Molecular genetic analysis of primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is the term used to encompass the diseases known as Kartagener syndrome (OMIM 244000) and immotile cilia syndrome (OMIM 242650/242680/242670). PCD is an autosomal recessive disease with an estimated prevalence of 1 in 20,000. The main clinical features of PCD are recurrent sinopulmonary infections as a direct consequence of a primary abnormality of cilia. Cilia are highly complex organelles and this has led to the hypothesis that mutations in a number of different genes may lead to the PCD phenotype. At the time that this research project was begun none of the disease genes causing PCD had been identified. The aim of this project was to map and clone the gene(s) for PCD using a positional cloning strategy. This thesis describes the results of two genome screens; the first genome screen used the technique of homozygosity mapping in a large consanguineous German family. This highlighted 3 areas of interest which were then further evaluated in families that shared an identical ultrastructural phenotype. The results did not achieve statistical significance but suggested potential loci for PCD on chromosome 17q and chromosome 11q. The second genome screen was performed in individuals from the isolated community of the Faroe Islands. This screen revealed an area of interest on chromosome 16p. This area continues to be evaluated. During the course of this thesis a mutation in a gene that codes for an intermediate dynein (IC78) (Pennarun, Escudier et al. 1999) was identified and significant evidence for linkage was also found on chromosome 19q. (Meeks, Walne et al. 2000). In summary PCD is a genetically heterogeneous disease. Two loci have been published (Pennarun, Escudier et al. 1999) (Meeks, Walne et al. 2000) and at least two further potential loci have been identified as part of this thesis