The immotile cilia syndromes (ICS) are a genetically determined set of disorders characterized by dysmotility or immotility of the cilia in airway epithelial cells, spermatozoa and other ciliated cells of the body. Kartagener syndrome (KS) is a subgroup of ICS characterized by a classic triad of symptoms: situs inversus, bronchiectasis and chronic sinusitis. Ciliary immotility is caused by various ultrastructural defects of cilia, predominantly by a lack of dynein arms. The clinical consequences of KS include pronounced craniofacial manifestations. In 1994, we initiated a large-scale collaborative genetic epidemiology study of KS with Dr. Michal Witt of Poznan, Poland. Polish families with at least one child affected with KS are being recruited for this study. Coded DNA samples and research medical records are being sent to our laboratory for genotyping and statistical analyses using linkage and linkage disequilibrium approaches. We use microsatellite markers and fluorescence-based automated DNA fragment analysis hardware and software. We performed a genome scan and have followed up promising regions with very high density STR mapping. To date, over 83,000 genotypes have been assayed for this study. We have reported exclusion of a candidate region on chromosome 7 for KS families. We have now obtained strong evidence of linkage to chromosome 15 with a multipoint LOD score of 5.0. In collaboration with bioinformatics collaborators at the National Center for Biotechnology Information, we have been conducting advanced searches of the rapidly growing DNA sequence databases for the human genome with the aim of identifying a candidate gene for this disease located in this chromosomal region. We have recently identified a strong candidate and are pursuing experiments aimed at evaluating this gene further to determine if mutations in this gene are actually responsible for causing Kartagener syndrome.
| Witt, M; Wang, Y f; Wang, S et al. (1999) Exclusion of chromosome 7 for Kartagener syndrome but suggestion of linkage in families with other forms of primary ciliary dyskinesia. Am J Hum Genet 64:313-8 |
