Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice / 医学前沿

Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.

Clinical phenotypes of primary ciliary dyskinesia / 中南大学学报(医学版)

Primary ciliary dyskinesia (PCD) is a hereditary disease characterized by airway mucociliary clearance dysfunction. The estimated prevalence of PCD is 1꞉10 000 to 1꞉20 000. The main respiratory manifestations in children are cough, expectoration, chronic rhinitis, sinusitis, and chronic otitis media, while the most common symptoms in adults are chronic sinusitis, bronchiectasis, and infertility. About 50% of patients with certain PCD-related gene variants are combined with situs inversus, and the incidence of congenital heart disease is also high. The pathogenesis behind PCD is that gene variants cause structural or functional disorders of respiratory cilia and motile cilia of other organs, leading to a series of heterogeneous clinical manifestations, which makes it difficult to identify and diagnose PCD. Combining different disease screening tools and understanding the relationship between genotypes and phenotypes may facilitate early diagnosis and treatment for PCD.