ABCMdb

ABCC7 p.Arg31Leu

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Publications

PMID: 15536480 [PubMed] Modiano G et al: "A large-scale study of the random variability of a coding sequence: a study on the CFTR gene."

No. Sentence Comment

33 In the Tajima`s test,19 the null hypothesis of neutrality is rejected if a statistically significant difference between p Common and rare nonsynonymous and synonymous cSNSs G Modiano et al European Journal of Human Genetics Table 1 List of the 61 cSNSsa encountered in the present survey The random samples of genes (and the technique utilized) cSNS variants found NE Italy (DGGE) Central Italy (DGGE) Southern France (DGGE) Northern France (DHPLC) Spain (SSCA) Czechia (DGGE) Hb Â 104 Exon Exon Length (bp) Ref. no. SNS SASc 1st 100d 2nd 500 1st 100d 2nde 1st 100d 2nd 500 1st 100 2nde 82d 72 Abs. Freq. Total sample size q Â 104 se Â 104 NSf Sf 1g 53 0 0 0 0 0/452 0 924 2 111 1 223C4T R31C 1 1 1/500 1 1 0 0/450 0 5 (11) 1 932 (2 432) 45.23 13.61 90 2 224G4T R31L 0 0 0/500 0 0 0 1/450 0 1 1 932 5.17 5.17 10 3 257C4T S42F 0 0 1/500 0 0 0 0/450 0 1 1 932 5.17 5.17 10 3 109 4 334A4G K68E 1 0 0 0/498 0 0 0 0/452 0 0 1 2 504 3.99 3.99 8 5 352C4T R74W 0 0 0 0/498 0 0 0 1/452 0 0 1 2 504 3.99 3.99 8 6 356G4A R75Q 1 7 1 7/498 2 9 2 9/452 0 2 40 (40) 2 504 (2 544) 157.23 24.66 310 7 386G4A G85E 0 0 1 1/498 0 0 0 0/452 0 0 2 2 504 7.99 5.65 16 4 216 8 482G4A R117H 0 0 0 0/292 0 2 0 1/456 0 0 3 2 302 13.03 7.52 26 9 528T4G I132M 0 0 0 0/292 0 0 0 1/456 0 0 1 2 302 4.34 4.34 8 10 575T4C I148T 1 2 0 1/292 0 0 0 1/456 0 1 6 2 302 26.06 10.63 52 5 90 11 640C4T R170C 0 0 0 0/6 0 0 1/448 0 1 1 436 6.96 6.96 14 12 641G4A R170H 1 1 0 0/6 0 0 2/448 0 4 (4) 1 436 (1 930) 20.73 10.35 41 6a 164 0 0 0/6 0 0 0/432 0 0 992 6b 126 0 0 0/6 0 0 0/454 0 942 7 247 0 0 0/6 0 0 0/796 0 1 284 8 93 13 1281G4A L383 0 0 0 0/6 0 0 1/456 0 0 1 1 516 6.60 6.60 13 9 183 14 1402G4A G424S 0 0 0/6 0 0 1/454 0 1 940 10.64 10.64 21 15 1459G4T D443Y 0 0 0/6 0 0 1/454 0 1 940 10.64 10.64 21 10 192 16 1540A4G M470Vh 42 197 30 37/96 39 199 (i) (i) 27 571(736) 1 484 (1 912) 3849.37 111.28 4 735 17 1598C4A S489X 0 0 0 0/96 0 0 0 1/796 0 1 2 374 4.21 4.21 8 18 1648A4G I506V 1 0 0 0/96 0 0 0 0/796 0 1 2 374 4.21 4.21 8 19 1655T4G F508C 0 1 0 0/96 0 0 0 1/796 0 2 2 038 8.42 5.96 17 20 1716G4A Q528 2 16 1 0/96 0 19 i I 5 43 (58) 1 478 (2 024) 286.56 37.08 557 11 95 21 1756G4T G542X 0 2 0 0/134 0 0 0/796 0 0 2 1 984 10.08 7.12 20 22 1764T4G G544 0 0 0 0/134 0 0 1/796 0 0 1 1 984 5.04 5.04 10 23 1784G4A G551D 0 0 0 0/134 0 0 1/796 0 0 1 1 984 5.04 5.04 10 12 87 24 1816G4A V562I 0 0 0 0 1 0 0/450 0 0 1 (1) 2 004 (2 504) 3.99 3.99 8 25 1816G4C V562L 0 0 0 1 0 0 1/450 0 0 2 (3) 2 004 (2 504) 11.98 6.91 24 26 1859G4C G576A 1 2 0 1 11 0 8/450 0 0 23 (27) 2 004 (2 538) 106.38 20.36 213 13 724j 449 27 1997G4A G622D 0 0 0/80 0/96 1 0 0 0/444 0 1 2 002 5.00 5.00 10 28 2082C4T F650 1 0 0/80 0/20 0 0 0 0/444 0 1 (1) 1 926 (2 412) 4.15 4.15 8 29 2134C4T R668C 1 2 0/80 0/96 1 11 0 12/444 0 27(32) 2 