Characterization and regulation of protocadherin-1, a novel gene for asthma

PhD ceremony: Mr. H. Koning, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Characterization and regulation of protocadherin-1, a novel gene for asthma

Promotor(s): prof. G.H. Koppelman, prof. A.J.M. van Oosterhout, prof. D.S. Postma

Faculty: Medical Sciences

Asthma is a chronic disease of the airways, characterized by shortness of breath and bronchial hyper responsiveness. It is a complex disease caused by genetic and environmental factors. In asthma patients, the epithelial cell layer of the airways have less integrity and the epithelium becomes ‘leaky’. In 2009 we discovered Protocadherin-1 as a novel susceptibility gene for asthma. Furthermore we identified an association of Protocadherin-1 gene-variants with eczema, a skin disease. We observed expression of Protocadherin-1 in the airway epithelium, and specifically in differentiated cells that were exposed to air. In addition, we identified a strong association of Protocadherin-1 with asthma in families that were exposed to cigarette smoke. We investigated the influence of cigarette smoke on Protocadherin-1 expression levels, and identified decreased Protocadherin-1 expression levels in mice exposed to smoke. Furthermore we discovered a direct interaction of Protocadherin-1 with SMAD3, a novel asthma gene. We believe that Protocadherin-1 plays an important role in the maintenance of the integrity of the airway epithelium, possibly by interacting with SMAD3. Furthermore we think that a defect in the Protocadherin-1 protein, or a decrease in expression levels, by for example cigarette smoke, may weaken the integrity of the airway epithelium, and subsequently result in an increased risk for asthma. These findings are potentially of great interest for the asthma patient, as they may eventually lead to a novel treatment method aimed at recovery of the integrity of the airways.