title: Processing and function of CFTR-DeltaF508 are species-dependent.
abstract: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis. The most common mutation, a deletion of the phenylalanine at position 508 (DeltaF508), disrupts processing of the protein. Nearly all human CFTR-DeltaF508 is retained in the endoplasmic reticulum and degraded, preventing maturation to the plasma membrane. In addition, the F508 deletion reduces the activity of single CFTR channels. Human CFTR-DeltaF508 has been extensively studied to better understand its defects. Here, we adopted a cross-species comparative approach, examining human, pig, and mouse CFTR-DeltaF508. As with human CFTR-DeltaF508, the DeltaF508 mutation reduced the single-channel activity of the pig and mouse channels. However, the mutant pig and mouse proteins were at least partially processed like their wild-type counterparts. Moreover, pig and mouse CFTR-DeltaF508 partially restored transepithelial Cl(-) transport to CF airway epithelia. Our data, combined with earlier work, suggest that there is a gradient in the severity of the CFTR-DeltaF508 processing defect, with human more severe than pig or mouse. These findings may explain some previously puzzling observations in CF mice, they have important implications for evaluation of potential therapeutics, and they suggest new strategies for discovering the mechanisms that disrupt processing of human CFTR-DeltaF508.
authors.affiliation: Howard Hughes Medical Institute, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Lynda S
authors.initials: LS
authors.lastname: Ostedgaard
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Rogers
authors.forename: Qian
authors.initials: Q
authors.lastname: Dong
authors.forename: Christoph O
authors.initials: CO
authors.lastname: Randak
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Vermeer
authors.forename: Tatiana
authors.initials: T
authors.lastname: Rokhlina
authors.forename: Philip H
authors.initials: PH
authors.lastname: Karp
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
mesh_terms: D000818:Animals; D001692:Biological Transport; D019556:COS Cells; D002713:Chlorine / Q000378:metabolism; D002522:Chlorocebus aethiops; D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000378:metabolism*; D004594:Electrophysiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D010649:Phenylalanine / Q000737:chemistry; D013045:Species Specificity; D013552:Swine
chemical_list: C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D010649:Phenylalanine; D002713:Chlorine