ABCC7 p.Gln207Ala
| ClinVar: |
c.619C>T
,
p.Gln207*
?
, not provided
|
| Predicted by SNAP2: | A: D (75%), C: D (75%), D: D (85%), E: D (75%), F: D (85%), G: D (80%), H: D (85%), I: D (85%), K: D (85%), L: D (85%), M: D (75%), N: D (80%), P: D (91%), R: D (85%), S: D (71%), T: D (75%), V: D (80%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] The cystic fibrosis V232D mutation inhibits CFTR m... Biochem Pharmacol. 2014 Mar 1;88(1):46-57. doi: 10.1016/j.bcp.2013.12.027. Epub 2014 Jan 9. Loo TW, Clarke DM
The cystic fibrosis V232D mutation inhibits CFTR maturation by disrupting a hydrophobic pocket rather than formation of aberrant interhelical hydrogen bonds.
Biochem Pharmacol. 2014 Mar 1;88(1):46-57. doi: 10.1016/j.bcp.2013.12.027. Epub 2014 Jan 9., [PMID:24412276]
Abstract [show]
Processing mutations that inhibit folding and trafficking of CFTR are the main cause of cystic fibrosis. Repair of CFTR mutants requires an understanding of the mechanisms of misfolding caused by processing mutations. Previous studies on helix-loop-helix fragments of the V232D processing mutation suggested that its mechanism was to lock transmembrane (TM) segments 3 and 4 together by a non-native hydrogen bond (Asp232(TM4)/Gln207(TM3)). Here, we performed mutational analysis to test for Asp232/Gln207 interactions in full-length CFTR. The rationale was that a V232N mutation should mimic V232D and a V232D/Q207A mutant should mature if the processing defect was caused by hydrogen bonds. We report that only Val232 mutations to charged amino acids severely blocked CFTR maturation. The V232N mutation did not mimic V232D as V232N showed 40% maturation compared to 2% for V232D. Mutation of Val232 to large nonpolar residues (Leu, Phe) had little effect. The Q207L mutation did not rescue V232D because Q207L showed about 50% maturation in the presence of corrector VX-809 while V232D/Q207A could no longer be rescued. These results suggest that V232D inhibits maturation by disrupting a hydrophobic pocket between TM segments rather than forming a non-native hydrogen bond. Disulfide cross-linking analysis of cysteines W356C(TM6) and W1145C(TM12) suggest that the V232D mutation inhibits maturation by trapping CFTR as a partially folded intermediate. Since correctors can efficiently rescue V232D CFTR, the results suggest that hydrophilic processing mutations facing a hydrophobic pocket are good candidates for rescue with pharmacological chaperones.
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No. Sentence Comment
19 The rationale was that a V232N mutation should mimic V232D and a V232D/Q207A mutant should mature if the processing defect was caused by hydrogen bonds.
X
ABCC7 p.Gln207Ala 24412276:19:71
status: NEW23 The Q207L mutation did not rescue V232D because Q207L showed about 50% maturation in the presence of corrector VX-809 while V232D/Q207A could no longer be rescued.
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ABCC7 p.Gln207Ala 24412276:23:130
status: NEW100 The V232D, V232D/Q207A, V232D/Q207L, and V232D/Q207C mutants were then expressed in the presence or absence of corrector VX-809 to test for maturation.
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ABCC7 p.Gln207Ala 24412276:100:17
status: NEW104 By contrast, none of the Gln207 mutations rescued V232D CFTR (Fig. 1B and C) as no mature CFTR was observed when mutants V232D/Q207A, V232D/Q207L, or V232D/Q207C were expressed in the presence or absence of VX-809 (Fig. 1B).
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ABCC7 p.Gln207Ala 24412276:104:127
status: NEW107 Mutations to Gln207 inhibit CFTR maturation Since V232D but not mutants V232D/Q207A, V232D/Q207L, or V232D/Q207C could be rescued with VX-809 (Fig. 1B), we tested if maturation of CFTR was also sensitive to changes to Gln207 in a wild-type background.
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ABCC7 p.Gln207Ala 24412276:107:78
status: NEW109 Mutants V232D/Q207A, L, or C do not mature.
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ABCC7 p.Gln207Ala 24412276:109:14
status: NEW112 (B) Whole cell extracts of cells expressing V232D or V232D/Q207A, L, or C mutants in the absence () or presence (+) of VX-809 were subjected to immunoblot analysis.
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ABCC7 p.Gln207Ala 24412276:112:59
status: NEW117 the Q207A, Q207L or Q207C changes.
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ABCC7 p.Gln207Ala 24412276:117:4
status: NEW184 In the presence of corrector VX-809 however, the amount of mature CFTR in mutants V510D/Q207A V510D/Q207L, V510D/Q207C, V510D/Q207E, V510D/Q207F and V510D/Q207S were significantly increased (25-85% mature product).
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ABCC7 p.Gln207Ala 24412276:184:88
status: NEW284 Although mutants such as A207A, Q207L and Q207C could be rescued with corrector VX-809 (Fig. 2), the V232D mutation appeared to have an effect that was independent of that of Gln207 since mutants Q207A/V232D, Q207L/V232D and Q207C/V232D could no longer be rescued by VX-809 (Fig. 1B).
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ABCC7 p.Gln207Ala 24412276:284:196
status: NEW