ABCMdb

ABCC7 p.Pro1290Ser

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Publications

PMID: 17413420 [PubMed] Grangeia A et al: "Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens."

No. Sentence Comment

93 DeltaF508 was the second most common mutation, representing 21 (23.3%) of total alleles, followed by R334W (6, Table 1 CFTR gene mutations and polymorphisms in patients with congenital absence of the vas deferens Mutation Location Nucleotide alteration Effect Method 1 CFTRdele2,3 Exons 2-3 Deletion of exons 2 and 3 Frameshift QFM-PCR 2 R117H Exon 4 G¡A at 482 AA substitution 31 mutation panel 3 P205S Exon 6a C¡T at 745 AA substitution DGGE/dHPLC 4 L206W Exon 6a T¡G at 749 AA substitution DGGE/dHPLC 5 R258G Exon 6b A¡G at 904 AA substitution DGGE/dHPLC 6 R334W Exon 7 C¡T at 1132 AA substitution 31 mutation panel 7 T5 allele Intron 8 Deletion of 2T at 1342-12 to -6 Aberrant splicing DGGE/DNA sequencing 8 P439S Exon 9 C¡T at 1447 AA substitution DGGE/dHPLC 9 D443Ya Exon 9 G¡T at 1459 AA substitution DGGE/dHPLC 10 I507del Exon 10 Deletion of 3 bp at 1648-1653 AA deletion 31 mutation panel 11 DeltaF508 Exon 10 Deletion of 3 bp at 1652-1655 AA deletion 31 mutation panel 12 G542X Exon 11 G¡T at 1756 Truncation 31 mutation panel 13 V562I Exon 12 G¡A at 1816 AA substitution DGGE/dHPLC 14 G576Aa Exon 12 G¡C at 1859 Aberrant splicing DGGE/dHPLC 15 D614G Exon 13 A¡G at 1973 AA substitution DGGE/dHPLC 16 R688Ca Exon 13 C¡T at 2134 AA substitution DGGE/dHPLC 17 V754M Exon 13 G¡A at 2392 AA substitution DGGE/dHPLC 18 E831X Exon 14a G¡T at 2623 Truncation DGGE/dHPLC 19 3272-26AϾG Intron 17a A¡G at 3272-26 Aberrant splicing DGGE/dHPLC 20 2789ϩ5G¡A Intron 14b G¡A at 2789ϩ5 Aberrant splicing 31 mutation panel 21 V1108L Exon 17b G¡C at 3454 AA substitution DGGE/dHPLC 22 L1227S Exon 19 T¡C at 3812 AA substitution DGGE/dHPLC 23 S1235R Exon 19 T¡G at 3837 AA substitution DGGE/dHPLC 24 P1290S Exon 20 C¡T at 4000 AA substitution DGGE/dHPLC 25 N1303K Exon 21 C¡G at 4041 AA substitution 31 mutation panel 26 E1401K Exon 23 G¡A at 4333 AA substitution DGGE/dHPLC Polymorphisms 1 TG repeats Intron 8 9-13 copies at 1342-12 to -35 Sequence variation DGGE/DNA sequencing 2 M470V Exon 10 A or G at 1540 Sequence variation DNA sequencing 3 125G/C Exon 1 G¡C at 125 Sequence variation DGGE/dHPLC 4 1001ϩ11T/C Intron 6b C¡4T at 1001ϩ11 Sequence variation DGGE/dHPLC 5 1716G/A Exon 10 G¡A at 1716 Sequence variation DGGE/dHPLC 6 1899-136T/G Intron 12 T¡G at 1899-136 Sequence variation DGGE/dHPLC 7 T854T Exon 14a T¡G at 2694 Sequence variation DGGE/dHPLC 8 3601-65C/A Intron 18 C¡A at 3601-65 Sequence variation DGGE/dHPLC 9 4521G/A Exon 24 G¡A at 4521 Sequence variation DGGE/dHPLC QFM-PCR, semiquantitative fluorescent multiplex polymerase chain reaction; bp, base pair; DGGE, denaturing gradient gel electrophoresis; dHPLC, denaturing high-performance liquid chromatography. Login to comment
