Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus

• Published in: American journal of human genetics Vol. 103; no. 6; pp. 984 - 994
• Main Authors: Fassad, Mahmoud R., Shoemark, Amelia, Legendre, Marie, Hirst, Robert A., Koll, France, le Borgne, Pierrick, Louis, Bruno, Daudvohra, Farheen, Patel, Mitali P., Thomas, Lucie, Dixon, Mellisa, Burgoyne, Thomas, Hayes, Joseph, Nicholson, Andrew G., Cullup, Thomas, Jenkins, Lucy, Carr, Siobhán B., Aurora, Paul, Lemullois, Michel, Aubusson-Fleury, Anne, Papon, Jean-François, O’Callaghan, Christopher, Amselem, Serge, Hogg, Claire, Escudier, Estelle, Tassin, Anne-Marie, Mitchison, Hannah M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.12.2018; Elsevier (Cell Press); Elsevier
• Subjects: Adolescent; Amino Acid Sequence; Axonemal Dyneins - genetics; Child; Child, Preschool; Cilia - genetics; Ciliary Motility Disorders - genetics; DNAH9; dynein; Dyneins - genetics; Genetics; High-Throughput Nucleotide Sequencing - methods; Human genetics; Human health and pathology; Humans; Life Sciences; Male; motile cilia; mutation; Mutation - genetics; primary ciliary dyskinesia; Pulmonology and respiratory tract; Respiratory System - pathology; Sequence Alignment; situs inversus; Situs Inversus - genetics; tomography; dynein; mutation; tomography; motile cilia; DNAH9; situs inversus; primary ciliary dyskinesia; genetics; genes; diagnosis; dyskinesia
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2018.10.016

Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum.