TY - JOUR T1 - CCDC103 encodes a novel cilia dynein arm factor that is mutated in primary ciliary dyskinesia JF - European Respiratory Journal JO - Eur Respir J VL - 40 IS - Suppl 56 SP - P4807 AU - Claudius Werner AU - Anita Becker-Heck AU - Jennifer R. Panizzi AU - Victoria H. Castleman AU - Dalal Al-Mutari AU - Eamonn Sheridan AU - Niki T. Loges AU - Heike Olbrich AU - Rahul Chodhari AU - Christopher O'Callaghan AU - Eddie M.K. Chung AU - Richard Reinhardt AU - Hannah M. Mitchison AU - Iain A. Drummond AU - Heymut Omran Y1 - 2012/09/01 UR - http://erj.ersjournals.com/content/40/Suppl_56/P4807.abstract N2 - 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. ER -