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Published ahead of print on March 4, 2005, doi:10.1164/rccm.200411-1583OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 12, June 2005, 1343-1349

A more recent version of this article appeared on June 15, 2005
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Submitted on November 24, 2004
Accepted on February 22, 2005

Mis-localization of DNAH5 and DNAH9 in Respiratory Cells From Primary Ciliary Dyskinesia Patients

Manfred Fliegauf1, Heike Olbrich1, Judit Horvath1, Johannes H Wildhaber2, Maimoona A Zariwala3, Marcus Kennedy3, Michael R Knowles3, and Heymut Omran1*

1 Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany, 2 Swiss Paediatric Respiratory Physiology Research Group, Department of Respiratory Medicine, University Children's Hospital, Zurich, Switzerland, 3 Department of Medicine, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA

* To whom correspondence should be addressed. E-mail: omran{at}kikli.ukl.uni-freiburg.de.

Rationale: Primary ciliary dyskinesia (PCD) is a genetically heterogenous disorder characterized by recurrent infections of the airways and situs inversus in half of the affected off-spring. The most frequent genetic defects comprise recessive mutations of DNAH5 and DNAI1, which encode outer dynein arm (ODA) components. Diagnosis of PCD usually relies on electron microscopy, which is technically demanding and sometimes difficult to interpret. Methods: Using specific antibodies we determined the sub-cellular localization of the ODA heavy chains DNAH5 and DNAH9 in human respiratory epithelial and sperm cells of PCD patients and controls with high-resolution immuno-fluorescence imaging. We also assessed cilia and sperm tail function by high-speed video microscopy. Results: In normal ciliated airway epithelium, DNAH5 and DNAH9 show a specific regional distribution along the ciliary axoneme indicating the existence of at least two distinct ODA types. DNAH5 was completely or only distally absent from the respiratory ciliary axoneme in PCD patients with DNAH5- (n=3) or DNAI1- (n=1) mutations, respectively, and instead accumulated at the microtubule organizing centers. In contrast to respiratory cilia, sperm tails from a patient with DNAH5 mutations had normal ODA heavy chain distribution, suggesting different modes of ODA generation in these cell types. Blinded investigation of a large cohort of PCD patients and controls, identified DNAH5 mis-localization in all patients diagnosed with ODA defects by electron microscopy (n=16). Cilia with complete axonemal DNAH5 deficiency were immotile, whereas cilia with distal DNAH5 deficiency showed residual motility. Conclusions: Immuno-fluorescence staining can detect ODA defects, which will possibly aid PCD diagnosis.
Key words: genetics, respiratory tract diseases, fluorescent antibody technique




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