Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis.
Cystic fibrosis (CF) is a recessive disease that affects multiple organs. It is caused by mutations in CFTR. Animal modeling of this disease has been challenging, with species- and strain-specific differences in organ biology and CFTR function influencing the emergence of disease pathology. Here, we report the phenotype of a CFTR-knockout ferret model of CF. Neonatal CFTR-knockout ferrets demonstrated many of the characteristics of human CF disease, including defective airway chloride transport and submucosal gland fluid secretion; variably penetrant meconium ileus (MI); pancreatic, liver, and vas deferens disease; and a predisposition to lung infection in the early postnatal period. Severe malabsorption by the gastrointestinal (GI) tract was the primary cause of death in CFTR-knockout kits that escaped MI. Elevated liver function tests in CFTR-knockout kits were corrected by oral administration of ursodeoxycholic acid, and the addition of an oral proton-pump inhibitor improved weight gain and survival. To overcome the limitations imposed by the severe intestinal phenotype, we cloned 4 gut-corrected transgenic CFTR-knockout kits that expressed ferret CFTR specifically in the intestine. One clone passed feces normally and demonstrated no detectable ferret CFTR expression in the lung or liver. The animals described in this study are likely to be useful tools for dissecting CF disease pathogenesis and developing treatments.
Sun
Xingshen
X
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Sui
Hongshu
H
Fisher
John T
JT
Yan
Ziying
Z
Liu
Xiaoming
X
Cho
Hyung-Ju
HJ
Joo
Nam Soo
NS
Zhang
Yulong
Y
Zhou
Weihong
W
Yi
Yaling
Y
Kinyon
Joann M
JM
Lei-Butters
Diana C
DC
Griffin
Michelle A
MA
Naumann
Paul
P
Luo
Meihui
M
Ascher
Jill
J
Wang
Kai
K
Frana
Timothy
T
Wine
Jeffrey J
JJ
Meyerholz
David K
DK
Engelhardt
John F
JF
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005289:Ferrets / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation; D010641:Phenotype; D012137:Respiratory System / Q000378:metabolism / Q000473:pathology; D014649:Vas Deferens / Q000378:metabolism / Q000473:pathology
D019005:Cystic Fibrosis Transmembrane Conductance Regulator