ABCMdb

ABCC7 p.Pro99Leu

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II-III (maturation defect, gating defect) <a href="https://www.ncbi.nlm.nih.gov/pubmed/26823392">Veit et al.</a>
admin on 2016-08-19 15:16:22

Publications

PMID: 10220340 [PubMed] Guinamard R et al: "Arg352 is a major determinant of charge selectivity in the cystic fibrosis transmembrane conductance regulator chloride channel."

No. Sentence Comment

283 The mutation P99L also changed the halide permeability ratios (37); however, this is presumably due to effects of the mutation on protein conformation because this residue is not on the water-accessible surface of the protein (18, 19). Login to comment

PMID: 11933191 [PubMed] Ravnik-Glavac M et al: "DHPLC screening of cystic fibrosis gene mutations."

No. Sentence Comment

42 The following mutations have been studied: exon 3: W57G, R74W, R75Q, G85E, 394delTT, 405+ 1G>A; exon 4: E92X, P99L, 441delA, 444delA, 457TAT>G, D110H, R117C, R117H, A120T, 541delC, 544delCA, Q151X, 621+1G>T, 662- 2A>C; exon 7: 1078delT, F331L, R334W, I336K, R347C, R347P, A349V, R352Q, 1221delCT; exon 10: S492F, Q493X, 1609delCA, deltaI507, deltaF508; exon 11: G542X, S549N, G551D, R553X, A559T, R560K, R560T; exon 13: K716X, Q685X, G628R, L719X; exon 17b: H1054D, G1061R, 3320ins5, R1066H, R1066L, R1070Q, 3359delCT, L1077P, H1085R, Y1092X; exon 19: R1162X, 3659delC, 3662delA, 3667del4, 3737delA, I1234V, S1235R, 3849G>A; exon 20: 3860ins31,S1255X,3898insC,3905insT,D1270N, W1282X, Q1291R; and exon 21: N1303H, N1303K, W1316X. Login to comment

PMID: 14872121 [PubMed] Gilljam M et al: "Cystic fibrosis diagnosed in an elderly man."

No. Sentence Comment

21 Genetic testing later confirmed two CFTR gene mutations, 394delTT and P99L, and the R75Q variant. Login to comment
33 P99L is a missense mutation in exon 4 that was originally described in a patient with the 'F508 mutation on the other allele and presenting with very mild CF [7]. Login to comment

PMID: 15776432 [PubMed] Clain J et al: "Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype."

No. Sentence Comment

274 p.P99L, p.R117H, p.R334W, and p.R347D/H/P form ClÀ channels with altered permeation properties but are processed normally and are therefore indexed as class IV mutants [Sheppard et al., 1993, 1996; Tabcharani et al., 1993]. Login to comment

PMID: 21594800 [PubMed] Cai Z et al: "Application of high-resolution single-channel recording to functional studies of cystic fibrosis mutants."

No. Sentence Comment

297 For example, the CF mutant, P99L, in the first transmembrane segment attenuated the single-channel conductance (wild-type, 7.72 ± 0.22 pS (means ± SEM; n = 4); P99L, 4.97 ± 0.24 pS (n = 5, p < 0.0001)) and altered the anion selectivity sequence (wild-type, Br- ≥ Cl- > I-; P99L, Br- ≥ Cl- = I-) (62). Login to comment

PMID: 9922375 [PubMed] Sheppard DN et al: "Structure and function of the CFTR chloride channel."

No. Sentence Comment

124 When the basic arginine at this position was re- gle-channel Cl0 conductance in the rank order: wild type ' P99G ú P99L ' P99A (119). Login to comment

PMID: 9922376 [PubMed] Dawson DC et al: "CFTR: mechanism of anion conduction."