002 (2 558) 125.10 21.98 247 275 30 2377C4T L748 0 0 0/6 0 1 1 388 25.77 25.77 52 14a 129 31 2670G4A W846X 0 0 0/6 0 1 0/452 0/80 0 1 1 010 9.90 9.90 20 32 2694T4G T854 33 23 0/6 33 38 149/452 14/80 11 301 1 010 2980.20 143.92 4 184 33 2695G4A V855I 0 0 0/6 0 0 1/452 0/80 0 1 1 010 9.90 9.90 20 14b 38 0 0 0 0/520 0 0 0 0/446 0 2 448 15 251 34 2816G4C S895T 0 0 0/6 0 0 2/436 0 0 2 996 20.08 14.18 40 35 2831A4C N900T 0 0 0/6 0 0 1/436 0 0 1 996 10.04 10.04 20 36 2988G4C M952I 0 0 0/6 0 0 1/436 0 0 1 996 10.04 10.04 20 37 3030G4A T966 (2)k (1)k 0 6/436 0 6 (25)k 618 (1814)k 137.82 27.37 272 38 3032T4C L967S 0 0 0/6 0 0 1/436 0 0 1 996 10.04 10.04 20 16 80 0 0 0/498 0 0 0/450 0 0 1 502 17a 151 39 3123G4C L997F 0 2 2 1/494 0 7 1 4/454 0 0 17 2 502 67.95 16.42 135 40 3157G4A A1009T 0 2 0 0/494 0 0 0 0/454 0 0 2 2 502 7.99 5.65 16 41 3212T4C I1027T 1 0 0 0/494 0 0 0 0/454 0 0 1 2 502 4.00 4.00 8 17b 228 42 3286T4G F1052V 1 1 0 1/194 0 0 0 0/452 0 0 3 (3) 2 200 (2 240) 13.39 7.73 27 43 3337G4A G1069R 0 1 0 0/194 0 0 0 0/452 0 0 1 2 200 4.55 4.55 9 CommonandrarenonsynonymousandsynonymouscSNSs GModianoetal 186 EuropeanJournalofHumanGenetics 44 3345G4T Q1071H 0 0 0 0/194 0 1 0 0/452 0 0 1 2 200 4.55 4.55 9 45 3417A4T T1995 1 3 0 0/194 1 1 0 0/452 0 0 6 (8) 2 200 (2 506) 31.92 11.27 64 46 3419T4G L1096R 0 0 0 0/194 1 0 0 0/452 0 0 1 2 200 4.55 4.55 9 47 3477C4A T1115 0 0 0 0/194 0 0 0 1/452 0 0 1 2 200 4.55 4.55 9 18 101 48 3523A4G I1131V 0 0 1 0/10 0 0 0/448 0 0 1 (2) 1 512 (1 908) 10.48 7.07 21 49 3586G4C D1152H 0 0 0 0/10 0 0 1/448 0 0 1 1 512 6.61 6.61 13 19 249 50 3617G4T R1162L 0 0 1 1/494 0 0/260 0 0/454 0 0 2 2 262 8.84 6.25 18 51 3690A4G Q1186 0 0 0 0/494 0 0/260 0 0/454 1 0 1 2 262 4.42 4.42 9 52 3813A4G L1227 0 1 0 0/494 0 0/260 0 0/454 0 0 1 2 262 4.42 4.42 9 53 3837T4G S1235R 1 1 0 1/494 0 4/260 0 7/454 0 1 15 (15) 2 262 (2 310) 69.94 16.71 140 20 156 54 4002A4G P1290 2 3 0/6 3 5 18/454 3/80 2 36 1 012 357.73 58.22 690 21 90 55 4009G4A V1293I 0 0 0/6 0 0/300 0 1/456 0 0 1 1 316 7.60 7.60 15 56 4029A4G T1299 1 0 0/6 0 1/300 0 1/456 0 0 3 (8) 1 316 (2 330) 34.33 12.12 69 57 4041C4G N1303K 1 0 0/6 0 0/300 0 0/456 0 0 1 1 316 7.60 7.60 15 58 4085T4C V1318A 0 0 0/6 0 0/300 0 1/456 0 0 1 1 316 7.60 7.60 15 22 173 0 0 0/18 0 0 0/450 0 0 1 022 23 106 0 0 0 0/6 0 0 0/448 0 1 436 24l 198+3 59 4404C4T Y1424 1 0 0/6 1 2 5/420 0 2 11 (32) 980 (2 516) 127.19 22.34 251 60m 4521G4A Q1463 (21) (16) (3/32) (14/80) (30) (94/420) 15/76 (17) 15 (227) 76 (1052) 2142.86 131.07 3 367 61 4563T4C D1477 0 0 0/6 0 1 0/420 0 0 1 980 10.20 10.20 20 Totals 6 525 9 584 16 109 The bracketed figures include also the RFLP analysis data (see Materials and methods); the NE Italy, Central Italy, Southern and Northern France are each subdivided into two samples where the 1st is made up of 100 genes. 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PMID: 16339147 [PubMed] Jurkuvenaite A et al: "Mutations in the amino terminus of the cystic fibrosis transmembrane conductance regulator enhance endocytosis."

