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

• Published in: American journal of respiratory and critical care medicine Vol. 174; no. 2; pp. 120 - 126
• Main 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, Nusslein, Thomas, Ahrens, Peter, Griese, Matthias, Kuhl, Heiner, Sudbrak, Ralf, Knowles, Michael R, Reinhardt, Richard, Omran, Heymut
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 15.07.2006; American Lung Association; American Thoracic Society
• Subjects: A. Airway Biology; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Axonemal Dyneins; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; DNA Mutational Analysis; Dyneins - genetics; Dyneins - ultrastructure; Dyskinesia; Fluorescent Antibody Technique; Haplotypes; Humans; Intensive care medicine; Kartagener Syndrome - genetics; Medical sciences; Mutation; Mutation, Missense; Neurology; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; RNA Splicing; Vascular diseases and vascular malformations of the nervous system; North America; Europe; outer dynein arm; Nervous system diseases; Intensive care; Enzyme; DNAH5; Dynein ATPase; Cerebral disorder; Involuntary movement; Central nervous system disease; Hydrolases; Mutation; Neurological disorder; Resuscitation; primary ciliary dyskinesia; Extrapyramidal syndrome; Cilia; Dyskinesia
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200601-084OC

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. We screened 109 white PCD families originating from Europe and North America for presence of DNAH5 mutations by haplotype analyses and/or sequencing. 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. DNAH5 is frequently mutated in patients with PCD exhibiting outer dynein arm defects and mutations cluster in five exons.