Published ahead of print on April 20, 2006, doi:10.1164/rccm.200601-084OC
Am. J. Respir. Crit. Care Med., Volume 174, Number 2, July 2006, 120-126
A more recent version of this article appeared on July 15, 2006
Submitted on January 20, 2006
Accepted on April 20, 2006
DNAH5 Mutations are a Common Cause of Primary Ciliary Dyskinesia with Outer Dynein Arm Defects
Nada Hornef1, Heike Olbrich1, Judit Horvath1, Maimoona A Zariwala2, Manfred Fliegauf1, Niki Tomas Loges1, Johannes Wildhaber3, Peadar G Noone2, Marcus Kennedy2, Stylianos E Antonarakis4, Jean-Louis Blouin5, Lucia Bartoloni6, Thomas NuBlein7, Peter Ahrens8, Matthias Griese9, Heiner Kuhl10, Ralf Sudbrak10, Michael R Knowles2, Richard Reinhardt10, and Heymut Omran1*
1 Department of Pediatric and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany,
2 Department of Medicine, University of North Carolina, Chapel Hill, NC, USA,
3 Department of Respiratory Medicine, University Children's Hospital, Zurich, Switzerland,
4 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; University Hospitals of Geneva, Switzerland,
5 University Hospitals of Geneva, Switzerland,
6 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland,
7 Children's Hospital of the Ruhr University Bochum, Bochum, Germany,
8 Darmstadter Kinderkliniken Prinzessin Margaret, Darmstadt, Germany,
9 Dr. von Haunersches Kinderspital, Ludwig-Maximilians University, Munich, Germany,
10 Max-Planck Institute for Molecular Genetics, Berlin, Germany
* To whom correspondence should be addressed. E-mail: omran{at}kikli.ukl.uni-freiburg.de.
Rationale: Primary ciliary dyskinesia (PCD) is characterized by recurrent airway infections and randomization of left-right body asymmetry. To date, autosomal recessive mutations have only been identified in a small number of patients involving DNAI1 and DNAH5, which encode outer dynein arm components. Methods: We screened 109 Caucasian PCD families originating from Europe and North America for presence of DNAH5 mutations by haplotype analyses and/or sequencing. Results: Haplotype analyses excluded linkage in 26 families. In 30 PCD families we identified 33 novel (12 nonsense, 8 frameshift, 5 splicing and 8 missense mutations), and two known DNAH5 mutations. We observed clustering of mutations within five exons harbouring 27 mutant alleles (52%) out of the 52 detected mutant alleles. Interestingly, six (32%) of 19 PCD families with DNAH5 mutations from North America carry the novel founder mutation 10815delT. Electron microscopic analyses in 22 PCD patients with mutations detected invariably outer dynein arm ciliary defects. High-resolution immunofluorescence imaging of respiratory epithelial cells from eight patients with DNAH5 mutations showed mislocalization of mutant DNAH5 and accumulation at the microtubule organizing centers. Mutant DNAH5 was absent throughout the ciliary axoneme in seven patients and remained detectable in the proximal ciliary axoneme in one patient carrying compound heterozygous splicing mutations at the 3'-end (IVS75-2A>T, IVS76+5G>A). In a pre-selected subpopulation with documented outer dynein arm defects (n=47), DNAH5 mutations were identified in 53%. Conclusions: DNAH5 is frequently mutated in PCD patients exhibiting outer dynein arm defects and mutations cluster in five exons.
Key words: Primary ciliary dyskinesia, DNAH5, outer dynein arm, cilia
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