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Document Version Version Comment Date Status
305175.0 Automatic journal name synchronization 26.03.2007 12:02 Released

ID: 305175.0, MPI für molekulare Genetik / Sequencing Group
DNAH5 Mutations are a Common Cause of Primary Ciliary Dyskinesia with Outer Dynein Arm Defects
Authors:Hornef, Nada; Olbrich, Heike; Horvath, Judit; Zariwala, Maimoona A.; Fliegauf, Manfred; Loges, Niki Tomas; Wildhaber, Johannes; Noone, Peadar G.; Kennedy, Marcus; Antonarakis, Stylianos E.; Blouin, Jean-Louis; Bartoloni, Lucia; Nüsslein, Thomas; Ahrens, Peter; Griese, Matthias; Kuhl, Heiner; Sudbrak, Ralf; Knowles, Michael R.; Reinhardt, Richard; Omran, Heymut
Date of Publication (YYYY-MM-DD):2006-07-15
Title of Journal:American Journal of Respiratory and Critical Care Medicine : an Official Journal of the American Thoracic Society, Medical Section of the Lung Association
Journal Abbrev.:Am J Respir Crit Care Med
Issue / Number:2
Start Page:120
End Page:126
Copyright:© 2006 American Thoracic Society
Review Status:not specified
Audience:Experts Only
Abstract / Description: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 white 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 harboring 27 mutant alleles (52%) of the 52 detected mutant alleles. Interestingly, 6 (32%) of 19 PCD families with DNAH5 mutations from North America carry the novel founder mutation 10815delT. Electron microscopic analyses in 22 patients with PCD with mutations invariably detected 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 preselected subpopulation with documented outer dynein arm defects (n = 47), DNAH5 mutations were identified in 53% of patients.
Conclusions: DNAH5 is frequently mutated in patients with PCD exhibiting outer dynein arm defects and mutations cluster in five exons.
Free Keywords:cilia • DNAH5 • outer dynein arm • primary ciliary dyskinesia
Comment of the Author/Creator:Correspondence and requests for reprints should be addressed to Heymut Omran, M.D., Department of Pediatrics and Adolescent Medicine, Mathildenstrasse 1, 79106 Freiburg, Germany. E-mail:
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Richard Reinhardt
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany;
2.Children's Hospital of the Ruhr University Bochum, Bochum, Germany;
3.Darmstädter Kinderkliniken Prinzessin Margaret, Darmstadt, Germany;
4.Dr. von Haunersches Kinderspital, Ludwig-Maximilians University, Munich, Germany;
5.Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA;
6.Department of Respiratory Medicine, University Children's Hospital, Zurich, Switzerland;
7.Department of Genetic Medicine and Development, University of Geneva Medical School, and University Hospitals of Geneva, Geneva, Switzerland.