TY - JOUR
T1 - A severe phenotype in mice with a duplication of exon 3 in the cystic fibrosis locus
AU - O'neal, Wanda K.
AU - Hasty, Paul
AU - Mccray, Paul B.
AU - Casey, Brett
AU - Riverapérez, Jalme
AU - Welsh, Michael J.
AU - Beaudet, Arthur L.
AU - Bradley, Allan
N1 - Funding Information:
We thank Dr Milton Finegold for advice and guidance regarding pathological studies. We also would like to acknowledge die technical assistance of Tim Joseph, Kelly Armstrong, Aurita Puga, Phil Karp and Karen Liu. This investigation was supported by a predoctoral fellowship from the March of Dimes Birth Defects Foundation (W.K.O.) and grants from the Cystic Fibrosis Foundation (P.H., A.L.B., A.B., and M.J.W.), and the NIH (A.L.B., A.B., and P.B.M.).
PY - 1993/10
Y1 - 1993/10
N2 - To develop an animal model for cystic fibrosis (CF), targeted gene disruption in embryonic stem (ES) cells was used to generate a duplication of exon 3 (cftrm1Bray allele) of the mouse CF gene. ES cells containing this mutation were used to generate chimeric animals that transmitted the mutant allele through the germline. Homozygous mutant animals display a severe phenotype, with approximately 40% dying within 1 week from intestinal obstruction. RNAase protection analysis of the cftrm1Bray allele did not detect any normal mRNA (<1-2% of wild-type) In mutant animals. Pathologic changes in the intestines from mutant mice included mucus accumulation in the crypts and intestinal lumen, dilatation of the bases of the crypts, enlargement of goblet cells, and the presence of concretions in the crypts or between the villi. Changes were also present in the mucosal glands of the pharynx and the minor sublingual glands, where dilatation of acini and accumulation of eosinophilic material were evident. Atrophy of acinar cells that may be secondary to nutritional deficiency and mild inflammation in the main pancreatic duct were present in the pancreas of mutant animals. No changes were noted in the lung, trachea, liver, or male reproductive tract of mutant animals, and mutant males were fertile. Homozygous mutant mice showed defects In cAMP-mediated ion transport both in lleum and in cultured fetal tracheal explants. Thus, an additional mouse model for CF has been generated that should prove useful for the understanding of the pathogenesis and the development of treatments for CF.
AB - To develop an animal model for cystic fibrosis (CF), targeted gene disruption in embryonic stem (ES) cells was used to generate a duplication of exon 3 (cftrm1Bray allele) of the mouse CF gene. ES cells containing this mutation were used to generate chimeric animals that transmitted the mutant allele through the germline. Homozygous mutant animals display a severe phenotype, with approximately 40% dying within 1 week from intestinal obstruction. RNAase protection analysis of the cftrm1Bray allele did not detect any normal mRNA (<1-2% of wild-type) In mutant animals. Pathologic changes in the intestines from mutant mice included mucus accumulation in the crypts and intestinal lumen, dilatation of the bases of the crypts, enlargement of goblet cells, and the presence of concretions in the crypts or between the villi. Changes were also present in the mucosal glands of the pharynx and the minor sublingual glands, where dilatation of acini and accumulation of eosinophilic material were evident. Atrophy of acinar cells that may be secondary to nutritional deficiency and mild inflammation in the main pancreatic duct were present in the pancreas of mutant animals. No changes were noted in the lung, trachea, liver, or male reproductive tract of mutant animals, and mutant males were fertile. Homozygous mutant mice showed defects In cAMP-mediated ion transport both in lleum and in cultured fetal tracheal explants. Thus, an additional mouse model for CF has been generated that should prove useful for the understanding of the pathogenesis and the development of treatments for CF.
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U2 - 10.1093/hmg/2.10.1561
DO - 10.1093/hmg/2.10.1561
M3 - Article
C2 - 7505691
AN - SCOPUS:0027379757
VL - 2
SP - 1561
EP - 1569
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 10
ER -