Homozygosity mapping of a gene locus for primary ciliary dyskinesia on chromosome 5p and identification of the heavy dynein chain DNAH5 as a candidate gene

Reduced mucociliary clearance in primary ciliary dyskinesia (PCD) causes re current infections of the upper and lower respiratory tract. The disease is usually inherited as an autosomal recessive trait. To identify a gene locu s for PCD, we studied a large consanguineous family of Arabic origin. Direc t examination of the respiratory cilia revealed ciliary akinesia, Electron microscopic examination of cilia showed absence of the outer dynein arms. T wo of four affected individuals exhibited a situs inversus, typical for Kar tagener syndrome, due to randomization of the left/right body axis. A total genome scan with 340 highly polymorphic microsatellites was performed. We localized a new gene locus for PCD to a region of homozygosity by descent o n chromosome 5p15-p14 with a parametric multipoint logarithm of odds ratio (LOD) score of Zmax = 3.51 flanked by markers D5S2095 and D5S502 within an interval of 20 centimorgans sex-averaged genetic distance. Applying a polym erase chain reaction-based approach, we identified a 1.5-kb partial complem entary DNA of DNAH5 encoding a Chlamydomonas-related axonemal heavy dynein chain within the critical disease interval of this new PCD locus. On the ba sis of the Chlamydomonas model for PCD, this gene represents an excellent c andidate for PCD.