Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis.
The gene associated with cystic fibrosis (CF) encodes a membrane-associated, N-linked glycoprotein called CFTR. Mutations were introduced into CFTR at residues known to be altered in CF chromosomes and in residues believed to play a role in its function. Examination of the various mutant proteins in COS-7 cells indicated that mature, fully glycosylated CFTR was absent from cells containing delta F508, delta 1507, K464M, F508R, and S5491 cDNA plasmids. Instead, an incompletely glycosylated version of the protein was detected. We propose that the mutant versions of CFTR are recognized as abnormal and remain incompletely processed in the endoplasmic reticulum where they are subsequently degraded. Since mutations with this phenotype represent at least 70% of known CF chromosomes, we argue that the molecular basis of most cystic fibrosis is the absence of mature CFTR at the correct cellular location.
Cheng
S H
SH
Genzyme Corporation, Framingham, Massachusetts 01701.
Gregory
R J
RJ
Marshall
J
J
Paul
S
S
Souza
D W
DW
White
G A
GA
O'Riordan
C R
CR
Smith
A E
AE
D000818:Animals; D002460:Cell Line; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005455:Fluorescent Antibody Technique; D006026:Glycoside Hydrolases; D006031:Glycosylation; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D010957:Plasmids; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000032:analysis; D014162:Transfection
C505032:CFTR protein, human; D008565:Membrane Proteins; D011994:Recombinant Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D006026:Glycoside Hydrolases