Abstract
Mice that have been made deficient for the cystic fibrosis transmembrane conductance regulator (Cftr) usually die of intestinal obstruction. We have created Cftr-deficient mice and demonstrate prolonged survival among backcross and intercross progeny with different inbred strains, suggesting that modulation of disease severity is genetically determined. A genome scan showed that the major modifier locus maps near the centromere of mouse chromosome 7. Electrophysiological studies on mice with prolonged survival show that the partial rectification of Clâ and Na+ ion transport abnormalities can be explained in part by up-regulation of a calcium-activated Clâ conductance. Identification of modifier genes in our Cftrm1HSC/Cftrm1HSC mice should provide important insight into the heterogeneous disease presentation observed among CF patients.
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References
Welsh, M.J., Tsui, L.-C., Boat, T.F. & Beaudet, A.L. Cystic Fibrosis. In The Metabolic and Molecular Bases of Inherited Disease, Seventh Edition (eds. Scriver C.R., Beaudet A.L., Sly W.S. & Valle D.) 3799â3876 (McGraw-Hill Inc, New York, 1995).
Corey, M., Durie, P., Moore, D., Forstner, G. & Levison, H. Familial concordance of pancreatic function in cystic fibrosis. J. Pediatr. 115, 274â277 (1989).
Kristidis, P. etal. Genetic determination of exocrine pancreatic function in cystic fibrosis. Am. J. Hum. Genet. 50, 1178â1184 (1992).
Unpublished data from the CF Genetic Analysis Consortium (see Tsui, L-C: The spectrum of cystic fibrosis mutations. Trend Genet. 8, 392â398 (1992).
Rommens, J.M. et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245, 1059â1065 (1989).
Riordan, J.R. et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DMA. Science 245, 1066â1073 (1989).
Kerem, E. et al. The relation between genotype and phenotype in cystic fibrosis â analysis of the most common mutation (ÎF508). New Engl. J. Med. 323, 1517â1522 (1990).
Snouwaert, J.N. et al. An animal model for cystic fibrosis made by gene targeting. Science 257, 1083â1088 (1992).
Ratliff, R. et al. Production of a severe cystic fibrosis mutation in mice by gene targeting. Nature Genet. 4, 35â41 (1992).
O'Neal, W.K. et al. A severe phenotype in mice with a duplication of exon 3 in the cystic fibrosis locus. Hum. Molec. Genet. 2, 1561â1569 (1993).
Dorin, J.R. et al. Cystic fibrosis in the mouse by targeted insertional mutagenesis. Nature 359, 211â215 (1992).
Bear, C.E. et al. Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell 68, 809â818 (1992).
Anderson, M.R., Rich, D.R., Gregory, R.J., Smith, A.E. & Welsh, M.J. Generation of cAMP-activated chloride currents by expression of CFTR . Science 251, 679â682 (1991).
Tabcharani, J.A., Chang, X.-B., Riordan, J.R. & Hanrahan, J.W., Clâ channel in CHO cells stably expressing the cystic fibrosis gene. Nature 352, 628â631 (1991).
Clarke, L.L. et al. Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis. Science. 257, 1125â1128 (1992).
Clarke, L.L. et al. Relationship of a non-cystic fibrosis transmembrane conductance regulator-mediated chloride conductance to organ-level disease in Cftr (â/â) mice. Proc. Natl. Acad. Sci. USA 91, 479â483 (1994).
Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J.C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl. Acad. Sci. USA 90, 8424â8428 (1993).
Brilliant, M.H. et al. Mouse chromosome 7. Mamm. Genome. 5, S104âS123 (1994).
Grubb, B.R., Vick, R.N. & Boucher, R.C. Hyperabsorption of Na+ and raised Ca2+-mediated Clâ secretion in nasal epithelia of CF mice. Am. J. Physiol. 266, C1478âC1483 (1994).
Quinton, P.M. Chloride impermeability in cystic fibrosis. Nature 301, 421â422 (1983).
Knowles, M.R. et al. Abnormalion permeation through cystic fibrosis respiratory epithelium. Science 221, 1067â1070 (1983).
Quinton, P.M., Fibrosis: a disease in electrolyte transport. FASEB J. 4, 2709â2717 (1990).
Anderson, M.R. & Welsh, M.J. Calcium and cAMP activate different chloride channels in the apical membrane of normal and cystic fibrosis epithelia. Proc. Natl. Acad. Sci. USA 88, 6003â6007 (1991).
Zhou, L. et al. Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR. Science 266, 1705â1708 (1994).
Eckman, E., Cotton, C., Kube, D. & Davis, P. Prolonged survival of the UNC CF knock-out mouse. Pediatr. Pulmonol. suppl. 10, A62 (1994).
Lison, L. Alcian blue 8 G with chlorantine fast red 5 B. A technique for selective staining of mucopolysaccharides. Stain Technol. 29, 13 (1954).
Mansour, S.L., Thomas, K.R. & Capecchi, M.R. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature 336, 348â352 (1988).
Nagy, A. & Rossant, J. Production of completely ES cell-derived fetuses,. in Gene Targeting: A Practical Approach. (ed. Joyner, A.L.) 147â179 (Oxford University Press, Oxford, 1993).
Dietrich, W.F. et al. A genetic map of the mouse with 4,006 simple sequence length polymorphisms. Nature Genet. 7, 220â245 (1994).
Asada, Y., Varnum, D.S., Frankel, W.N. & Nadeau, J.H. A mutation in the Ter gene causing increased susceptibility to testicular teratomas maps to mouse chromosome 18. Nature Genet. 6, 363â368 (1994).
Knowles, M.R., Carson, J.L., Collier, A.M., Gatzy, J.T. & Boucher, R.C. Measurements of nasal transepithelial electric potential differences in normal human subjects in vivo. Am. Rev. Respir. Dis. 124, 484â490 (1981).
Hamill, O.R., Marty, A., Neher, E., Sakmann, B. & Sigworth, F.J. Improved patch-clamp technique for high resolution current recording from cells and cell-free membrane patches. Pflügers Arch. 391, 85â100 (1981).
Evans, G.S., Flint, N., Somers, A.S., Eyden, B. & Potten, C.S. The development of a method for the preparation of rat intestinal epithelial cell primary cultures. J. Cell Sci. 101, 219â231 (1992).
Bjerknes, M. & Cheng, H. Methods for the isolation of intact epithelium from the mouse intestine. Anatomical Record. 199, 565â574 (1981).
Chang, X.-B. et al. Protein kinase A (PKA) still activates CFTR chloride channel after mutagenesis of all 10 PKA consensus phosphorylation sites. J. Biol. Chem. 268, 11304â11311 (1993).
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Rozmahe, R., Wilschanski, M., Matin, A. et al. Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet 12, 280â287 (1996). https://doi.org/10.1038/ng0396-280
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DOI: https://doi.org/10.1038/ng0396-280