%0 Journal Article %A Claudius Werner %A Anita Becker-Heck %A Jennifer R. Panizzi %A Victoria H. Castleman %A Dalal Al-Mutari %A Eamonn Sheridan %A Niki T. Loges %A Heike Olbrich %A Rahul Chodhari %A Christopher O'Callaghan %A Eddie M.K. Chung %A Richard Reinhardt %A Hannah M. Mitchison %A Iain A. Drummond %A Heymut Omran %T CCDC103 encodes a novel cilia dynein arm factor that is mutated in primary ciliary dyskinesia %D 2012 %J European Respiratory Journal %P P4807 %V 40 %N Suppl 56 %X Primary ciliary dyskinesia (PCD) is a genetically heterogenous disorder characterized by chronic destructive respiratory tract disease. In about 50 % of cases it is associated with situs inversus, because embryonic cilia play a critical role in establishing organ left-right asymmetry.Zebrafish schmalhans mutants exhibit characteristic features of ciliopathy caused by a mutation in ccdc 103; in electron microscopy cilia lack inner (IDA) and outer (ODA) dynein arms.Screening individuals for CCDC103 (the human ccdc103 ortholog) identified ten patients with mutations. We found homozygous loss-of-function mutations in six individuals (c.383_384insG) predicting a frame shift and premature termination of translation. In four affected individuals a homozygous transversion (c.A461C; p.H154P) was identified.All affected individuals exhibited typical clinical findings for PCD. Three patients had situs inversus totalis, one had situs inversus abdominalis and two dextrocardia.High-speed videomicroscopy (HVM) of patient OP-1192II1 (c.383_384insG) showed ciliary immotiliy with only residual flickering. By contrast, in two patients with the p.H154P variant, HVM showed reduced beat amplitude and coordination and few immotile cilia.In patient OP-1192II1, Immunofluorescence microscopy demonstrated distal ODA deficiency. Cells from PCD patient OP-1194II1 (p.H154P variant) displayed a normal localization of ODA components. Both patients showed a normal localization of the IDA component DNALI1.Our findings indicate that CCDC103 mutations cause PCD in humans. Whereas the loss-of-function mutation results in ciliary immotility and distal ODA deficiency, the p.H154P variant presents as a hypomorphic mutation. %U https://erj.ersjournals.com/content/erj/40/Suppl_56/P4807.full.pdf