A novel pathogenic variant of CFAP221 is a cause of a mild form of primary ciliary dyskinesia

Abstract

Primary ciliary dyskinesia (PCD) is a heritable disease caused by the dysfunction of motile cilia, with a highly heterogeneous genetic background. CFAP221 (Cilia and Flagella Associated Protein 221) is one of the genes, whose role in the PCD pathogenesis requires further evidence.

Using whole-exome sequencing we found a novel, homozygous protein-truncating variant in CFAP221 in a Polish PCD patient. To better understand the effect of the identified pathogenic variant on motile cilia structure and function, the proband's nasal epithelium was examined using immunofluorescence, high-speed videomicroscopy, and mucociliary transport assay. Subtle abnormalities in the protein composition of the ciliary central apparatus were consistent with the asynchronous, circular motion of cilia and reduced ciliary beat frequency in the proband; importantly, the motility of proband's sperm cells was within the normal range. To independently confirm the role of CFAP221, the impact of RNA interference (RNAi)-mediated knockdown of CFAP221 homolog on motile cilia function in a ciliated flatworm, Schmidtea mediterranea, was analyzed. Knockdown of CFAP221 homolog impaired motile cilia function and led to a visible change in the speed of worms' locomotion.

Taken together, our study provided an independent confirmation of the involvement of CFAP221 in the PCD pathogenesis. The subtle effect of Smed-cfap221 knockdown in worms was consistent with the mild course of PCD in the proband.