CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms

Cilia are essential for fertilization, respiratory clearance, cerebrospinal fluid circulation, and to establish laterality(1). Cilia motility defects cause Primary Ciliary Dyskinesia (PCD, MIM 242650), a disorder affecting 1:15-30,000 births. Cilia motility requires the assembly of multisubunit dynein arms that drive cilia bending(2). Despite progress in understanding the genetic basis of PCD, mutations remain to be identified for several PCD linked loci(3). Here we show that the zebrafish cilia paralysis mutant schmalhans(tn222) (smh) mutant encodes the coiled-coil domain containing 103 protein (Ccdc103), a foxj1a regulated gene. Screening 146 unrelated PCD families identified patients in six families with reduced outer dynein arms, carrying mutations in CCDC103. Dynein arm assembly in smh mutant zebrafish was rescued by wild-type but not mutant human CCDC103. Chlamydomonas Ccdc103 functions as a tightly bound, axoneme-associated protein. The results identify Ccdc103 as a novel dynein arm attachment factor that when mutated causes Primary Ciliary Dyskinesia.