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Article: The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs

TitleThe ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs
Authors
Issue Date2011
Citation
Science Translational Medicine, 2011, v. 3 n. 74, article no. article no. 74ra24 How to Cite?
AbstractCystic 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 ΔF508, which deletes a phenylalanine in position 508. In vitro studies indicate that the resultant protein, CFTR-ΔF508, is misprocessed, although the in vivo consequences of this mutation remain uncertain. To better understand the effects of the ΔF508 mutation in vivo, we produced CFTR ΔF508/ΔF508 pigs. Our biochemical, immunocytochemical, and electrophysiological data on CFTR-ΔF508 in newborn pigs paralleled in vitro predictions. They also indicated that CFTR ΔF508/ΔF508 airway epithelia retain a small residual CFTR conductance, with maximal stimulation producing ∼6% of wild-type function. Cyclic adenosine 3′,5′-monophosphate (cAMP) agonists were less potent at stimulating current in CFTR ΔF508/ΔF508 epithelia, suggesting that quantitative tests of maximal anion current may overestimate transport under physiological conditions. Despite residual CFTR function, four older CFTR ΔF508/ΔF508 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-ΔF508 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.
Persistent Identifierhttp://hdl.handle.net/10722/137012
ISSN
2015 Impact Factor: 16.264
2015 SCImago Journal Rankings: 8.931
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
NIHHL51670
HL091842
DK54759
R01 DK084049
Cystic Fibrosis Foundation
AI076671
Funding Information:

This work was supported by the NIH (HL51670, HL091842, and DK54759) and Cystic Fibrosis Foundation. D. A. S. was supported by AI076671. A.U. is funded in part by NIH R01 DK084049. M.J.W. is an Investigator of the Howard Hughes Medical Institute.

References

 

DC FieldValueLanguage
dc.contributor.authorOstedgaard, LSen_HK
dc.contributor.authorMeyerholz, DKen_HK
dc.contributor.authorChen, JHen_HK
dc.contributor.authorPezzulo, AAen_HK
dc.contributor.authorKarp, PHen_HK
dc.contributor.authorRokhlina, Ten_HK
dc.contributor.authorErnst, SEen_HK
dc.contributor.authorHanfland, RAen_HK
dc.contributor.authorReznikov, LRen_HK
dc.contributor.authorLudwig, PSen_HK
dc.contributor.authorRogan, MPen_HK
dc.contributor.authorDavis, GJen_HK
dc.contributor.authorDohrn, CLen_HK
dc.contributor.authorWohlfordLenane, Cen_HK
dc.contributor.authorTaft, PJen_HK
dc.contributor.authorRector, MVen_HK
dc.contributor.authorHornick, Een_HK
dc.contributor.authorNassar, BSen_HK
dc.contributor.authorSamuel, Men_HK
dc.contributor.authorZhang, Yen_HK
dc.contributor.authorRichter, SSen_HK
dc.contributor.authorUc, Aen_HK
dc.contributor.authorShilyansky, Jen_HK
dc.contributor.authorPrather, RSen_HK
dc.contributor.authorMcCray Jr, PBen_HK
dc.contributor.authorZabner, Jen_HK
dc.contributor.authorWelsh, MJen_HK
dc.contributor.authorStoltz, DAen_HK
dc.date.accessioned2011-07-29T02:14:16Z-
dc.date.available2011-07-29T02:14:16Z-
dc.date.issued2011en_HK
dc.identifier.citationScience Translational Medicine, 2011, v. 3 n. 74, article no. article no. 74ra24en_HK
dc.identifier.issn1946-6234en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137012-
dc.description.abstractCystic 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 ΔF508, which deletes a phenylalanine in position 508. In vitro studies indicate that the resultant protein, CFTR-ΔF508, is misprocessed, although the in vivo consequences of this mutation remain uncertain. To better understand the effects of the ΔF508 mutation in vivo, we produced CFTR ΔF508/ΔF508 pigs. Our biochemical, immunocytochemical, and electrophysiological data on CFTR-ΔF508 in newborn pigs paralleled in vitro predictions. They also indicated that CFTR ΔF508/ΔF508 airway epithelia retain a small residual CFTR conductance, with maximal stimulation producing ∼6% of wild-type function. Cyclic adenosine 3′,5′-monophosphate (cAMP) agonists were less potent at stimulating current in CFTR ΔF508/ΔF508 epithelia, suggesting that quantitative tests of maximal anion current may overestimate transport under physiological conditions. Despite residual CFTR function, four older CFTR ΔF508/ΔF508 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-ΔF508 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.en_HK
dc.languageengen_US
dc.relation.ispartofScience Translational Medicineen_HK
dc.titleThe ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigsen_HK
dc.typeArticleen_HK
dc.identifier.emailChen, JH: jhlchen@hku.hken_HK
dc.identifier.authorityChen, JH=rp01518en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1126/scitranslmed.3001868en_HK
dc.identifier.pmid21411740-
dc.identifier.pmcidPMC3119077-
dc.identifier.scopuseid_2-s2.0-79952779452en_HK
dc.identifier.hkuros250830-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79952779452&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume3en_HK
dc.identifier.issue74en_HK
dc.identifier.eissn1946-6242-
dc.identifier.isiWOS:000292974200004-
dc.identifier.scopusauthoridOstedgaard, LS=6701764343en_HK
dc.identifier.scopusauthoridMeyerholz, DK=6602303240en_HK
dc.identifier.scopusauthoridChen, JH=7501878156en_HK
dc.identifier.scopusauthoridPezzulo, AA=9234179500en_HK
dc.identifier.scopusauthoridKarp, PH=7006431484en_HK
dc.identifier.scopusauthoridRokhlina, T=6602243260en_HK
dc.identifier.scopusauthoridErnst, SE=36706048700en_HK
dc.identifier.scopusauthoridHanfland, RA=25031092200en_HK
dc.identifier.scopusauthoridReznikov, LR=36725696000en_HK
dc.identifier.scopusauthoridLudwig, PS=36922073800en_HK
dc.identifier.scopusauthoridRogan, MP=7005036276en_HK
dc.identifier.scopusauthoridDavis, GJ=7404344013en_HK
dc.identifier.scopusauthoridDohrn, CL=23767084300en_HK
dc.identifier.scopusauthoridWohlfordLenane, C=6602418655en_HK
dc.identifier.scopusauthoridTaft, PJ=9250095900en_HK
dc.identifier.scopusauthoridRector, MV=36626398000en_HK
dc.identifier.scopusauthoridHornick, E=25644222800en_HK
dc.identifier.scopusauthoridNassar, BS=37112935900en_HK
dc.identifier.scopusauthoridSamuel, M=7102728185en_HK
dc.identifier.scopusauthoridZhang, Y=37113448500en_HK
dc.identifier.scopusauthoridRichter, SS=7201953506en_HK
dc.identifier.scopusauthoridUc, A=6701324824en_HK
dc.identifier.scopusauthoridShilyansky, J=6604056911en_HK
dc.identifier.scopusauthoridPrather, RS=24406140400en_HK
dc.identifier.scopusauthoridMcCray Jr, PB=7007180790en_HK
dc.identifier.scopusauthoridZabner, J=7005928925en_HK
dc.identifier.scopusauthoridWelsh, MJ=35447946600en_HK
dc.identifier.scopusauthoridStoltz, DA=35273807000en_HK

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