101 The missense M470V polymorphism was evaluated in all 45 pa- tientswithCAVD(Table2).TheallelicfrequencyoftheM470variant Table 2 CFTR genotypes identified in patients with congenital absence of the vas deferens CFTR mutation genotypes [(TG)mTn] genotype M470V Patients N % DeltaF508 (TG)10T9 (TG)12T5 M V 11 24.4 DeltaF508 (TG)10T9 (TG)11T5 M M 1 2.2 DeltaF508 R117H (TG)10T9 (TG)10T7 M M 2 4.4 G542X (TG)10T9 (TG)12T5 M V 2a 4.4 DeltaF508 R334W (TG)10T9 (TG)11T7 M V 1 2.2 DeltaF508 D443Y-G576A-R668C (TG)10T9 (TG)10T7 M M 1 2.2 DeltaF508 D614G (TG)10T9 (TG)11T7 M V 1 2.2 DeltaF508 E831X (TG)10T9 (TG)11T7 M V 1 2.2 DeltaF508 L1227S (TG)10T9 (TG)11T7 M M 1 2.2 DeltaF508 E1401K (TG)10T9 (TG)11T7 M V 1 2.2 I507del D614G (TG)11T7 (TG)10T7 M V 1 2.2 N1303K L206W (TG)10T9 (TG)9T9 M M 1 2.2 R117H P205S (TG)11T7 (TG)10T7 M V 1 2.2 R117H R334W (TG)10T7 (TG)11T7 M V 1 2.2 R334W P439S (TG)11T7 (TG)11T7 M V 1 2.2 R334W R334Wb (TG)11T7 (TG)11T7 V V 1 2.2 R334W V562I (TG)11T7 (TG)11T5 V M 1 2.2 D443Y-G576A-R668C 3272-26A¡G (TG)10T7 (TG)10T7 M M 1 2.2 G576A-R668C V754Mb (TG)10T7 (TG)11T7 M M 1 2.2 S1235R S1235Rb (TG)13T5 (TG)13T5 M M 1 2.2 2789ϩ5G¡A S1235Rb (TG)10T7 (TG)13T5 M M 1 2.2 3272-26A¡G P1290S (TG)11T7 (TG)10T7 M V 1 2.2 P205S (TG)11T7 (TG)12T5 V V 1 2.2 G576A-R668C b (TG)10T7 (TG)11T5 M M 1 2.2 V1108L b (TG)11T7 (TG)11T5 V M 1 2.2 N1303K (TG)10T9 (TG)12T5 M V 1 2.2 3272-26A¡G b (TG)10T7 (TG)12T5 M V 1 2.2 CFTRdele2,3 b (TG)11T7 (TG)13T5 V M 1 2.2 b (TG)11T5 (TG)12T5 M V 1 2.2 b (TG)13T5 (TG)12T5 M V 1 2.2 DeltaF508 - (TG)10T9 (TG)11T7 M V 1a 2.2 L206W -b (TG)9T9 (TG)11T7 M V 1 2.2 R258G -b (TG)11T7 (TG)11T7 V V 1 2.2 a CUAVD. Login to comment
110 Large Table 3 Allelic frequencies of CFTR mutations in patients with congenital absence of the vas deferens CBAVD CUAVD Total Patients 42 3 45 Alleles 84 6 90 Mutations N % N % N % 1 T5 allele 26a 31 2 33.3 28 31.1 2 DeltaF508 20 23.8 1 16.7 21 23.3 3 R334W 6a 7.1 0 0 6 6.7 4 R117H 4 4.8 0 0 4 4.4 5 G576A 4b 4.8 0 0 4 4.4 6 R688C 4b 4.8 0 0 4 4.4 7 S1235R 3a 3.6 0 0 3 3.3 8 3272-26A¡G 3 3.6 0 0 3 3.3 9 P205S 2 2.4 0 0 2 2.2 10 L206W 2 2.4 0 0 2 2.2 11 D443Y 2b 2.4 0 0 2 2.2 13 D614G 2 2.4 0 0 2 2.2 14 N1303K 2 2.4 0 0 2 2.2 12 G542X 0 0 2 33.3 2 2.2 15 R258G 1 1.2 0 0 1 1.1 16 P439S 1 1.2 0 0 1 1.1 17 I507del 1 1.2 0 0 1 1.1 18 V562I 1 1.2 0 0 1 1.1 19 V754M 1 1.2 0 0 1 1.1 20 E831X 1 1.2 0 0 1 1.1 21 2789ϩ5G¡A 1 1.2 0 0 1 1.1 22 V1108L 1 1.2 0 0 1 1.1 23 L1227S 1 1.2 0 0 1 1.1 24 P1290S 1 1.2 0 0 1 1.1 25 E1401K 1 1.2 0 0 1 1.1 26 CFTRdele2,3 1 1.2 0 0 1 1.1 CBAVD, congenital bilateral absence of the vas deferens; CUAVD, congenital unilateral absence of the vas deferens. Login to comment

PMID: 18769034 [PubMed] Grangeia A et al: "Molecular and functional characterization of CBAVD-causing mutations located in CFTR nucleotide-binding domains."

