Processing and function of CFTR-ΔF508 are species-dependent

Lynda S Ostedgaard; Christopher S Rogers; Qian Dong; Christoph O Randak; Daniel W Vermeer; Tatiana Rokhlina; Philip H Karp; Michael J Welsh

doi:10.1073/pnas.0706974104

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Processing and function of CFTR-ΔF508 are species-dependent

Journal article

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Processing and function of CFTR-ΔF508 are species-dependent

Lynda S Ostedgaard, Christopher S Rogers, Qian Dong, Christoph O Randak, Daniel W Vermeer, Tatiana Rokhlina, Philip H Karp and Michael J Welsh

Proceedings of the National Academy of Sciences - PNAS, Vol.104(39), pp.15370-15375

09/25/2007

DOI: 10.1073/pnas.0706974104

PMCID: PMC1976592

PMID: 17873061

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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 (Î”F508), disrupts processing of the protein. Nearly all human CFTR-Î”F508 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-Î”F508 has been extensively studied to better understand its defects. Here, we adopted a cross-species comparative approach, examining human, pig, and mouse CFTR-Î”F508. As with human CFTR-Î”F508, the Î”F508 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-Î”F508 partially restored transepithelial Cl âˆ’ transport to CF airway epithelia. Our data, combined with earlier work, suggest that there is a gradient in the severity of the CFTR-Î”F508 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-Î”F508.

Biological Sciences

Cystic Fibrosis

mouse models

chloride transport

airway epithelia

Details

Title: Subtitle: Processing and function of CFTR-ΔF508 are species-dependent
Creators: Lynda S Ostedgaard - Departments of Internal Medicine and
Christopher S Rogers - Departments of Internal Medicine and
Qian Dong - Howard Hughes Medical Institute
Christoph O Randak - Departments of Internal Medicine and
Daniel W Vermeer - Departments of Internal Medicine and
Tatiana Rokhlina - Departments of Internal Medicine and
Philip H Karp - Departments of Internal Medicine and
Michael J Welsh - Howard Hughes Medical Institute
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.104(39), pp.15370-15375
DOI: 10.1073/pnas.0706974104
PMID: 17873061
PMCID: PMC1976592
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 09/25/2007
Academic Unit: Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Pulmonary Medicine; Stead Family Department of Pediatrics; Neurosurgery; Internal Medicine
Record Identifier: 9984020759702771

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