Partner und Internationale Organisationen
(Englisch)
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Coordinator: Humboldt University, Berlin, Valencia University, CNRS 249, Montpellier, University College, London, Pavia University, Center for Human Genetics, Leuven, ICRF, London, University of Zurich, University of Stockholm
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Abstract
(Englisch)
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Primary Ciliary Dyskinesia (PCD), or Immotile Cilia Syndrome (ICS), is an autosomal recessive disorder affecting ciliary movement with an incidence of 1 in 20,000-30,000. Dysmotility to complete immotility of cilia results in a multisystem disease of variable severity with recurrent respiratory tract infections leading to bronchiectasis, and male subfertility. Ultrastructural defects seen by electron microscopy are present in ciliated mucosa or spermatozoa. Situs inversus is found in about half of the patients (Kartagener syndrome). PCD is probably a genetically heterogeneous disorder, the causative genes for which are unknown.
We have collected blood samples from 61 European and North American families with PCD. A genome-wide linkage search was performed in 31 multiplex families (at least 2 affecteds per family, 169 individuals including 70 affecteds) using 188 evenly-spaced (19 cM average interval) and highly polymorphic markers. Both parametric (recessive model) and non-parametric (IBD allele sharing) linkage analyses were used. No major locus showing linkage to the majority of the families was identified, although the sample was powerful enough to detect linkage if 40% of the families studied were linked to one locus. These results strongly suggest extensive locus heterogeneity. Potential genomic regions harboring PCD loci were localized on chromosomes 3p, 4q, 5p, 8q, 15q, 16p, 17q and 19q. Although numerous proteins are present in the ciliary structures, genes encoding dyneins are excellent candidates for PCD since electron microscopy reveals a dynein arm deficiency in about half of affected individuals. Linkage analyses using PCD families with a dynein arm deficiency provided 'suggestive' evidence for linkage to chromosomal regions 8q, 16pter and 19q, while analyses using only PCD families with situs inversus resulted in 'suggestive' scores for chromosomes 8q, and 19q.
Mutation searches in candidate dynein genes in a few chromosomal localizations is now
in progress in order to identify a subgroup of PCD due to abnormalities in dynein genes.
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