ABCMdb

ABCC7 p.Leu375Ala

ClinVar:	c.1125A>C , p.Leu375Phe ? , not provided
CF databases:	c.1125A>C , p.Leu375Phe (CFTR1) ? , The above mutation was detected by DGGE and identified by direct sequencing using two different sequencing kits (both strands) in a patient with CUAVD. This mutation creates an MboII restriction site. This patient was also found to carry G551D.
Predicted by SNAP2:	A: D (53%), C: N (66%), D: D (80%), E: D (75%), F: N (61%), G: D (75%), H: D (63%), I: N (78%), K: D (71%), M: N (87%), N: D (66%), P: D (75%), Q: D (59%), R: D (71%), S: D (63%), T: N (78%), V: N (72%), W: D (63%), Y: D (53%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

[switch to compact view]
Comments [show]

None has been submitted yet.

Publications
[hide] VX-809 corrects folding defects in cystic fibrosis... Mol Biol Cell. 2013 Oct;24(19):3016-24. doi: 10.1091/mbc.E13-05-0240. Epub 2013 Aug 7. Ren HY, Grove DE, De La Rosa O, Houck SA, Sopha P, Van Goor F, Hoffman BJ, Cyr DM
VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1.
Mol Biol Cell. 2013 Oct;24(19):3016-24. doi: 10.1091/mbc.E13-05-0240. Epub 2013 Aug 7., [PMID:23924900]

Abstract [show]
Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
72 Despite the severe biogenic defects exhibited by F374A-CFTR, L375A-CFTR, the double mutation F374A/L375A-CFTR (Figure 3A), F374A-CFTR 380, and L375A-CFTR 380 (Figure 3B), VX-809 almost completely suppressed the biogenic defects caused by the F374A and L375A mutations at the 5-bc;M concentration that maximally suppressed folding defects in F508del-CFTR (Figure 3, A and B). Login to comment
153 (D) F374A L375A CFTR exhibits a folding defect that is not efficaciously suppressed by VX-809. Login to comment
159 100 520 14 123 CFTR 380 L375A % of Cont. Login to comment
162 380- CFTR 380 Trypsin (ug/ml) 25 20 15- - - - + Vehicle +VX-809 * CFTR 370 CFTR 370 2520- 15- CFTR 380 * +Vehicle + VX-809 ** ** + _ Wt _ VX-809 + _ + _ F374A L375A F374A L375A + _ ࢞371-375 Tub- C- BC- 100 4 108 6 115 2 12 8 7 B31 24 28 23 24 25 27 22 19 CFTR %-Wt C-band C. VX-809 0 5 10 15 _ ࢞371-375 -C -B CFTR Wt %-Wt 100 4 6 5 2 C-band 25 12 18 11 8 + CFTR 3800 25 2 1 7 3 0 25 2 1 7 3 D. Login to comment
219 Soluble lysates were obtained by centrifugation at 20,000 &#d7; g combined mutation of F374A and L375A but efficaciously suppresses folding defects caused by each individual mutation. Login to comment