IMPC Mouse Moldels Targeting Odad3 Gene Recapitulate Human Primary Ciliary Dyskinesia Rare Disease

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous autosomal recessive disorder caused by defects in motile cilia. Coordinated ciliary beating is essential for cerebrospinal fluid circulation, mucus clearance, and reproductive cell movement, while embryonic nodal cilia generate leftward flow, triggering asymmetric gene expression that establishes left-right body asymmetry. Consistent with cilia function across multiple organs, PCD is characterized by chronic respiratory infections, middle ear disease, situs abnormalities, congenital heart defects, hydrocephalus, and infertility, with no specific drugs currently available for PCD. The motile ciliary axoneme comprises over 250 proteins, mutations in which can cause ciliary defects. The ODAD3 gene encodes an axonemal protein essential for ciliary motility, and human ODAD3 mutations cause PCD. Using targeted ES cells from the International Mouse Phenotyping Consortium (IMPC), we generated an allelic series of mice with constitutive and conditional loss of Odad3 function. In Odad3 tm1b animals (gene replaced by LacZ reporter), expression is observed in organs requiring fluid movement affected by PCD: lungs, testis, and ependymal cells lining the brain ventricles. Homozygous Odad3 knockout animals exhibited severe hydrocephalus, laterality defects, and infertility, demonstrating the phenotypic validity of the PCD model. However, most animals die perinatally, due to severity of the hydrocephalus. To circumvent perinatal lethality, we generated conditional knockout Odad3tm1c mice. Adult-inducible ablation of Odad3 produced persistent rhinosinusitis and impaired fertility, thereby recapitulating chronic adult PCD phenotypes. These IMPC-derived models provide a robust validated platform for systematic functional characterization of motile cilia genes and for future preclinical therapeutic testing in PDC.