No. Sentence Comment

1 In the present studies, two naturally occurring cystic fibrosis mutations in the amino terminus of CFTR, R31C, and R31L were examined. Login to comment
8 Together, the results suggest that both R31C and R31L mutations compromise biogenesis and enhance internalization of CFTR. Login to comment
25 In the present studies, we examined two naturally occurring mutations, R31C and R31L, which cause mild CF.3 To determine the defects caused by these missense mutations, we expressed them in COS-7 cells and analyzed their biogenesis and trafficking. Login to comment
26 Our results indicate that both R31C and R31L have compromised biogenesis and enhanced endocytosis compared with wild-type CFTR. Login to comment
29 MATERIALS AND METHODS Construction of CFTR Mutants-The R31C and R31L mutants were prepared by PCR mutagenesis. Login to comment
32 Using the CFTR gene contained in plasmid pCDNA3.1ϩ as template, the R31L and R31C mutants were constructed by PCR-mutagenesis using a pair of internal primers for each mutant, annealing at the Arg-31 coding site, and a pair of external primers, one annealing at the Nhe-I site of the multilinker of the vector, and one annealing at the BspE-I site in the CFTR gene. Login to comment
96 EC, extracellular; IC, intracellular; L/C, R31L and R31C mutations. Login to comment
102 With the R31C and R31L mutants, however, very little processing occurredduringthefirst2hofchase(0and4.7 Ϯ 1.5%,respectively).By4h, 10.3 Ϯ 3.0% (R31C) and 11.3 Ϯ 2.1% (R31L) of CFTR was converted to the mature form, indicating that, although there is a processing defect, it does not cause complete inhibition. Login to comment
106 The results indicate that the protein half-life of the wild-type protein is 13.3 Ϯ 1.2 h, and the R31C and R31L half-lives are 12.7 Ϯ 0.6 and 14.3 Ϯ 3.1 h, respectively, indicating that, FIGURE 3. Login to comment
108 Wild-type, R31C, and R31L CFTR half-lives were determined in COS-7 cells 24 h after transfection. Login to comment
111 A, representative gels of wild-type (WT), R31C, and R31L CFTR half-lives are shown. Login to comment
115 Protein maturation of R31C and R31L CFTR is inefficient compared with wild-type CFTR. Login to comment
120 A, representative metabolic labeling experiments are shown for wild type (WT), R31C, and R31L (left panels). Login to comment
126 Maturation efficiencies of wild type, R31C, and R31L were calculated after 4 h of chase (average Ϯ S.D., n ϭ 3; *, p Ͻ 0.005; **, p Ͻ 0.001). Login to comment
127 C, R31C (C) and R31L (L) are not temperature-sensitive. Login to comment
128 WT, R31C and R31L CFTR were immunoprecipitated from COS-7 cells 48 h after transfection. Login to comment
131 A 27 °C incubation increased the amount of B band but did not influence C band production for R31C or R31L CFTR. Login to comment
133 Reduced Surface Expression of R31C and R31L-Because some mutant protein was processed correctly and the protein half-life appeared normal, the surface pool of the Arg-31 mutants was examined next. Login to comment
136 For the R31C and R31L mutants, however, staining was much more restricted to an intracellular, reticular pattern. Login to comment
138 To confirm this observation, cells expressing wild-type, R31C, and R31L CFTR were surface-biotinylated (Fig. 4B), CFTR was immunoprecipitated, and the biotinylated fraction was detected by Western blot analysis. Login to comment