No. Sentence Comment

2 A previous screening of the entire coding region of the cystic fibrosis transmembrane conductance regulator gene (CFTR [MIM 602421]) in CBAVD patients identified three novel mutations: P439S is located in the first nucleotide binding domain (NBD1) of CFTR, whereas P1290S and E1401K are located in NBD2. Login to comment
4 Results: Although maturation patterns were not affected, total amounts of mature P439S-CFTR and P1290S-CFTR were reduced. Login to comment
5 Confocal microscopy showed correct membrane localisation of E1401K-CFTR, whereas P439S-CFTR and P1290S-CFTR mutants were located mainly in the cytoplasm. Login to comment
7 Conclusion: Dysfunction of CFTR is caused by either defective CFTR trafficking (P439S and P1290S) or/and Cl-channel function (P1290S and E1401K). Login to comment
59 Plasmids, cell culture, transient transfection CFTR mutations (P439S, P1290S and E1401K) were generated (QuikChange site-directed mutagenesis kit, Stratagene, La Jolla, CA) in the eukaryotic expression vector pCMVCFTRNot6.2, according to the manufacturer`s instructions. Login to comment
103 P1290S (NBD2) was identified in a 45 year old patient heterozygous for the Table 1. Login to comment
112 Multiple alignments of CFTR amino acid sequences from different species and localization of NBD1, NBD2 and three novel CFTR mutations (P439S, P1290S, E1401K). Login to comment
126 Biosynthesis of CFTR mutants Maturation patterns of wild-type (wt) CFTR and mutant CFTR (F508del-CFTR, P439S-CFTR, P1290S-CFTR and E1401K-CFTR) were compared by Western blotting. Login to comment
130 However, total amounts of mature P439S-CFTR and P1290S-CFTR were significantly reduced compared to wtCFTR, as indicated by densitometric analysis (Fig. 2B). Login to comment
137 The mutants P439S-CFTR and P1290S-CFTR were mainly expressed in the cytoplasm with little membrane expression, while E1401K-CFTR was clearly present in the cell membrane, similar to wtCFTR (Fig. 3A-B). Login to comment
143 P439S-CFTR and P1290S-CFTR are detected predominantly in the cytoplasm but to some degree also in the plasma membrane. Login to comment
159 Intracellular cAMP was enhanced by stimulation of the cells with 2 µM FSK and 100 µM IBMX, which largely increased the rate of I- influx in HEK293 cells expressing wtCFTR, while non-transfected cells or F508del-CFTR expressing cellsdidnotrespondtostimulation(Fig.4A-B).Expression of all three mutants P439S-CFTR, P1290S-CFTR and E1401K-CFTR allowed for cAMP-induced increase in I- influx, although the rate of I- influx was significantly lower than that for wtCFTR (Fig. 4A-B). Login to comment
160 Reduced I- influx seems to be in accordance with the reduced levels of protein expression for two mutants P439S-CFTR, P1290S-CFTR.Although E1401K did not interfere with Fig. 5. Login to comment
165 GFP = green fluorescence protein, wt = wtCFTR, F508del = F508del-CFTR, P439S = P439S-CFTR, P1290S = P1290S-CFTR, E1401K = E1401K-CFTR. Login to comment
168 C) Effect of IBMX (100 µM) and forskolin (2 µM) on whole-cell currents of non-transfected cells and in cells expressing wtCFTR, F508del-CFTR and P1290S-CFTR. Login to comment
169 Current-voltage curves where mean whole-cell currents (in nA) were plotted against the Vc values (in mV), in non-transfected (black trace) and wtCFTR (red trace) expressing cells (left panel), and in cells expressing F508del-CFTR (black trace) or P1290S-CFTR (blue trace) (right panel). Login to comment
178 Similar to the results from I- uptake studies, CFTR mutants P439S-CFTR, P1290S-CFTR and E1401K-CFTR showed a reduced but significant current increase and activation of whole cell conductance. Login to comment
180 Figure 5C represents current-voltage (IV) curves, where mean whole-cell currents (in nA) were plotted against the Vc values (in mV), in non-transfected cells and HEK293 cells expressing wtCFTR (left panel), and in HEK293 cells expressing F508del-CFTR and P1290S-CFTR (right panel). Login to comment
188 Highlights of the possible location of E1401K and P1290S mutations refer to the SAV1866 model. Login to comment
198 While P439S and E1401K are close toATP binding sites and therefore likely to affect NBD-dimerization andATP binding, respectively, P1290S is located near the interface NBD/MSD, and may interfere with side-chain contacts within the membrane spanning subunit. Login to comment
200 In the present study, we report biochemical and functional data on three CFTR missense mutations located in NBD1 (P439S) and in NBD2 (P1290S, E1401K). Login to comment
212 P1290S was detected in a patient with additional 3272-26A→G mild mutation on the other chromosome. Login to comment
220 Densitometric analysis showed that the ratio of mature fully-glycosylated to immature core-glycosylated bands detected for P439S-CFTR and P1290S-CFTR was lower than those obtained for wtCFTR, indicating that P439S and P1290S mutations cause dysfunction of CFTR by decreasing total amounts of mature protein. Login to comment
221 Sub-cellular localization of the three CFTR mutants in HEK293 cells indicated dramatically reduced membrane staining for P439S-CFTR and P1290S-CFTR and suggests biosynthetic arrest of CFTR maturation similar to F508del-CFTR [43, 47]. Login to comment
224 Thus E1401K probably reduces the activity of CFTR Cl- chan- nels while P439S-CFTR and P1290S-CFTR reduce the number of CFTR channels in the membrane. Login to comment
225 Further studies using single channel patch clamp will assess if E1401K reduces whole cell conductance by affecting channel open probability or single channel conductance, and if P439S and P1290S also affect CFTR channel pore/gating mechanism. Login to comment
228 P1290S (proline → serine) is located just before the Q-loop glutamine residue, near the interface between NBD and MSD (Figs. Login to comment
247 Polyphen analysis indicated that while E1401K (PSIC 1.609) is "possibly damaging", P439S (PSIC 2.396) and P1290S (PSIC 2.108) are "probably damaging" (deleterious) to protein function. Login to comment
250 Although, data obtained with the available bioinformatic tools must be interpreted with caution, these results confirmed experimental data, suggesting that P439S, P1290S and E1401K interfere with protein function. Login to comment
253 The other two missense mutations, P439S and P1290S, cause a decrease in the total amounts of the mature protein that might be attributed to a defective processing or an increased protein turnover. Login to comment
255 Conversely, P1290S appears to affect the NBD1-MSD interaction and thus the overall folding of the entire protein. Login to comment
256 Based on present data and in what has been established for the classification of different CFTR mutations, P439S and P1290S might be classified as class V mutations, associated with reduced levels of normally functioning CFTR. Login to comment
258 In addition, P1290S is also likely to cause a defective CFTR activity by affecting signalling with the MSD, and therefore P1290S might also be classified as a class III mutation. Login to comment
259 This observation might explain the lower whole-cell Cl- currents determined for P1290S-CFTR when compared with P439S-CFTR and E1401K-CFTR. Login to comment
264 Although P439S, P1290S and E1401K might not lead to a typical CF phenotpye, the knowledge of the mechanism by which they affect CFTR, improve the ability to interpret and predict the clinical phenotype in patients carrying the studied mutations and may give important insights about the molecular consequences of similar sequence alterations that have been, or remain to be characterized. Login to comment

