Journal article
The ΔF508 Mutation Causes CFTR Misprocessing and Cystic Fibrosis–Like Disease in Pigs
Science translational medicine, Vol.3(74), pp.74ra24-74ra24
03/16/2011
DOI: 10.1126/scitranslmed.3001868
PMCID: PMC3119077
PMID: 21411740
Abstract
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. The most common CF-associated mutation is Delta F508, which deletes a phenylalanine in position 508. In vitro studies indicate that the resultant protein, CFTR-Delta F508, is misprocessed, although the in vivo consequences of this mutation remain uncertain. To better understand the effects of the Delta F508 mutation in vivo, we produced CFTR Delta F508/Delta F508 pigs. Our biochemical, immunocytochemical, and electrophysiological data on CFTR-Delta F508 in newborn pigs paralleled in vitro predictions. They also indicated that CFTR Delta F508/Delta F508 airway epithelia retain a small residual CFTR conductance, with maximal stimulation producing similar to 6% of wild-type function. Cyclic adenosine 3',5'-monophosphate (cAMP) agonists were less potent at stimulating current in CFTR Delta F508/Delta F508 epithelia, suggesting that quantitative tests of maximal anion current may overestimate transport under physiological conditions. Despite residual CFTR function, four older CFTR Delta F508/Delta F508 pigs developed lung disease similar to human CF. These results suggest that this limited CFTR activity is insufficient to prevent lung or gastrointestinal disease in CF pigs. These data also suggest that studies of recombinant CFTR-Delta F508 misprocessing predict in vivo behavior, which validates its use in biochemical and drug discovery experiments. These findings help elucidate the molecular pathogenesis of the common CF mutation and will guide strategies for developing new therapeutics.
Details
- Title: Subtitle
- The ΔF508 Mutation Causes CFTR Misprocessing and Cystic Fibrosis–Like Disease in Pigs
- Creators
- Lynda S Ostedgaard - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242David K Meyerholz - Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Jeng-Haur Chen - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Alejandro A Pezzulo - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Philip H Karp - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Tatiana Rokhlina - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Sarah E Ernst - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Robert A Hanfland - Department of Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Leah R Reznikov - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Paula S Ludwig - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Mark P Rogan - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Greg J Davis - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Cassie L Dohrn - Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Christine Wohlford-Lenane - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Peter J Taft - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Michael V Rector - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Emma Hornick - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Boulos S Nassar - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Melissa Samuel - Division of Animal Sciences, University of Missouri, Columbia, MO 65211Yuping Zhang - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Sandra S Richter - Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Aliye Uc - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Joel Shilyansky - Department of Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Randall S Prather - Division of Animal Sciences, University of Missouri, Columbia, MO 65211Paul B McCray - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Joseph Zabner - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242Michael J Welsh - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242David A Stoltz - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.3(74), pp.74ra24-74ra24
- DOI
- 10.1126/scitranslmed.3001868
- PMID
- 21411740
- PMCID
- PMC3119077
- NLM abbreviation
- Sci Transl Med
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Grant note
- K08 AI076671-04 || AI / National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID P01 HL091842-04 || HL / National Heart, Lung, and Blood Institute : NHLBI P01 HL051670-15 || HL / National Heart, Lung, and Blood Institute : NHLBI HHMI_WELSH_M || HHMI_ / Howard Hughes Medical Institute :
- Language
- English
- Date published
- 03/16/2011
- Academic Unit
- Neurology; Microbiology and Immunology; Pathology; Surgery; Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Pulmonary Medicine; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Radiation Oncology; Obstetrics and Gynecology; Gastroenterology, Hepatology, Pancreatology, and Nutrition; Neurosurgery; Internal Medicine
- Record Identifier
- 9984013115502771
Metrics
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