139 The results indicate that the surface pool of the R31C and R31L mutants is 20.3 Ϯ 7.5 and 33.6 Ϯ 11.7% of the wild-type protein, respectively (n ϭ 4, p Ͻ 0.005, and p Ͻ 0.05, respectively. Login to comment
141 R31C and R31L Are Internalized More Rapidly than the Wild-type CFTR-Because the surface pool was smaller than predicted, we next tested whether the mutations affected CFTR clearance from the cell surface. Login to comment
145 The R31C and R31L mutants, however, have dramatically altered internalization kinetics with 54 Ϯ 4 and 55 Ϯ 13.9% of the R31C and R31L mutants, respectively (internalized during the same warm-up period). Login to comment
147 The Functional Activity of the R31C and R31L Mutants Is Severely Compromised-As a final measure of the total CFTR chloride channels at the cell surface, we tested the functional activity of the R31C and R31L mutants in two complementary functional assays, macroscopic patch clamp experiments and SPQ assays. Login to comment
152 Cells transfected with the R31L and R31C mutants exhibited two differences as compared with wild-type-transfected cells. Login to comment
157 R31C and R31L surface expression is lower than wild-type CFTR. Login to comment
158 A, wild-type, R31C, and R31L CFTR distributions were examined in COS-7 cells 48 h after transfection using indirect immunofluorescence. Login to comment
160 Arrows indicate the prominant cell surface expression of the wild-type protein CFTR and the diminished amount of surface staining in the R31C and R31L CFTR-expressing cells. Login to comment
165 Internalization of the R31C and R31L CFTR mutants is dramatically enhanced compared with the wild-type protein. Login to comment
166 A, wild-type, R31C, and R31L CFTR internalization in COS-7 cells. Login to comment
181 DISCUSSION The R31C and R31L are naturally occurring missense CF mutations that appear to have a mild phenotype (31).3 Both of these mutations are rare (identified once in 284 CF chromosomes, for the R31L mutation). Login to comment
184 The R31L was found in a 24-year-old female CF patient who was pancreatic-sufficient with normal lung function but a positive sweat test. Login to comment
194 R31C and R31L mutants have diminished channel activity compared with the wild-type protein. Login to comment
195 A-C, representative current traces for wild-type (WT) and R31C and R31L mutants. Login to comment
204 Note that the data for the L and C mutants overestimate their functional activities, because unlike WT, most excised mutant patches exhibited undetectable CFTR activity and were excluded from this analysis (R31L, 4 active patches of 13 total; R31C, 4 active patches of 19 total; wild type, 4 active patches of 6 total). Login to comment
206 E, functional analysis of wild-type and R31C and R31L CFTR using SPQ fluorescence. Login to comment
207 The change in SPQ fluorescence is shown for COS-7 cells expressing wild-type, R31C, and R31L CFTR. Login to comment
232 Analysis of the ⌬F508, N287Y, and R31L and R31C indicate that alterations in the transport of CFTR at the cell surface, whether it is enhanced internalization or compromised recycling, can result in a disease phenotype. Login to comment