No. Sentence Comment

585 A patient mutation, P99L, was associated with reduced single-chan-tion reduced the single-channel conductance by Ç30%. Login to comment

PMID: 9374552 [PubMed] Fanen P et al: "Cystic fibrosis phenotype associated with pancreatic insufficiency does not always reflect the cAMP-dependent chloride conductive pathway defect. Analysis of C225R-CFTR and R1066C-CFTR."

No. Sentence Comment

101 Six CF-associated mutations (P99L, R117H, P205S, R334W, R347P, and R347H) located in putative membrane-spanning domains that have already been analyzed for their functional properties (2-5) were all associated with a mild phenotype (pancreatic sufficiency, PS). Login to comment

PMID: 9511930 [PubMed] Akabas MH et al: "Probing the structural and functional domains of the CFTR chloride channel."

No. Sentence Comment

143 A similar mechanism is likely involved in the alteration of the halide permeability sequence by the P99L mutation (Sheppard et al., 1996) because Pro99 is also not a channel-lining residue (Akabas et al., 1994b). Login to comment

PMID: 8810276 [PubMed] Price MP et al: "Function of Xenopus cystic fibrosis transmembrane conductance regulator (CFTR) Cl channels and use of human-Xenopus chimeras to investigate the pore properties of CFTR."

No. Sentence Comment

260 In MSD1, two mutations (P99L and K335E) that alter both anion permeability and conductance have been identified (15, 30); these are conserved in human and Xenopus CFTR. Login to comment
279 In MSD1, two mutations (P99L and K335E) that alter both anion permeability and conductance have been identified (15, 30); these are conserved in human and Xenopus CFTR. Login to comment

PMID: 8663008 [PubMed] Sheppard DN et al: "Contribution of proline residues in the membrane-spanning domains of cystic fibrosis transmembrane conductance regulator to chloride channel function."

