ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry

Hjeij R., Lindstrand A., Francis R., Zariwala M., Liu X., Li Y., Damerla R., Dougherty G., Abouhamed M., Olbrich H., Loges N., Pennekamp P., Davis E., Carvalho C., Pehlivan D., Werner C., Raidt J., Köhler G., Häffner K., Reyes-Mugica M., Lupski J., Leigh M., Rosenfeld M., Morgan L., Knowles M., Lo C., Katsanis N., Omran H.

Abstract

The motive forces for ciliary movement are generated by large multiprotein complexes referred to as outer dynein arms (ODAs), which are preassembled in the cytoplasm prior to transport to the ciliary axonemal compartment. In humans, defects in structural components, docking complexes, or cytoplasmic assembly factors can cause primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease and defects in laterality. By using combined high resolution copy-number variant and mutation analysis, we identified ARMC4 mutations in twelve PCD individuals whose cells showed reduced numbers of ODAs and severely impaired ciliary beating. Transient suppression in zebrafish and analysis of an ENU mouse mutant confirmed in both model organisms that ARMC4 is critical for left-right patterning. We demonstrate that ARMC4 is an axonemal protein that is necessary for proper targeting and anchoring of ODAs. © 2013 The American Society of Human Genetics.