Abstract
Cystic flbrosis is a fatal genetic disorder which afflicts 50,000 people worldwide. A viable animal model would be invaluable for investigating and combating this disease. The mouse cystic flbrosis transmembrane conductance regulator gene was disrupted in embryonal stem cells using an insertional gene targeting vector. Germ-line chimaeras were derived and the offspring of heterozygous crosses studied. These homozygous mutant mice survive beyond weaning. In vivo electrophysiology demonstrates the predicted defect in chloride ion transport in these mice and can distinguish between each genotype. Histological analysis detects important hallmarks of human disease pathology, including abnormalities of the colon, lung and vas deferens. This insertional mouse mutation provides a valid model system for the development and testing of therapies for cystic fibrosis patients.
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References
Boat, T. F., Welsh, M. J. & Beaudet, A. L. in The Metabolic Basis of Inherited Disease 6th edn (eds Scriver, C. R., Beaudet, A. L. Sly, W. S. & Valle, D.) 2649–2680 (McGraw-Hill, New York, 1989).
Jackson, A. D. M. in Cystic Fibrosis (ed. Goodfellow, P.) 1–11 (Oxford Univ. Press, Oxford, 1989).
Kaplan, E. et al. New Engl. J. Med. 279, 65–69 (1968).
Rommens, J. M. et al. Science 245, 1059–1065 (1989).
Riordan, J. R. et al. Science 245, 1066–1073 (1989).
Kerem, B. et al. Science 245, 1073–1080 (1989).
Collins, F. S. Science 256, 774–779 (1992).
Kristidis, P. et al. Am. J. hum. Genet. 50, 1178–1184 (1992).
Cutting, G. R. et al. New Engl. J. Med. 323, 1685–1689 (1990).
Jones, C. T. et al. Hum. molec. Gen. 1, 11–17 (1992).
Ivanschenko, T. E. et al. Genomics 10, 298–299 (1991).
Shoshani, T. et al. Am. J. hum. Genet. 50, 222–228 (1992).
Anderson, M. P. et al. Science 253, 202–205 (1991).
Diamond, G. et al. J. biol. Chem. 266, 22761–22768 (1991).
Dorin, J. R. et al. Transgen. Res. 1, 101–105 (1992).
Knowles, M., Gatzy, J. & Boucher, R. New Engl. J. Med. 303, 1489–1495 (1981).
Goldstein, J. L. et al. Am. J. Physiol. 254, 718–724 (1988).
Quinton, P. M. Nature 347, 226 (1990).
Smith, S. N., Alton, E. W. F. W. & Geddes, D. M. Clin. Sci. 82, 667–672 (1992).
Willumsen, N. J. & Boucher, R. C. Am. J. Physiol. 261, 319–331 (1991).
Alton, E. W. F. W. et al. Eur. Resp. J. 4, 5–9 (1991).
Alton, E. W. F. W. et al. Thorax (in the press).
Widdicombe, J. H., Welsh, M. J. & Finkbeiner, W. E. Proc. natn. Acad. Sci. U.S.A. 82, 6167–6171 (1985).
Oppenheimer, E. H. & Esterly, J. R. in Perspectives in Pediatric Pathology Vol. 2 (eds Rosenberg, H. S. & Bolande, R. P.) 241–278 (Yearbook Medical Publishers, New York, 1975).
Schwachman, H., Kuiczycki L. L. & Khaw, K. T. Pediatrics 36, 689–699 (1965).
Wine, J. J. Nature Genet. 1, 10 (1992).
Hasty, P., Rivera-Perez, J. & Bradley, A. Molec. cell. Biol. 12, 1464–2474 (1992).
Koller, B. H. et al. Proc. natn. Acad. Sci. U.S.A. 88, 10730–10734 (1991).
Deng, C. & Capecchi, M. R. Molec. cell. Biol. 12, 3365–3371 (1992).
Hasty, P. et al. Nature 350, 243–246 (1991).
Moens, C. B. et al. Genes Dev. 6, 691–704 (1992).
Egan, M. et al. Nature 358, 581–584 (1992).
Snouwaert, J. N. et al. Science 257, 1083–1088 (1992).
Clarke, L. L. et al. Science 257, 1125–1128 (1992).
Alton, E. W. F. W. et al. Eur. Resp. J. 3, 922–926 (1990).
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Dorin, J., Dickinson, P., Alton, E. et al. Cystic fibrosis in the mouse by targeted insertional mutagenesis. Nature 359, 211–215 (1992). https://doi.org/10.1038/359211a0
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DOI: https://doi.org/10.1038/359211a0
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