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 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 ) mutations in individuals with PCD.

METHODS

Eight individuals aged 14-22 with clinical PCD symptoms and confirmed mutations were included. We analyzed the correlation between abnormalities and preassembly/chaperone proteins using immunofluorescence labeling. Nasal swabs were double-labeled (-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 , 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.