PMID: 17098864 [PubMed] Roxo-Rosa M et al: "Revertant mutants G550E and 4RK rescue cystic fibrosis mutants in the first nucleotide-binding domain of CFTR by different mechanisms."

No. Sentence Comment

180 Jurkuvenaite et al. (42) recently studied R31C and R31L, two CF mutations in the N terminus of CFTR that affect the first AFT (R29QR31). Login to comment

PMID: 17235394 [PubMed] Thelin WR et al: "Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR."

No. Sentence Comment

258 For example, the R31L or N287Y mutations may introduce a nonnative internalization motif in CFTR and result in increased plasma membrane internalization (8, 9). Login to comment

PMID: 18193900 [PubMed] Cheung JC et al: "Misfolding of the cystic fibrosis transmembrane conductance regulator and disease."

No. Sentence Comment

99 As further examples, the N-terminal mutations R31L/C produce CFTR molecules that are processed to Band C but have increased rates of endocytosis (77), while C-terminal truncation mutants can process to complex N-glycosylated forms but are subject to premature proteolysis by the proteasome (78). Login to comment

PMID: 18306312 [PubMed] Gene GG et al: "N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel."

No. Sentence Comment

247 A recent report analyzing the natural mutations p.R31C and p.R31L, has shown that these subtle N-terminus alterations compromise biogenesis and enhance internalization of CFTR, contributing to the loss of surface expression and the associated defect in chloride conductance of the channel [Jurkuvenaite et al., 2006]. Login to comment

PMID: 17098482 [PubMed] Ameen N et al: "Endocytic trafficking of CFTR in health and disease."

No. Sentence Comment

680 R31C and R31L are CFTR mutations that also give rise to a mild clinical phenotype [71]. Login to comment
683 Expression of R31C and R31L CFTR leads to reduced macroscopic currents compared to expression of wt CFTR; however, since single channel records were not determined it is not possible to determine whether the reduced macroscopic currents are due to endocytic defects alone, or whether there are also altered gating kinetics. Login to comment
681 R31C and R31L are CFTR mutations that also give rise to a mild clinical phenotype [71]. Login to comment
684 Expression of R31C and R31L CFTR leads to reduced macroscopic currents compared to expression of wt CFTR; however, since single channel records were not determined it is not possible to determine whether the reduced macroscopic currents are due to endocytic defects alone, or whether there are also altered gating kinetics. Login to comment

PMID: 12454843 [PubMed] Durno C et al: "Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis."

