ABCC7 p.Pro1072Ala
| CF databases: |
c.3215C>T
,
p.Pro1072Leu
(CFTR1)
?
, P1072L was detected by DGGE analysis and identified by automatic sequencing in a COPD patient with chronic bronchitis. The mutation creates an Alu I restriction site. It was found once out of 104 chromosomes of COPD patients. It was never observed in 120 control chromosomes, in 46 chromosomes of DBE patients, and in 104 chromosomes of CF patients.
|
| Predicted by SNAP2: | A: N (57%), C: D (59%), D: N (53%), E: N (61%), F: D (85%), G: D (53%), H: D (53%), I: D (63%), K: N (57%), L: N (53%), M: D (63%), N: N (72%), Q: N (61%), R: N (57%), S: N (78%), T: N (72%), V: D (59%), W: D (85%), Y: D (75%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] Human-mouse cystic fibrosis transmembrane conducta... Proc Natl Acad Sci U S A. 2012 Jan 17;109(3):917-22. Epub 2011 Dec 30. Dong Q, Ostedgaard LS, Rogers C, Vermeer DW, Zhang Y, Welsh MJ
Human-mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-DeltaF508 processing and alter its gating defect.
Proc Natl Acad Sci U S A. 2012 Jan 17;109(3):917-22. Epub 2011 Dec 30., [PMID:22210114]
Abstract [show]
The DeltaF508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is the most common cause of cystic fibrosis. The mutation disrupts biosynthetic processing, reduces channel opening rate, and decreases protein lifetime. In contrast to human CFTR (hCFTR)-DeltaF508, mouse CFTR-DeltaF508 is partially processed to the cell surface, although it exhibits a functional defect similar to hCFTR-DeltaF508. To explore DeltaF508 abnormalities, we generated human-mouse chimeric channels. Substituting mouse nucleotide-binding domain-1 (mNBD1) into hCFTR partially rescued the DeltaF508-induced maturation defect, and substituting mouse membrane-spanning domain-2 or its intracellular loops (ICLs) into hCFTR prevented further DeltaF508-induced gating defects. The protective effect of the mouse ICLs was reverted by inserting mouse NBDs. Our results indicate that the DeltaF508 mutation affects maturation and gating via distinct regions of the protein; maturation of CFTR-DeltaF508 depends on NBD1, and the DeltaF508-induced gating defect depends on the interaction between the membrane-spanning domain-2 ICLs and the NBDs. These appear to be distinct processes, because none of the chimeras repaired both defects. This distinction was exemplified by the I539T mutation, which improved CFTR-DeltaF508 processing but worsened the gating defect. Our results, together with previous studies, suggest that many different NBD1 modifications improve CFTR-DeltaF508 maturation and that the effect of modifications can be additive. Thus, it might be possible to enhance processing by targeting several different regions of the domain or by targeting a network of CFTR-associated proteins. Because no one modification corrected both maturation and gating, perhaps more than a single agent will be required to correct all CFTR-DeltaF508 defects.
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No. Sentence Comment
90 The P1072A and G1069R variants failed to prevent a ΔF508 effect on interburst interval.
X
ABCC7 p.Pro1072Ala 22210114:90:4
status: NEW155 Other substitutions increased the Po of CFTR-ΔF508 by lengthening the burst duration rather than preventing ΔF508 from A G1069R P1072T hmMSD2 mCFTR hCFTR LNT964-966ISK LNT964-966AAA P1072A hmNBD1/P1072T hmNBD2/P1072T Wild-type ΔF508 D C B hmNBD1 LNT964-966ISK hmNBD2 LNT964-966ISK Fig. 4.
X
ABCC7 p.Pro1072Ala 22210114:155:194
status: NEW