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DNAH5 Mutations Are a Common Cause of Primary Ciliary Dyskinesia with Outer Dynein Arm Defects

Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg; Children's Hospital of the Ruhr University Bochum, Bochum; Darmstädter Kinderkliniken Prinzessin Margaret, Darmstadt; Dr. von Haunersches Kinderspital, Ludwig-Maximilians University, Munich; Max-Planck Institute for Molecular Genetics, Berlin, Germany; Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; Department of Respiratory Medicine, University Children's Hospital, Zurich; and Department of Genetic Medicine and Development, University of Geneva Medical School, and University Hospitals of Geneva, Geneva, Switzerland

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: 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 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.

Key Words: cilia • DNAH5 • outer dynein arm • primary ciliary dyskinesia

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