ABCMdb

ABCC7 p.Phe508Asp

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Publications

PMID: 15516474 [PubMed] Fajac I et al: "Nasal airway ion transport is linked to the cystic fibrosis phenotype in adult patients."

No. Sentence Comment

185 We have previously shown in a group of 95 adult patients with CF that patients with the lowest basal nasal PD had better respiratory function, irrespective of the severity of the genotype.13 Other groups have suggested some correlation between the severity of lung disease and cAMP mediated chloride secretion.14 15 Moreover, in 114 twins and siblings homozygous for the F508D mutation, the most common CFTR mutation, the expression of basal chloride conductance was identified as a positive predictor of milder respiratory disease.16 In contrast, in 51 young CF patients, a recent study showed no correlation between any component of ion transport measurement and respiratory function.17 In the present study we examined whether some components of nasal epithelial ion transport were associated with the pancreatic and respiratory expression of the disease and/or the genotype in adults with CF. Login to comment
219 RESULTS Patients Four of the 79 CF patients included in the study had a normal sweat test; three were compound heterozygous for the F508D mutation and the R117H, D1152H and R347H mutations, respectively, and one patient was compound heterozygous for the G542X and 3849+10 kb (C)R (T) mutations. Login to comment
224 The 73 patients for whom two mutations were identified were classified into two genotype groups: the ''severe`` genotype group included 51 patients of whom 25 were homozygous for the F508D mutation, and the ''mild`` genotype group comprised 22 patients. Login to comment
240 Tracings are shown for two CF patients with pancreatic insufficiency (top panels) and FEV1 ,50% pred (left panel) or FEV1 .50% pred (right panel), both of whom were homozygous for the F508D mutation and belonged to the ''severe`` genotype group; and two CF patients with pancreatic sufficiency (bottom panels) and FEV1 ,50% pred (left panel) or FEV1 .50% pred (right panel), both of whom were compound heterozygous for the F508D mutation and the R117H and G85E mutations, respectively, and belonged to the ''mild`` genotype group. Login to comment
255 A relationship between residual chloride transport in intestinal tissue and a mildly affected phenotype, as assessed by the predicted weight for height and the FEV1, has previously been described in F508D homozygous twins and siblings by Bronsveld et al16 but the reverse-that is, the relationship between nasal airway ion transport and the nutritional status-was not examined by these researchers nor in a recent study of 51 young CF patients of whom only three were pancreatic sufficient.17 The relationship we have observed after both low chloride and isoproterenol solutions may reflect the fact that the pancreatic status in CF is related to the residual function of CFTR. Login to comment
269 In contrast to our results, Bronsveld et al found that, in 114 F508D homozygous twins and siblings, the expression of basal chloride conductance was a positive predictor of milder respiratory disease.16 The discrepancies between our study and that of Bronsveld et al might be due to the different study populations: the respiratory function appears to be related to chloride transport in a highly selected and defined population such as the one studied by Bronsveld et al.16 However, in a population with a wide range of genotypes such as ours, the pulmonary outcome appears to be mostly influenced by increased sodium absorption in the airway epithelium. Login to comment

PMID: 15619636 [PubMed] Thibodeau PH et al: "Side chain and backbone contributions of Phe508 to CFTR folding."

No. Sentence Comment

33 The F508A,F508M,F508P,F508D,F508Q,F508R and F508S mutant proteins were more similar to the wild type than the ∆F508 protein in their temperature-dependence of refolding (Fig. 1b,c). Login to comment
43 The missense mutant proteins F508A, F508M,F508P,F508D,F508Q,F508R and F508S had similar ∆Gunfolding and m-values, 3.4-3.8 kcal mol-1 and 1.5-1.7 kcal mol-1 M-1 denaturant, respectively, highlighting the fact that changes in the bulk or chemical properties of the substituted side chain had little effect on the native-state stabilities of these domains as measured by denaturation with GuHCl (Table 1). Login to comment
46 How does the isolated NBD accommodate such Temperature (ºC) 4 10 16 22 Fractionalyield 0.0 0.5 1.0 Temperature (ºC) 4 10 16 22 Temperature (ºC) 4 10 16 22 Wild type ∆F508 Wild type ∆F508 ̄ F508A ̄ F508M F508P F508W ͷ F508W W496F Wild type ∆F508 F508Q F508R F508D F508S a b c Figure 1 NBD1 folding efficiency as a function of folding temperature. Login to comment
53 Table 1 Stability of wild-type and mutant NBD proteins Protein ∆Gunfolding ∆∆Gunfolding m-value (kcal mol-1) (kcal mol-1) (kcal mol-1 M-1) Wild type 3.7 ± 0.1 0 1.7 ∆F508 3.6 ± 0.1 0.1 1.7 F508A 3.6 ± 0.2 0.1 1.6 F508M 3.5 ± 0.1 0.1 1.6 F508P 3.5 ± 0.3 0.2 1.6 F508D 3.6 ± 0.1 0.1 1.6 F508Q 3.5 ± 0.2 0.2 1.6 F508R 3.4 ± 0.3 0.3 1.6 F508S 3.8 ± 0.2 -0.1 1.6 considerable changes in amino acid character at position 508 when this position is critical to the proper biogenesis of the full-length protein, and what are the underlying structural changes associated with these substitutions? Login to comment
92 The known polymorphism F508C and the non-CF-causing variant F508S both showed measurable quantities of band C at steady-state levels, as would be expected for non-CF-causingsubstitutions.Thehydrophobicaminoacidsubstitutions F508I,F508W and F508Y did not produce substantial steady-state levels of band C as measured by western blotting, nor did the ionizable amino acid substitutions F508D, F508E, F508K, F508H or F508R. Login to comment
113 W ild type ∆∆F508 F508 F508D F508K F508E F508R F508H F508S F508T F508N F508Q C B Charged Polar F508A F508C F508I F508L ∆F508 F508 W ild type C B F508W F508Y F508G F508P Hydrophobic F508M F508V ̅̆ ̆ ̅ Figure 3 Maturation of full-length CFTR mutants. Login to comment

PMID: 20667826 [PubMed] Thibodeau PH et al: "The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis."

No. Sentence Comment

114 The inclusion of the -3M mutations failed to significantly rescue the folding of the F508D and F508K mutants, suggesting that the -3M suppressors do not directly influence the interaction between NBD1 and other domains of CFTR (Fig. 1B). Login to comment
250 The suppression of the ⌬F508 and F508P substitutions, but not the F508D and F508K mutants, indicates that these mutations alter CFTR folding by discrete mechanisms or are of differing severities. Login to comment

PMID: 22265408 [PubMed] Rabeh WM et al: "Correction of both NBD1 energetics and domain interface is required to restore DeltaF508 CFTR folding and function."

No. Sentence Comment

69 These results in concert with the effect of F508E, F508R, F508G, F508S, F508D, and F508N mutations revealed that the CD4T-NBD1 PM density was proportional to the domain stability if the NBD1 Tm was >38 C (Figures 3D and S4D). Login to comment