No. Sentence Comment

2 These residues are conserved across species, and mutations of two (P99L and P205S) are associated with cystic fibrosis. Login to comment
6 The anion selectivity sequence of the mutants (Br- Cl- > I- ) resembled wild-type except for P99L (Br- Cl- ‫؍‬ I- ). Login to comment
9 Mutant channels were regulated like wild-type CFTR; however, single-channel conductance was decreased in the rank order: wild-type CFTR P99G > P99L P99A. Login to comment
23 These residues are conserved across species and mutations of two (P99L and P205S) are associated with cystic fibrosis (CF) (12, 13). Login to comment
24 Because P99L and P205S are associated with a milder clinical phenotype characterized by retention of some pancreatic function (termed pancreatic sufficiency) (2), these mutants may retain some residual Cl- channel function. Based on the above information, the aims of this study were to determine the contribution of proline residues located within the MSDs of CFTR to Cl- channel function and to understand how P99L and P205S cause a loss of Cl- channel function. Login to comment
76 Cyclic AMP agonists activated whole cell currents in cells expressing each of the individual proline to alanine or glycine mutations and in cells expressing the CF-associated mutations, P99L and P205S. Login to comment
77 As an example, Fig. 2 shows data from studies of P99A, P99G, and P99L; qualitatively similar results were obtained with the Pro205 , Pro324 , and Pro1021 mutants (data not shown). Login to comment
85 However, the CF-associated mutation P99L had an altered anion selectivity sequence, Br- Ն Cl- ϭ I- (Fig. 3 and Table I). Login to comment
119 Reversal potentials (Erev) of baseline subtracted cAMP-activated whole cell currents were P99A, -30 Ϯ 1 mV (n ϭ 7); P99G, -34 Ϯ 2 mV (n ϭ 5); and P99L, -24 Ϯ 3 mV (n ϭ 6). Login to comment
122 Mutant n Px/PCl Gx/GCl Br- Cl- IBr- ClI- CFTR 5 1.18 Ϯ 0.08 1.00 0.73 Ϯ 0.05 1.27 Ϯ 0.16 1.00 0.61 Ϯ 0.08 P99A 7 0.98 Ϯ 0.03 1.00 0.70 Ϯ 0.06 1.04 Ϯ 0.05 1.00 0.72 Ϯ 0.05 P99G 5 1.06 Ϯ 0.02 1.00 0.75 Ϯ 0.08 1.04 Ϯ 0.07 1.00 0.66 Ϯ 0.05 P99L 5 1.21 Ϯ 0.07 1.00 1.06 Ϯ 0.07 1.33 Ϯ 0.11 1.00 0.95 Ϯ 0.08 P205A 4 1.09 Ϯ 0.07 1.00 0.64 Ϯ 0.09 0.95 Ϯ 0.04 1.00 0.46 Ϯ 0.11 P205G 5 1.09 Ϯ 0.05 1.00 0.45 Ϯ 0.05 1.05 Ϯ 0.03 1.00 0.44 Ϯ 0.06 P205S 2 1.01 Ϯ 0.01 1.00 0.55 Ϯ 0.28 1.09 Ϯ 0.09 1.00 0.59 Ϯ 0.08 P324A 7 1.08 Ϯ 0.04 1.00 0.72 Ϯ 0.06 1.15 Ϯ 0.07 1.00 0.60 Ϯ 0.08 P324G 6 1.12 Ϯ 0.07 1.00 0.69 Ϯ 0.04 1.22 Ϯ 0.14 1.00 0.57 Ϯ 0.04 P1021A 3 1.15 Ϯ 0.17 1.00 0.73 Ϯ 0.11 1.17 Ϯ 0.10 1.00 0.47 Ϯ 0.19 P1021G 7 1.17 Ϯ 0.06 1.00 0.78 Ϯ 0.02 1.21 Ϯ 0.08 1.00 0.59 Ϯ 0.06 though for P99G the reduction was small, for P99A and P99L the effect was marked. Login to comment
126 The conductance for P99G was 7.31 Ϯ 0.24 pS (n ϭ 5), not significantly different from wild type (p ϭ 0.26). Login to comment
127 In contrast, the conductances of P99A and P99L were significantly decreased at 4.66 Ϯ 0.25 pS (n ϭ 5, p Ͻ 0.0001) and 4.97 Ϯ 0.24 pS (n ϭ 5, p Ͻ 0.0001), respectively. Login to comment
129 Because the single-channel current amplitudes of P99A and P99L were much reduced and because in most cases the patches of membrane contained large numbers of channels, we could not accurately measure single-channel kinetics. Login to comment
145 The number of cells responding to cAMP agonists with Cl- current activation relative to the total number of cells tested for each construct was: CFTR (8/16; 50%), P99A (11/12; 92%), P99G (9/19; 47%), P99L (10/19; 53%), P205A (7/12; 58%), P205G (5/9; 56%), P205S (7/20; 35%), P324A (9/18; 50%), P324G (9/22; 41%), P1021A (8/18; 44%), and P1021G (7/16; 44%). Login to comment
176 Similar results were observed with P99G and P99L; n Ͼ 5 for each mutant. Login to comment
177 B, representative single-channel recordings are from excised inside-out membrane patches from HeLa cells transiently expressing wild-type CFTR, P99A, P99G, and P99L. Login to comment
180 C, single-channel I-V relationships of CFTR (circles), P99A (squares), P99G (triangles), and P99L (inverted triangles. Login to comment
194 When Pro99 was mutated to leucine, the channel lost its ability to discriminate between Cl- and I- . Login to comment
199 Substitution of alanine, glycine, and leucine at Pro99 decreased single-channel conductance in the rank order: wild-type CFTR Ն P99G Ͼ P99L Ն P99A. Login to comment
