DeltaF508 CFTR Protein Expression in Tissues from Patients with Cystic Fibrosis

Overview

Journal J Clin Invest

Specialty General Medicine

Date 1999 May 20

PMID 10330420

Citations 81

Authors

N Kalin

A Claass

M Sommer

E Puchelle

B Tummler

Affiliations

Soon will be listed here.

Abstract

Heterologous expression of the cystic fibrosis transmembrane conductance regulator (CFTR) provided evidence that the major cystic fibrosis (CF) mutation DeltaF508 leads to defective protein folding in the endoplasmic reticulum, which prevents its processing and targeting to the cell surface. In this study, we investigated endogenous CFTR expression in skin biopsies and respiratory and intestinal tissue specimens from DeltaF508 homozygous and non-CF patients, using immunohistochemical and immunoblot analyses with a panel of CFTR antibodies. CFTR expression was detected at the luminal surface of reabsorptive sweat ducts and airway submucosal glands, at the apex of ciliated cells in pseudostratified respiratory epithelia and of isolated cells of the villi of duodenum and jejunum, and within intracellular compartments of intestinal goblet cells. In DeltaF508 homozygous patients, expression of the mutant protein proved to be tissue specific. Whereas DeltaF508 CFTR was undetectable in sweat glands, the expression in the respiratory and intestinal tracts could not be distinguished from the wild-type by signal intensity or localization. The tissue-specific variation of DeltaF508 CFTR expression from null to apparently normal amounts indicates that DeltaF508 CFTR maturation can be modulated and suggests that determinants other than CFTR mislocalization should play a role in DeltaF508 CF respiratory and intestinal disease.

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References

Montserrat C, Merten M, FIGARELLA C . Defective ATP-dependent mucin secretion by cystic fibrosis pancreatic epithelial cells. FEBS Lett. 1996; 393(2-3):264-8. DOI: 10.1016/0014-5793(96)00900-3. View

French P, van Doorninck J, Peters R, Verbeek E, Ameen N, Marino C . A delta F508 mutation in mouse cystic fibrosis transmembrane conductance regulator results in a temperature-sensitive processing defect in vivo. J Clin Invest. 1996; 98(6):1304-12. PMC: 507556. DOI: 10.1172/JCI118917. View

Dorin J, Farley R, Webb S, Smith S, Farini E, Delaney S . A demonstration using mouse models that successful gene therapy for cystic fibrosis requires only partial gene correction. Gene Ther. 1996; 3(9):797-801. View

Takahashi A, Watkins S, Howard M, Frizzell R . CFTR-dependent membrane insertion is linked to stimulation of the CFTR chloride conductance. Am J Physiol. 1996; 271(6 Pt 1):C1887-94. DOI: 10.1152/ajpcell.1996.271.6.C1887. View

Inglis S, Corboz M, Taylor A, Ballard S . Effect of anion transport inhibition on mucus secretion by airway submucosal glands. Am J Physiol. 1997; 272(2 Pt 1):L372-7. DOI: 10.1152/ajplung.1997.272.2.L372. View

Kelley T, Thomas K, Milgram L, Drumm M . In vivo activation of the cystic fibrosis transmembrane conductance regulator mutant deltaF508 in murine nasal epithelium. Proc Natl Acad Sci U S A. 1997; 94(6):2604-8. PMC: 20135. DOI: 10.1073/pnas.94.6.2604. View

Cooper S, Millar N . Host cell-specific folding and assembly of the neuronal nicotinic acetylcholine receptor alpha7 subunit. J Neurochem. 1997; 68(5):2140-51. DOI: 10.1046/j.1471-4159.1997.68052140.x. View

Annereau J, Wulbrand U, Vankeerberghen A, Cuppens H, Bontems F, Tummler B . A novel model for the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator. FEBS Lett. 1997; 407(3):303-8. DOI: 10.1016/s0014-5793(97)00363-3. View

Brown C, Biwersi J, Verkman A, Welch W . Chemical chaperones correct the mutant phenotype of the delta F508 cystic fibrosis transmembrane conductance regulator protein. Cell Stress Chaperones. 1996; 1(2):117-25. PMC: 248464. DOI: 10.1379/1466-1268(1996)001<0117:ccctmp>2.3.co;2. View

10.

Saftig P, Hartmann D, Lullmann-Rauch R, Wolff J, Evers M, Koster A . Mice deficient in lysosomal acid phosphatase develop lysosomal storage in the kidney and central nervous system. J Biol Chem. 1997; 272(30):18628-35. DOI: 10.1074/jbc.272.30.18628. View

11.

Kartner N, Riordan J . Characterization of polyclonal and monoclonal antibodies to cystic fibrosis transmembrane conductance regulator. Methods Enzymol. 1998; 292:629-52. DOI: 10.1016/s0076-6879(98)92049-3. View

12.

Hollande E, Fanjul M, Devaux C, Demolombe S, Van Rietschoten J, FIGARELLA C . Targeting of CFTR protein is linked to the polarization of human pancreatic duct cells in culture. Eur J Cell Biol. 1998; 76(3):220-7. DOI: 10.1016/S0171-9335(98)80037-X. View

13.

Lukacs G, Chang X, Bear C, Kartner N, Mohamed A, Riordan J . The delta F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator in the plasma membrane. Determination of functional half-lives on transfected cells. J Biol Chem. 1993; 268(29):21592-8. View

14.

Yang Y, JANICH S, Cohn J, Wilson J . The common variant of cystic fibrosis transmembrane conductance regulator is recognized by hsp70 and degraded in a pre-Golgi nonlysosomal compartment. Proc Natl Acad Sci U S A. 1993; 90(20):9480-4. PMC: 47592. DOI: 10.1073/pnas.90.20.9480. View

15.

Bjerknes M, Cheng H . Methods for the isolation of intact epithelium from the mouse intestine. Anat Rec. 1981; 199(4):565-74. DOI: 10.1002/ar.1091990412. View

16.

Field M, Dubinsky W . Isolation of transporting plasma membrane vesicles from bovine tracheal epithelium. Biochim Biophys Acta. 1983; 731(2):318-28. DOI: 10.1016/0005-2736(83)90024-x. View

17.

Pollard H, Pazoles C, Creutz C, Scott J, Zinder O, Hotchkiss A . An osmotic mechanism for exocytosis from dissociated chromaffin cells. J Biol Chem. 1984; 259(2):1114-21. View

18.

Berschneider H, Knowles M, Azizkhan R, Boucher R, Tobey N, Orlando R . Altered intestinal chloride transport in cystic fibrosis. FASEB J. 1988; 2(10):2625-9. DOI: 10.1096/fasebj.2.10.2838365. View

19.

Riordan J, Rommens J, Kerem B, Alon N, Rozmahel R, Grzelczak Z . Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989; 245(4922):1066-73. DOI: 10.1126/science.2475911. View

20.

Mak V, Jarvi K, Zielenski J, Durie P, Tsui L . Higher proportion of intact exon 9 CFTR mRNA in nasal epithelium compared with vas deferens. Hum Mol Genet. 1997; 6(12):2099-107. DOI: 10.1093/hmg/6.12.2099. View