Spontaneous rescue from cystic fibrosis in a mouse model

• Main Authors: Stanke Frauke, Jansen Silke, Jorna Huub, Bot Alice, Dorsch Martina, Wilke Martina, Charizopoulou Nikoletta, Hedrich Hans J, de Jonge Hugo R, Tümmler Burkhard
• Format: Article
• Language: English
• Published: BMC 2006-03-01
• Series: BMC Genetics
• Online Access: http://www.biomedcentral.com/1471-2156/7/18
• ISSN: 1471-2156

<p>Abstract</p> <p>Background</p> <p>From the original <it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu </it>}mutant mouse model with a divergent genetic background (129P2, C57BL/6, MF1) we have generated two inbred <it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu </it>}mutant strains named CF/1-<it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu </it>}and CF/3-<it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu</it>}, which are fertile and show normal growth and lifespan. Initial genome wide scan analysis with microsatellite markers indicated that the two inbred strains differed on the genetic level. In order to further investigate whether these genetic differences have an impact on the disease phenotype of cystic fibrosis we characterised the phenotype of the two inbred strains.</p> <p>Results</p> <p>Reduced amounts, compared to wild type control animals, of correctly spliced Cftr mRNA were detected in the nasal epithelia, lungs and the intestine of both inbred <it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu </it>}strains, with higher residual amount observed for CF/1-<it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu </it>}than CF/3-<it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu </it>}for every investigated tissue. Accordingly the amounts of wild type Cftr protein in the intestine were 9% for CF/1-<it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu </it>}and 4% for CF/3-<it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu</it>}. Unlike the apparent strain and/or tissue specific regulation of Cftr mRNA splicing, short circuit current measurements in the respiratory and intestinal epithelium revealed that both strains have ameliorated the basic defect of cystic fibrosis with a presentation of a normal electrophysiology in both tissues.</p> <p>Conclusion</p> <p>Unlike the outbred <it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu </it>}insertional mouse model, which displayed the electrophysiological defect in the gastrointestinal and respiratory tracts characteristic of cystic fibrosis, both inbred <it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu </it>}strains have ameliorated the electrophysiological defect. On the basis of these findings both CF/1-<it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu </it>}and CF/3-<it>Cftr</it>^{<it>TgH</it>(<it>neoim</it>)<it>Hgu </it>}offer an excellent model whereby determination of the minimal levels of protein required for the restoration of the basic defect of cystic fibrosis can be studied, along with the modulating factors which may affect this outcome.</p>