PMID: 20059485 [PubMed] Dorfman R et al: "Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene?"

No. Sentence Comment

64 Mutations in the CFTR gene grouped by clinical category Cystic fibrosis CFTR-related disease No disease T338I D614G L320V V920L L90S M470V H199R S1251N I203M G550R P111A I148T Q1291H R560K L1388Q L183I R170H I1027T S549R D443Y P499A L1414S T908N R668C S549N A455E E1401K Q151K G27E I1234L Y563N R347P C866R S1118C P1290S R75Q A559T V520F P841R M469V E1401G P67L G85E S50Y E1409K R933G G458V G178R Y1032C R248T I980K G85V V392G L973P L137H T351S R334W I444S V938G R792G R560T R555G L1339F D1305E P574H V1240G T1053I D58G G551D L1335P I918M F994C S945L L558S F1337V R810G D1152H G1247R P574S R766M D579G W1098R H949R F200I R352Q L1077P K1351E M244K L206W M1101K D1154G L375F N1303K R1066C E528D D110Y R347H R1070Q A800G P1021S S549K A1364V V392A damaging` (is supposed to affect protein function or structure) and 'probably damaging` (high confidence of affecting protein function or structure). Login to comment

PMID: 22842702 [PubMed] Ni WH et al: "The CFTR polymorphisms poly-T, TG-repeats and M470V in Chinese males with congenital bilateral absence of the vas deferens."

