Research ArticleCystic Fibrosis

The ΔF508 Mutation Causes CFTR Misprocessing and Cystic Fibrosis–Like Disease in Pigs

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Science Translational Medicine  16 Mar 2011:
Vol. 3, Issue 74, pp. 74ra24
DOI: 10.1126/scitranslmed.3001868

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Four Legs Good, Two Legs Bad

In Animal Farm, George Orwell describes a pasture in which the pigs lead an animal revolt, resulting eventually in the porcine dwellers becoming indistinguishable from the human ones against whom they revolted. Scientists similarly wish for pigs to model humans, although as large animal models of human disease, not despotic rulers. Ostedgaard et al. extended this idea to cystic fibrosis (CF), generating pigs that carry the most common human CF mutation, Δ508.

CF is a devastating genetic disease characterized by difficulty breathing, progressive disability, persistent infections, and, often, early death. CF is caused by a mutation in the gene that encodes the CF transmembrane conductance regulator (CFTR), which is an anion channel that modulates the components of sweat, digestive juices, and mucus. The most common mutation in CF patients results in an altered version of CFTR, CFTR-Δ508, which is found in 1 of 25 people of Caucasian descent. CF is difficult to study in human patients, and mouse models do not accurately reflect the human disease. Pigs may provide a better model of CF because they have more similar anatomy, biochemistry, physiology, size, and genetics to humans than mice.

Thus, the authors generated a pig model of CF with the CFTR-Δ508 mutation. Similar to pigs that completely lack expression of CFTR, the CFTR-Δ508 pigs developed CF symptoms that mimicked those in human patients. In these animals, much of the CFTR-Δ508 protein was misprocessed; specifically, it was retained in the endoplasmic reticulum and rapidly degraded. However, pigs with CFTR-Δ508 retained small amounts of CFTR conductance (~6%), although this level of function was not sufficient to prevent disease. This new model may help to determine which levels of CFTR are sufficient for function and, therefore, guide future therapeutic strategies. After all, all animal models are equal, but some are more equal than others.

Footnotes

  • * These authors contributed equally to this work.

  • Citation: L. S. Ostedgaard, D. K. Meyerholz, J.-H. Chen, A. A. Pezzulo, P. H. Karp, T. Rokhlina, S. E. Ernst, R. A. Hanfland, L. R. Reznikov, P. S. Ludwig, M. P. Rogan, G. J. Davis, C. L. Dohrn, C. Wohlford-Lenane, P. J. Taft, M. V. Rector, E. Hornick, B. S. Nassar, M. Samuel, Y. Zhang, S. S. Richter, A. Uc, J. Shilyansky, R. S. Prather, P. B. McCray Jr., J. Zabner, M. J. Welsh, D. A. Stoltz, The ΔF508 Mutation Causes CFTR Misprocessing and Cystic Fibrosis–Like Disease in Pigs. Sci. Transl. Med. 3, 74ra24 (2011).

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