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

Hornef, N., Olbrich, H., Horvath, J., Zariwala, M. A., Fliegauf, M., Loges, N. T., et al. (2006). DNAH5 Mutations are a Common Cause of Primary Ciliary Dyskinesia with Outer Dynein Arm Defects. American Journal of Respiratory and Critical Care Medicine: an Official Journal of the American Thoracic Society, Medical Section of the Lung Association, 174(2), 120-126. doi:10.1164/rccm.200601-084OC.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-83EA-7 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-83EB-5
Genre: Journal Article
Alternative Title : Am J Respir Crit Care Med

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 Creators:
Hornef, Nada, Author
Olbrich, Heike, Author
Horvath, Judit, Author
Zariwala, Maimoona A., Author
Fliegauf, Manfred, Author
Loges, Niki Tomas, Author
Wildhaber, Johannes, Author
Noone, Peadar G., Author
Kennedy, Marcus, Author
Antonarakis, Stylianos E., Author
Blouin, Jean-Louis, Author
Bartoloni, Lucia, Author
Nüsslein, Thomas, Author
Ahrens, Peter, Author
Griese, Matthias, Author
Kuhl, Heiner1, Author              
Sudbrak, Ralf2, Author              
Knowles, Michael R., Author
Reinhardt, Richard3, Author              
Omran, Heymut, Author
Affiliations:
1Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Manuela B. Urban), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
2Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              
3High Throughput Technologies, Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433552              

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Free keywords: cilia • DNAH5 • outer dynein arm • primary ciliary dyskinesia
 Abstract: 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.

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Language(s): eng - English
 Dates: 2006-07-15
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: eDoc: 305187
DOI: 10.1164/rccm.200601-084OC
 Degree: -

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Title: American Journal of Respiratory and Critical Care Medicine : an Official Journal of the American Thoracic Society, Medical Section of the Lung Association
  Alternative Title : Am J Respir Crit Care Med
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 174 (2) Sequence Number: - Start / End Page: 120 - 126 Identifier: ISSN: 1535-4970