u0131ent W\u0131th Pr\u0131mary Ciliary Dyskinesia: Cilium Preassembly Proteins in the Presence of the Outer Dynein Arm Defect. Proceedings of the 15th National\u20131st International Congress of Histology and Embryology (NICHE 2022), Online."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e34389","DOI":"10.7554\/eLife.34389","article-title":"Zmynd10 Functions in a Chaperone Relay During Axonemal Dynein Assembly","volume":"7","author":"Mali","year":"2018","journal-title":"eLife"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e2303448120","DOI":"10.1073\/pnas.2303448120","article-title":"Er Chaperone Grp78\/Bip Translocates to the Nucleus under Stress and Acts as a Transcriptional Regulator","volume":"120","author":"Liu","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","unstructured":"Erdem, I.L., Danis, A., Buyuksahin, H.N., Emiralioglu, N., Kaya, Z.B., Ozcelik, U., Atilla, P., Eylem, C.C., Nemutlu, E., and Bilgic, E. (2022). Examining the Connection between Dnah5 Abnormalities and Preassembly Proteins in Patients with Primary Ciliary Dyskinesia (Pcd): May Be Accompanied with Potential Organelle Dysfunctions. EMBO Cilia 2022, EMBO."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jprot.2018.07.001","article-title":"Comparative Proteomics of Respiratory Exosomes in Cystic Fibrosis, Primary Ciliary Dyskinesia and Asthma","volume":"185","author":"Bourderioux","year":"2018","journal-title":"J. Proteom."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e168836","DOI":"10.1172\/jci.insight.168836","article-title":"The Effect of Dnaaf5 Gene Dosage on Primary Ciliary Dyskinesia Phenotypes","volume":"8","author":"Horani","year":"2023","journal-title":"JCI Insight"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/12\/916\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:53:50Z","timestamp":1760032430000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/12\/916"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,17]]},"references-count":43,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["cells14120916"],"URL":"https:\/\/doi.org\/10.3390\/cells14120916","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,17]]}}}