Spontaneous rescue from cystic fibrosis in a mouse model.
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.


CONCLUSIONS
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.
Charizopoulou
Nikoletta
N
Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, D-30625 Hannover, Germany. ncharizopoulou@yahoo.com
Wilke
Martina
M
Dorsch
Martina
M
Bot
Alice
A
Jorna
Huub
H
Jansen
Silke
S
Stanke
Frauke
F
Hedrich
Hans J
HJ
de Jonge
Hugo R
HR
Tümmler
Burkhard
B
D000818:Animals; D002712:Chlorides / Q000032:analysis; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004553:Electric Conductivity; D005260:Female; D023281:Genomics; D005838:Genotype; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000503:physiopathology; D051379:Mice; D018181:Mice, Inbred CFTR; D008817:Mice, Mutant Strains; D018895:Microsatellite Repeats; D010641:Phenotype; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000503:physiopathology
D002712:Chlorides; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator