RT Journal Article
SR Electronic
T1 CCDC103 encodes a novel cilia dynein arm factor that is mutated in primary ciliary dyskinesia
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P4807
VO 40
IS Suppl 56
A1 Claudius Werner
A1 Anita Becker-Heck
A1 Jennifer R. Panizzi
A1 Victoria H. Castleman
A1 Dalal Al-Mutari
A1 Eamonn Sheridan
A1 Niki T. Loges
A1 Heike Olbrich
A1 Rahul Chodhari
A1 Christopher O'Callaghan
A1 Eddie M.K. Chung
A1 Richard Reinhardt
A1 Hannah M. Mitchison
A1 Iain A. Drummond
A1 Heymut Omran
YR 2012
UL http://erj.ersjournals.com/content/40/Suppl_56/P4807.abstract
AB 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.