Cystic fibrosis mice carrying the missense mutation G551D replicate human genotype-phenotype correlations.
We have generated a mouse carrying the human G551D mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR) by a one-step gene targeting procedure. These mutant mice show cystic fibrosis pathology but have a reduced risk of fatal intestinal blockage compared with 'null' mutants, in keeping with the reduced incidence of meconium ileus in G551D patients. The G551D mutant mice show greatly reduced CFTR-related chloride transport, displaying activity intermediate between that of cftr(mlUNC) replacement ('null') and cftr(mlHGU) insertional (residual activity) mutants and equivalent to approximately 4% of wild-type CFTR activity. The long-term survival of these animals should provide an excellent model with which to study cystic fibrosis, and they illustrate the value of mouse models carrying relevant mutations for examining genotype-phenotype correlations.
Delaney
S J
SJ
Centre for Molecular and Cellular Biology, University of Queensland, Brisbane, Australia.
Alton
E W
EW
Smith
S N
SN
Lunn
D P
DP
Farley
R
R
Lovelock
P K
PK
Thomson
S A
SA
Hume
D A
DA
Lamb
D
D
Porteous
D J
DJ
Dorin
J R
JR
Wainwright
B J
BJ
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004594:Electrophysiology; D018390:Gene Targeting; D005838:Genotype; D006801:Humans; D007415:Intestinal Obstruction / Q000235:genetics; D017136:Ion Transport / Q000235:genetics; D008470:Meconium; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009296:Nasal Cavity / Q000503:physiopathology; D010641:Phenotype; D017354:Point Mutation
C505032:CFTR protein, human; D002712:Chlorides; D017931:DNA Primers; D019005:Cystic Fibrosis Transmembrane Conductance Regulator