The classical genetic and genomic approach to the pathogenesis of primary ciliary dyskinesia.

PhD ceremony: Mr. M. Geremek, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The classical genetic and genomic approach to the pathogenesis of primary ciliary dyskinesia.

Promotor(s): prof. T.N. Wijmenga, prof. M. de Witt

Faculty: Medical Sciences

Primary ciliary dyskinesia (PCD) is a rare genetic disorder related to cilia motility. It is a highly heterogeneous, autosomal recessive trait in which eleven mutations have been identified so far, but most cases remain unexplained. Motile cilia propel fluid over tissues by synchronized beating, thereby generating the flow of mucus in the respiratory tract. Lack of ciliary beating leads to recurrent respiratory tract infections. We used genetic and genomic approaches to study the pathogenesis of PCD and identified several single nucleotide sequence variants correlating to PCD. Functional analysis led us to hypothesize that defects of multi-protein complexes in PCD cilia should be reflected by gene expression changes in the respiratory epithelium. We identified groups of genes that revealed highly correlated RNA expression patterns in PCD biopsies, which yielded a list of candidate genes. We further analyzed differential gene expression in bronchial tissue and showed that the genes down-regulated in PCD biopsies were significantly enriched for terms related to cilia. Our data suggest that the down-regulation of the ciliome genes plays an important role in the molecular pathomechanism of PCD.