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Open Access Research article

Spontaneous rescue from cystic fibrosis in a mouse model

Nikoletta Charizopoulou13, Martina Wilke2, Martina Dorsch3, Alice Bot2, Huub Jorna2, Silke Jansen1, Frauke Stanke1, Hans J Hedrich3, Hugo R de Jonge2 and Burkhard Tümmler1*

Author Affiliations

1 Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, D-30625 Hannover, Germany

2 Department of Biochemistry, Erasmus University Medical Centre, PO Box 1738, 3000 DR Rotterdam, The Netherlands

3 Zentrales Tierlaboratorium, OE 8600, Medizinische Hochschule Hannover, D-30625 Hannover, Germany

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BMC Genetics 2006, 7:18  doi:10.1186/1471-2156-7-18

Published: 29 March 2006

Abstract

Background

From the original CftrTgH(neoim)Hgu mutant mouse model with a divergent genetic background (129P2, C57BL/6, MF1) we have generated two inbred CftrTgH(neoim)Hgu mutant strains named CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu, 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.

Results

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 CftrTgH(neoim)Hgu strains, with higher residual amount observed for CF/1-CftrTgH(neoim)Hgu than CF/3-CftrTgH(neoim)Hgu for every investigated tissue. Accordingly the amounts of wild type Cftr protein in the intestine were 9% for CF/1-CftrTgH(neoim)Hgu and 4% for CF/3-CftrTgH(neoim)Hgu. 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.

Conclusion

Unlike the outbred CftrTgH(neoim)Hgu insertional mouse model, which displayed the electrophysiological defect in the gastrointestinal and respiratory tracts characteristic of cystic fibrosis, both inbred CftrTgH(neoim)Hgu strains have ameliorated the electrophysiological defect. On the basis of these findings both CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu 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.