DNAH10 mutation cause primary ciliary dyskinesia with defects of IDAf complex assembly and lung fibrosis manifestation.

Primary ciliary dyskinesia (PCD; MIM 244400) is a genetic disorder, and its morbidity has been previously underestimated. Mutations in ciliary proteins underlie the disease, resulting in ciliary dysfunction. DNAH10 is an inner arm dynein heavy chain that has been shown to play a critical role in the movement of sperm flagella. In the present study, we demonstrated the presence of loss-of-function mutations in the DNAH10 gene among two families affected by primary ciliary dyskinesia. Patients displayed characteristic symptoms associated with PCD, including chronic respiratory infections, productive cough, and rhinosinusitis. Additionally, a decrease in the expression of DNAH10 was confirmed in both patients. Dnah10 knockout (KO) mice exhibited phenotypic characteristics recapitulating the PCD symptoms observed in two patients. Scanning electron microscope results showed curved and defective cilia morphology in Dnah10 KO mice. Immunostaining also showed that DNAH10 was specifically expressed in the cilia cell. Ciliary structural studies highlighted that DNAH10 interacted with candidate PCD proteins, including CFAP57, DYNLL1, and CCDC73, contributing to the formation of a double-headed inner dynein arm f (IDAf) complex. Co-IP experiment confirmed that DNAH10 can interact with CFAP57, DYNLL1, and CCDC73. We then detected the reduced expression of CFAP57, DYNLL1, and CCDC73 in patient P02 and Dnah10 KO mice. Furthermore, through proteomic analysis, we demonstrated alterations in the expression of abnormal innate immune proteins, super-molecular fiber organization, and mitochondrial respiratory chains. These findings suggested that the loss of DNAH10 leads to improper assembly of the IDAf complex, resulting in ciliary dysfunction and pulmonary fibrosis as the signature manifestation. Notably, our research findings hold substantial implications for the advancement of therapeutic strategies aimed at addressing ciliopathies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-025-03977-w.