Functional analysis of F508del CFTR in native human colon.
The major cystic fibrosis mutation F508del has been classified by experiments in animal and cell culture models as a temperature-sensitive mutant defective in protein folding, processing and trafficking, but literature data on F508del CFTR maturation and function in human tissue are inconsistent. In the present study the molecular pathology of F508del CFTR was characterized in freshly excised rectal mucosa by bioelectric measurement of the basic defect and CFTR protein analysis by metabolic labelling or immunoblot. The majority of investigated F508del homozygous subjects expressed low amounts of complex-glycosylated mature F508del CFTR and low residual F508del CFTR-mediated chloride secretory activity in the rectal mucosa. The finding that some F508del CFTR escapes the ER quality control in vivo substantiates the hope that the defective processing and trafficking of F508del CFTR can be corrected by pharmacological agents.
van Barneveld
Andrea
A
Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Hannover, Germany. barneveld.andrea.va@nk-hannover.de
Stanke
Frauke
F
Tamm
Stephanie
S
Siebert
Benny
B
Brandes
Gudrun
G
Derichs
Nico
N
Ballmann
Manfred
M
Junge
Sibylle
S
Tümmler
Burkhard
B
D000293:Adolescent; D000328:Adult; D002648:Child; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D000242:Cyclic AMP / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006031:Glycosylation; D006720:Homozygote; D006801:Humans; D015151:Immunoblotting; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D017136:Ion Transport / Q000187:drug effects; D008168:Lung / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000378:metabolism / Q000502:physiology; D009154:Mutation; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
D002712:Chlorides; D050505:Mutant Proteins; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D000242:Cyclic AMP