No. Sentence Comment

105 CFTR Genotypes Among CF Patients With PS With and Without Pancreatitis Two mutations (n) ⌬F508/R117H (9) ⌬F508/(5T) (6) ⌬F508/3272-26A 3 G (4) ⌬F508/R347H (2) ⌬F508/P574H (2) ⌬F508/875 ϩ 1G Ͼ C (2) ⌬F508/3849 ϩ 10kb C 3 T (1) ⌬F508/A455E (1) ⌬F508/D614G (1) ⌬F508/G85E (1) ⌬F508/R347P (1) ⌬F508/S1251N (1) ⌬F508/⌬F508a (1) ⌬F508/3120G Ͼ A (1) ⌬F508/G551Da (1) G542X/R117H (1) R560T/L206W (1) R117H/R117H (1) R31L/P67L (1) 1461ins4 (AGAT)/G85E (1) G551D/(5T) (1) R1066C/3849 ϩ 10kb C Ͼ T (1) G551D/3849 ϩ 10kb C Ͼ T (1) R334W/R334W (1) R334W/681delC (1) W1282X/3489 ϩ 10kb C Ͼ T (1) One mutation (n) ⌬F508/- (18) L1077P/- (1) W1282X/- (1) M1137V/- (1) G551D/- (1) R347H/- (1) Q30X1/- (1) G1244E/- (1) R117H/- (1) 621 ϩ 2G621 ϩ 1G 3 T/- (1) NOTE. Login to comment

PMID: 7526685 [PubMed] Morral N et al: "Independent origins of cystic fibrosis mutations R334W, R347P, R1162X, and 3849 + 10kbC-->T provide evidence of mutation recurrence in the CFTR gene."

No. Sentence Comment

106 Slippage usually results in the addition or subtraction of one repeat unit either side Table 5 CpG Dinucleotides in CFTR Gene That Have More than One Mutational Event Position Change Mutation Reference 223 ......... CT R31C Ghanem et al. 1994 224 ......... GT R31L Zielenski et al., in press 355 ........ C- >T R75X Dork et al., in press 356 ......... G--*T R75L B. Costes, personal communication 356 ......... G-aA R75Q' Zielenski et al. 1991b 481 ......... CT R117C D6rk et al., in press 482 ......... G-oA R117H Dean etal. Login to comment

PMID: 7521710 [PubMed] Ravnik-Glavac M et al: "Sensitivity of single-strand conformation polymorphism and heteroduplex method for mutation detection in the cystic fibrosis gene."

No. Sentence Comment

120 Exon 1: S4X (24), 186-13C-G (F£rec et al., pers. comm.); Exon 2: G27X (Shacldeton and Harris, pers. comm.), Q30X (Chilldn aal., pers. comm.), R31L (Zielenski et al., pers. comm.), Q39X (25); Exon 3: 300delA (Malone et al., pers. comm.), W57G (Ferrari et al., pers. comm.), W57X (26), E60X (Malone et al., pers. comm.), R74W (Claustres et al., pers. comm.), R75Q (27), G85E (28), 394delTT (Claustres et al., pers. comm.), L88X (Maceketal., pers. comm.), L88S (Malone et al., pers. comm.), 405 + 1G-A (Dork and Tummler, pers. comm.); Exon 4: E92K (Chillon et al., pers. comm.), E92X (D6rk a al., pers. comm.), P99L (Schwartz and Holmberg, pers. comm.), 441delA (Zielenski et al., pers. comm.), 444delA (29), 457TAT-C- (F£rec et al., pers. comm., (21), Dl 10H (14), Rl 17C (D6rk et al., pers. comm.), Rl 17H (14), A120T (Chillon et al., pers. comm.), 541delC (30), 556delA (28), I148T (Rininsland et al., pers. comm.), Q151X (Shacldeton et al., pers. comm.), 621 + 1C-T (28), 622-2A-C (31); Exon5:G178R (28), 681delC (Zielenski a al., pers. comm.), 711 + 1G-T (28); Exon 6a: H199Y (Dork and Tummler, pers. comm.), H199Q (Dean etal., pers. comm.), L206W (Claustres et al., pers. comm.), Q220X (Shacldeton and Harris, pers. comm., Schwartz and Holmberg, pers. comm.), 852del22 (32); Exon 6b: 977insA (33); Exon7:F311L(34). Login to comment