ABCC7 p.Asp993Gly
| ClinVar: |
c.2977G>T
,
p.Asp993Tyr
?
, not provided
|
| CF databases: |
c.2977G>T
,
p.Asp993Tyr
(CFTR1)
D
, The above mutation was found by DGGE and then direct sequencing of DNA from a patient with severe phenotype from Southern France.
c.2978A>G , p.Asp993Gly (CFTR1) ? , The mutation was detected by DHPLC analysis and characterized by direct sequencing |
| Predicted by SNAP2: | A: D (71%), C: D (71%), E: D (66%), F: D (80%), G: D (80%), H: D (80%), I: D (75%), K: D (91%), L: D (85%), M: D (75%), N: D (80%), P: D (91%), Q: D (80%), R: D (91%), S: D (71%), T: D (80%), V: D (80%), W: D (85%), Y: D (85%), |
| Predicted by PROVEAN: | A: N, C: D, E: N, F: D, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: D, |
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[hide] Mutations at arginine 352 alter the pore architect... J Membr Biol. 2008 Mar;222(2):91-106. Epub 2008 Apr 18. Cui G, Zhang ZR, O'Brien AR, Song B, McCarty NA
Mutations at arginine 352 alter the pore architecture of CFTR.
J Membr Biol. 2008 Mar;222(2):91-106. Epub 2008 Apr 18., [PMID:18421494]
Abstract [show]
Arginine 352 (R352) in the sixth transmembrane domain of the cystic fibrosis transmembrane conductance regulator (CFTR) previously was reported to form an anion/cation selectivity filter and to provide positive charge in the intracellular vestibule. However, mutations at this site have nonspecific effects, such as inducing susceptibility of endogenous cysteines to chemical modification. We hypothesized that R352 stabilizes channel structure and that charge-destroying mutations at this site disrupt pore architecture, with multiple consequences. We tested the effects of mutations at R352 on conductance, anion selectivity and block by the sulfonylurea drug glipizide, using recordings of wild-type and mutant channels. Charge-altering mutations at R352 destabilized the open state and altered both selectivity and block. In contrast, R352K-CFTR was similar to wild-type. Full conductance state amplitude was similar to that of wild-type CFTR in all mutants except R352E, suggesting that R352 does not itself form an anion coordination site. In an attempt to identify an acidic residue that may interact with R352, we found that permeation properties were similarly affected by charge-reversing mutations at D993. Wild-type-like properties were rescued in R352E/D993R-CFTR, suggesting that R352 and D993 in the wild-type channel may interact to stabilize pore architecture. Finally, R352A-CFTR was sensitive to modification by externally applied MTSEA+, while wild-type and R352E/D993R-CFTR were not. These data suggest that R352 plays an important structural role in CFTR, perhaps reflecting its involvement in forming a salt bridge with residue D993.
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No. Sentence Comment
281 Several R352 mutations are CF-associated mutations, including R352G, R352W and R352Q (Cremonesi et al. 1992; Audre´zet et al. 1993; Brancolini et al. 1995; Feldmann et al. 2003); similarly, D993Y and D993G are associated with disease (Tsui et al. 2007).
X
ABCC7 p.Asp993Gly 18421494:281:205
status: NEW