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Mol Biol Cell. 2016 Feb 1;27(3):424-33. doi: 10.1091/mbc.E14-04-0935.

From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations.

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Department of Physiology, McGill University, Montréal, QC H3G 1Y6, Canada.
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260.
Marsico Lung Institute, School of Medicine, University of North Carolina, Chapel Hill, NC 27514.
School of Physiology & Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.
Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.
Department of Cellular, Developmental, and Integrative Biology, University of Alabama, Birmingham, AL 35294.
Department of Anatomy, Physiology and Genetics and Center for Medical Proteomics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Department of Physiology, Johns Hopkins University, Baltimore, MD 21205.
Department of Chemical Physiology, Skaggs Institute of Chemical Physiology, Scripps Research Institute, La Jolla, CA 92037.
Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239.
McKusick-Nathans Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322.
Department of Physiology, McGill University, Montréal, QC H3G 1Y6, Canada Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada GRASP, McGill University, Montréal, QC H3G 1Y6, Canada


More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients.

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