Primary ciliary dyskinesia caused by loss-of-function GAS8 mutations due to defects of the nexin-dynein regulatory complex

Introduction Primary Ciliary Dyskiensia (PCD) describes a clinically and genetically heterogeneous group of hereditary disorders characterized by chronic mucopurulent infections of the airways caused by dysfunction of multiple motile cilia. Mutations in u003e 30 genes have been described to cause PCD. We present a new genetic PCD-variant caused by defects of the nexin-dynein regulatory complex (N-DRC). Objectives PCD is widely underdiagnosed because of the great heterogeneity of phenotypes. We wanted to reveal rare PCD-variants with only subtle changes in ciliary beating or ultrastructure by further methods such as immunofluorescence microscopy (IF) and genetic analysis. Methods Patient material was supplied for routine diagnostic work-up including high-speed videomicroscopy (HVMA), transmission electron microscopy (TEM), IF and genetics. Within IF we used an antibody directed against the protein GAS8 (human DRC4). In case of abnormal results we performed whole-exome sequencing and confirmed findings with Sanger sequencing. Results IF showed the absence of GAS8 from the ciliary axoneme in three patients. We excluded mutations in the genes CCDC65 and CCDC164 , which lead to isolated nexin link-defects. Subsequent genetic analysis showed recessive loss-of-function mutations in GAS8 encoding for human protein DRC4 in the three families . HVMA and TEM did not show obvious abnormalities. Conclusions Defects of the N-DRC were difficult to diagnose because routinely performed HVMA and TEM showed almost normal findings. We could show that IF and genetic analysis in those patients can be very useful to detect rare PCD-variants e.g. with defects of the N-DRCs.