Abstract
ABSTRACTWe previously identified dipeptidylpeptidase 10 (DPP10) on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional role of DPP10 in asthma remains unclear. Using the MRC Harwell N-ethyl-N-nitrosourea (ENU) DNA archive, we identified a point mutation in Dpp10 that caused an amino acid change from valine to aspartic acid in the β-propeller region of the protein. Mice carrying this point mutation were recovered and a congenic line was established (Dpp10145D). Macroscopic examination and lung histology revealed no significant differences between wild-type and Dpp10145D/145D mice. However, after house dust mite (HDM) treatment, Dpp10 mutant mice showed significantly increased airway resistance in response to 100 mg/ml methacholine. Total serum IgE levels and bronchoalveolar lavage (BAL) eosinophil counts were significantly higher in homozygotes than in control mice after HDM treatment. DPP10 protein is present in airway epithelial cells and altered expression is observed in both tissue from asthmatic patients and in mice following HDM challenge. Moreover, knockdown of DPP10 in human airway epithelial cells results in altered cytokine responses. These results show that a Dpp10 point mutation leads to increased airway responsiveness following allergen challenge and provide biological evidence to support previous findings from human genetic studies. This article has an associated First Person interview with the first author of the paper.
Highlights
Using a Dpp10 point mutant, with a valine to aspartic acid change in the β-propeller region, we demonstrated that homozygous mutant mice exhibit greater airway hyper-responsiveness (AHR) following house dust mite (HDM) challenge than wild-type animals
We find that dipeptidylpeptidase 10 (DPP10) protein is present in airway epithelial cells and Dpp10 immunostaining is increased in mice following HDM challenge; this corresponds with clinical findings where asthmatic patients show increased DPP10 in lungs compared to controls
These results provide biological evidence to support previous findings from human genetic studies indicating that DPP10 is an asthma susceptibility gene
Summary
We have established that polymorphisms in DPP10 on human chromosome 2 were associated with asthma traits through positional cloning (Allen et al, 2003). These associations have since been replicated in different ethnic populations worldwide (Wu et al, 2010; Blakey et al, 2009; Zhou et al, 2009; Gao et al, 2010; Mathias et al, 2010). DPP10 has been associated with asthma in both genome-wide and wet-laboratory studies (Allen et al, 2003; Schade et al, 2008; Kim et al, 2015), its functional role in asthma is almost completely unknown, due in large part to the absence of any genetic models
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