A severe phenotype in mice with a duplication of exon 3 in the cystic fibrosis locus

To develop an animal model for cystic fibrosis (CF), targetedgene disruption in embryonic stem (ES) cells was used to generatea duplication of exon 3 (cftr^m1Bray allele) of the mouse CFgene. ES cells containing this mutation were used to generatechimeric animals that transmitted the mutant allele throughthe germline. Homozygous mutant animals display a severe phenotype,with approximately 40% dying within 1 week from intestinal obstruction.RNAase protection analysis of the cftr^m1Bray allele did notdetect any normal mRNA (<1–2% of wild-type) In mutantanimals. Pathologic changes in the intestines from mutant miceincluded mucus accumulation in the crypts and intestinal lumen,dilatation of the bases of the crypts, enlargement of gobletcells, and the presence of concretions in the crypts or betweenthe villi. Changes were also present in the mucosal glands ofthe pharynx and the minor sublingual glands, where dilatationof acini and accumulation of eosinophilic material were evident.Atrophy of acinar cells that may be secondary to nutritionaldeficiency and mild inflammation in the main pancreatic ductwere present in the pancreas of mutant animals. No changes werenoted in the lung, trachea, liver, or male reproductive tractof mutant animals, and mutant males were fertile. Homozygousmutant mice showed defects In cAMP-mediated ion transport bothin lleum and in cultured fetal tracheal explants. Thus, an additionalmouse model for CF has been generated that should prove usefulfor the understanding of the pathogenesis and the developmentof treatments for CF.