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Molekulare Charakterisierung von äußeren Dyneinarm-Defekten bei der Primären Ciliären Dyskinesie (PCD)

Fachliche Zuordnung Kinder- und Jugendmedizin
Förderung Förderung von 2006 bis 2017
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 27604571
 
Erstellungsjahr 2017

Zusammenfassung der Projektergebnisse

Primary ciliary dyskinesia (PCD) is a genetic disorder caused by inherited defects of motile ciliary function. The genetically, functionally, and ultrastructurally heterogenous disease affects approximately one in 20,000 individuals at birth. The lack of coordinated ciliary movement causes insufficient muco-ciliary clearance of upper airway compartments such as Eustachian tube and sinuses, and lower airways resulting in chronic inflammatory damage of the lung. Dysfunction of node monocilia located at the embryonic node is associated with randomization of left-right body asymmetry. Therefore half of PCD patients exhibit situs inversus (complete mirror image of organ position). The association of PCD and situs inversus is also referred to as Kartagener’s syndrome (OMIM #244400). At the beginning of the project in 2006, only a few projects focused on rare lung disease in children worldwide. However, early diagnosis of PCD is important for prevention of permanent lung damage. Diagnosis was (and still is) often delayed because diagnostic workup is complicated. At the beginning of our project diagnosis relied so far on a combination of clinical suspicion and confirmatory test such as ultrastructural (electron microscopy) and/or functional (direct observation by light microscopy) analysis of respiratory cilia. As a screening test, measurement of nasal nitric oxide (NO) was suggested but only available in few centers word wide. In addition, in 2006, only three genes had been linked to recessive PCD, all encode for outer dynein arm proteins: DNAI1, DNAH11 and DNAH5. Therefore, further analysis was urgently needed to improve knowledge about human motile cell biology and to improve patient care and patient´s quality of life. The identification and characterization of further genes which are responsible for ODA defects in humans was important for the genetic diagnosis and genetic counseling especially because some functional defects resulting in PCD can be easily overlooked by standard procedures (e.g. DNAH11: dysfunctional cilia, but normal TEM pattern). Using candidate gene approaches, SNP analysis and whole exome sequencing analyses we identified novel genes (list available at: https://campus.unimuenster.de/en/pcd/research/primary-ciliary-dyskinesia-pcd/genetics-of-pcd/) encoding for ODA components or influence preassembly of ODA complexes, resulting in the first description of preassembly of ODA complexes in humans. In addition, we identified novel genes responsible for ODA targeting to and docking onto the ciliary axoneme. We also identified and described the diverse subcellular localization of DNAH11 in different cell types finally explaining the finding of hyperkinetic and stiff beat pattern in respiratory cell cilia and immotile cilia found at the left-right organizer (node), leading to left-right axis developmental defects. We also generated and validated antibodies targeting ODA components and associated proteins. These are now in use not only in our laboratory to characterize the ciliary composition in humans and mouse models not only for research purpose, but also for diagnostic purposes. With our analyses, we were also successful to characterize ciliary beat pattern abnormalities in respiratory cells and to assign beat pattern deviations to diverse genetic defects. This also not only improved knowledge about motile cilia biology, but also improved diagnostic methods used to diagnose PCD earlier than previously possible. In summary, this proposal resulted in the identification and characterization of several novel genes for PCD variants with structural and/or functional ODA defects, improvement of diagnostic procedures and patient care and in continuous publication in high ranking journals.

Projektbezogene Publikationen (Auswahl)

 
 

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