No. Sentence Comment

107 N Engl J Med 1995; 332: 1475-80. 24 Grangeia A, Carvalho F, Fernandes S, Silva J, Sousa M et al. A novel missense mutation P1290S at exon-20 of the CFTR gene in a Portuguese patient with congenital bilateral absence of the vas deferens. Login to comment
103 N Engl J Med 1995; 332: 1475-80. 24 Grangeia A, Carvalho F, Fernandes S, Silva J, Sousa M et al. A novel missense mutation P1290S at exon-20 of the CFTR gene in a Portuguese patient with congenital bilateral absence of the vas deferens. Login to comment

PMID: 15705389 [PubMed] Grangeia A et al: "A novel missense mutation P1290S at exon-20 of the CFTR gene in a Portuguese patient with congenital bilateral absence of the vas deferens."

No. Sentence Comment

0 A novel missense mutation P1290S at exon-20 of the CFTR gene in a Portuguese patient with congenital bilateral absence of the vas deferens Ana Grangeia, B.Sc.,a Filipa Carvalho, Ph.D.,a Susana Fernandes, Ph.D.,a Joaquina Silva, M.D.,b Mário Sousa, M.D., Ph.D.,a,b,c and Alberto Barros, M.D., Ph.D.a,b a Department of Genetics, Faculty of Medicine, University of Porto; b Centre for Reproductive Genetics Alberto Barros; and c Lab Cell Biology, ICBAS, University of Porto, Porto, Portugal Objective: To report a novel cystic fibrosis transmembrane conductance regulator (CFTR) gene missense mutation in a compound heterozygote with congenital bilateral absence of the vas deferens (CBAVD). Login to comment
7 Result(s): The DNA analysis revealed a 7T/7T homozygote at IVS8-T, with a 4000C3T change (P1290S) in exon 20 of the CFTR gene, which was inherited from the patient`s father. Login to comment
9 Conclusion(s): The novel P1290S missense CFTR mutation causes an amino acid change in a highly conserved region of the CFTR protein that controls channel opening. Login to comment
58 Analysis of exon 20 in the patient revealed a novel missense mutation, with a C to T nucleotide change at position 4000 (P1290S mutation) that leads to substitution of a proline by a serine in the CFTR protein (Fig. 1A, B). Login to comment
60 Restriction analysis was thus used to screen and confirm the P1290S mutation as well as reveal that it was inherited from the father and not from the mother (see Fig. 1C). Login to comment
61 To rule out the possibility of P1290S being a polymorphism, we analyzed 218 normal chromosomes from 109 fertile and healthy Portuguese males, 64 chromosomes from 32 patients with obstructive azoospermia due to congenital absence of the vas deferens (some of them with CFTR mutations identified), 30 chromosomes from 15 children carrying one CFTR mutation, and 10 chromosomes from five patients with confirmed CF (two CFTR mutations detected). Login to comment
62 In all cases, absence of the P1290S mutation was confirmed as no C3T was found at position 4000 of exon 20 in the CFTR gene. Login to comment
64 DISCUSSION Direct sequencing and DGGE in a CBAVD heterozygote patient for the 3272-26A3G mutation identified a novel P1290S CFTR mutation. Login to comment
68 Several lines of evidence suggest that the present P1290S missense CFTR mutation might be pathogenic. Login to comment
71 Third, and although the isolated P1290S mutation had no substantial effect per se (the patient`s father is healthy and fertile), when associated with a mild CFTR mutation (P1290S/3272-26A3G) it caused a CBAVD phenotype in the present patient. Login to comment
74 These data thus support the present findings, where the novel P1290S CFTR mutation was diagnosed at the age of 46 in an infertile CBAVD patient who had no clinical CF phenotype. Login to comment
84 Novel P1290S CFTR mutation in CBAVD. Login to comment
87 Novel P1290S CFTR mutation in CBAVD Vol. 83, No. Login to comment