Manipulation of dipeptidylpeptidase 10 in mouse and human and models indicates a protective role in asthma
Authors: Laura L Yates
Youming Zhang
Ian M Adcock
Miriam F Moffatt
Martin S Taylor
Thanushiyan Poobalasingam
Lauren Chessum
Loukia Tsaprouni
Clare M Lloyd
William O Cookson
Charlotte H Dean
Jackie Harrison
Simone A Walker
Journal: Disease models & mechanisms (2018)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Airway resistance; Asthma; DPP10; IgE; Point mutation.
Affiliations: Genomics Medicine Section, National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK  ., Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK., Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3, 7BN., MRC Harwell Institute, Oxfordshire, OX11 0RD, UK., Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK., Genomics Medicine Section, National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK., Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK  .

Abstract:  We 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. 

Retracted: No

PubPeer comments:
 Could the authors please post original uncropped scans of the Western blots in figure 5D? There are some concerning patterns visible in the background. Thank you. *** Contrast enhanced ![file] *** Original ![file] , 
 #1 I will try to get original figures from the post-doc who did this work 13 years ago. Can you give further details regarding what is meant by concerning patterns . BW, Ian , 
 I have attached an annotated copy of the blots - I apologise but I do not have an original full size blot and I have not been able to contact Dr Tsaprouni who performed the original experiments in 2006. ![file] , 
 I appreciate the prompt response by the authors, and agree that the publication of the original images would be an ideal resolution. Absent the original images and without input from the u201cpost-doc who did this work 13 years agou201d for this paper **published in 2018**, perhaps Dr. Adcock could express some concern that the results as published may not be reliable. , 
 to whom would you wish me to express concern? , 
 #5 Iu2019m sorry that I came across as impertinent. I was only suggesting that without original gels, e.g., u201cdata,u201d the 2018 paper has some potential problems and your response that these experiments were performed in *2006* and the original data is no longer available seems incredible. , 
 The original work was based on a genetics paper from 2003. We worked for about 2 years (2004-2006), on this before the post-doc left to go to the Sanger and then off elsewhere. We have lost track since 2017 when they moved or left science and I do not have a current active email account. I did not do any further work on this as the story we were looking at relating to exposure to environmental particles was not leading anywherer. Incredible as it may seem, documentation of gel images was not as easy as it is now - you obtained x-ray films and then scanned those in and analysed off-line. As computer space available on the scanners was very limited with no internet connections between scanner and other computers devices. This often meant that people saved space by not scanning whole gel. In addition, the gel images on the films fade over time and were often coded with something that was recognisable by the researcher but not as clearly informative as now. This, of course, is now recognised as a problem. Hindsight is a wonderful thing as are technological advances. ,