206 Implications for Cystic Fibrosis-P99L and P205S are CF mutations located in MSD1 that are associated with a milder (pancreatic sufficiency) clinical phenotype (12, 13). Login to comment
207 Our studies of the processing and function of P99L and P205S explain why these mutants generate less Cl- current than wild-type CFTR. Login to comment
208 Loss of Cl- channel function caused by P205S was predominantly a result of defective protein processing; whereas that caused by P99L was a consequence of both defective protein processing and altered Cl- channel function. Login to comment
215 The present results complement and extend our previous study of mild CF mutants located in MSD1 (R117H, R334W, and R347P). Login to comment
218 Interestingly, P99L forms a Cl- channel with altered pore properties and is also misprocessed. Login to comment
221 We thank Dr. M. Schwartz (Department of Clinical Genetics, University Hospital, Copenhagen, Denmark) for generously providing details of the clinical phenotype of the patient with the P99L mutation prior to publication. Login to comment
78 As an example, Fig. 2 shows data from studies of P99A, P99G, and P99L; qualitatively similar results were obtained with the Pro205 , Pro324 , and Pro1021 mutants (data not shown). Login to comment
87 However, the CF-associated mutation P99L had an altered anion selectivity sequence, Br2 $ Cl2 5 I2 (Fig. 3 and Table I). Login to comment
123 Reversal potentials (Erev) of baseline subtracted cAMP-activated whole cell currents were P99A, 230 6 1 mV (n 5 7); P99G, 234 6 2 mV (n 5 5); and P99L, 224 6 3 mV (n 5 6). Login to comment
131 In contrast, the conductances of P99A and P99L were significantly decreased at 4.66 6 0.25 pS (n 5 5, p , 0.0001) and 4.97 6 0.24 pS (n 5 5, p , 0.0001), respectively. Login to comment
133 Because the single-channel current amplitudes of P99A and P99L were much reduced and because in most cases the patches of membrane contained large numbers of channels, we could not accurately measure single-channel kinetics. Login to comment
149 The number of cells responding to cAMP agonists with Cl2 current activation relative to the total number of cells tested for each construct was: CFTR (8/16; 50%), P99A (11/12; 92%), P99G (9/19; 47%), P99L (10/19; 53%), P205A (7/12; 58%), P205G (5/9; 56%), P205S (7/20; 35%), P324A (9/18; 50%), P324G (9/22; 41%), P1021A (8/18; 44%), and P1021G (7/16; 44%). Login to comment
181 Similar results were observed with P99G and P99L; n . Login to comment
183 B, representative single-channel recordings are from excised inside-out membrane patches from HeLa cells transiently expressing wild-type CFTR, P99A, P99G, and P99L. Login to comment
186 C, single-channel I-V relationships of CFTR (circles), P99A (squares), P99G (triangles), and P99L (inverted triangles. Login to comment
200 When Pro99 was mutated to leucine, the channel lost its ability to discriminate between Cl2 and I2 . Login to comment
214 Implications for Cystic Fibrosis-P99L and P205S are CF mutations located in MSD1 that are associated with a milder (pancreatic sufficiency) clinical phenotype (12, 13). Login to comment
216 Loss of Cl2 channel function caused by P205S was predominantly a result of defective protein processing; whereas that caused by P99L was a consequence of both defective protein processing and altered Cl2 channel function. Login to comment
226 Interestingly, P99L forms a Cl2 channel with altered pore properties and is also misprocessed. Login to comment
230 We thank Dr. M. Schwartz (Department of Clinical Genetics, University Hospital, Copenhagen, Denmark) for generously providing details of the clinical phenotype of the patient with the P99L mutation prior to publication. Login to comment

PMID: 24727426 [PubMed] Wang Y et al: "Understanding how cystic fibrosis mutations disrupt CFTR function: from single molecules to animal models."

No. Sentence Comment

2011 For example, the CF mutation P99L, which affects a residue that faces away from the pore (Akabas et al., 1994; Gao et al., 2013, but see Wang et al., 2011), had an altered anion selectivity sequence (wild-type: Br- ࣙ Cl- > I-; P99L: Br- ࣙ Cl- = I-) and reduced single-channel conductance (Sheppard et al., 1996). Login to comment