Abstract

Defective motile cilia are responsible for a group of heterogeneous genetic conditions characterised by dysfunction of the apparatus responsible for generating fluid flows. Primary ciliary dyskinesia (PCD) is the prototype for such disorders and presents with impaired pulmonary mucus clearance, susceptibility to chronic recurrent respiratory infections, male infertility and laterality defects in about 50 % of patients. Here we report biallelic variants in LRRC56 (also known as ODA8), identified in two unrelated consanguineous families. The phenotype comprises laterality defects and chronic pulmonary infections. High speed video microscopy of cultured patient epithelial cells showed severely dyskinetic cilia, but no obvious ultra-structural abnormalities on routine transmission electron microscopy (TEM). Further investigation revealed that LRRC56 interacts with the intraflagellar transport (IFT) protein IFT88. The link to IFT was interrogated in Trypanosoma brucei. In this protist, LRRC56 is recruited to the cilium during axoneme construction, where it co-localises with IFT trains and facilitates the addition of dynein arms to the distal end of the flagellum. In T. brucei carrying LRRC56 null mutations, or a mutation (p.Leu259Pro) corresponding to the p.Leu140Pro variant seen in one of the affected families, we observed abnormal ciliary beat patterns and an absence of outer dynein arms restricted to the distal portion of the axoneme. Together, our findings confirm that deleterious variants in LRRC56 result in a human disease, and suggest this protein has a likely role in dynein transport during cilia assembly that is evolutionarily important for cilia motility.