ABCMdb

PMID: 10923036

Claustres M, Guittard C, Bozon D, Chevalier F, Verlingue C, Ferec C, Girodon E, Cazeneuve C, Bienvenu T, Lalau G, Dumur V, Feldmann D, Bieth E, Blayau M, Clavel C, Creveaux I, Malinge MC, Monnier N, Malzac P, Mittre H, Chomel JC, Bonnefont JP, Iron A, Chery M, Georges MD
Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France.
Hum Mutat. 2000;16(2):143-56., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* The most common were F508del (67.18%; range 61-80), G542X (2.86%; range 1-6.7%), N1303K (2.10%; range 0.75-4.6%), and 1717-1G>A (1.31%; range 0-2.8%). Login to comment 32 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Analysis of more than 43,000 CF chromosomes from different continents has shown that only five mutations have relative world frequencies higher than 1% [F508del (66%), G542X (2.4%), G551D (1.6%), N1303K (1.3%), and W1282X (1.2%)] [The Cystic Fibrosis Genetic Analysis Consortium, 1994]. Login to comment 49 ABCC7 p.Gly1069Arg ABCC7 p.Arg117Gly Nine additional patients who reported with renal malformations, including two heterozygotes for G1069R and R117G, respectively, were excluded from the calculations. Login to comment 66 ABCC7 p.Arg75Gln ABCC7 p.Phe508Cys ABCC7 p.Gly576Ala ABCC7 p.Arg31Cys ABCC7 p.Arg1162Leu Five sequence changes (R31C, R75Q, F508C, G576A, R1162L) were reported as ''mutations`` in the forms; however, they are listed as ''polymorphisms`` in the CFGAC (designed respectively as 223C/T, 356G/A, 1655T/G, 1859G/ C, and 3617G>T). Login to comment 67 ABCC7 p.Ser1235Arg Ten mutations were reported as ''complex alleles`` (two sequence alterations associated in cis on the same gene): W57X+F87L, R117H+5T, R117H+I1027T, F508del+L467F, I507del+F508C, 1898+3A>G+186-13C>G, Y1092X+S1235R, 3732delA+K1200E, S1235R +5T, and D1270N+R74W. Login to comment 68 ABCC7 p.Phe508Cys ABCC7 p.Ile1027Thr ABCC7 p.Leu467Phe However, at least three of these changes are listed as neutral polymorphisms in the CFGAC: L467F (1531C/T), F508C (1655T/G), and I1027T (3212T/C). Login to comment 74 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Only three other mutations had relative frequencies ≥1%, G542X (2.86%), N1303K (2.10%), 1717-1G>A (1.31%). Login to comment 80 ABCC7 p.Gly542* A trend of decreasing frequency of F508del from Northwest (70%) to Southeast (61%) was generally observed; the second most common mutation was G542X in the Southwest (6.7%) or in the South (5.6%), whereas it was I507del in Normandy (2.7%). Login to comment 81 ABCC7 p.Arg553* Some mutations such as 394delTT (1.61%), R553X (2.15%), or 2789+ 5G>A (2.87%) were more frequent in the North. Login to comment 84 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* The most common mutations in this group were F508del (31.01%), 711+1G>T (11.39%), W1282X (6.33%), N1303K (5.7%), G542X (5.06%), and R1162X (3.8%), a distribution which seems different from the global French population. Login to comment 88 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Five genotypes are responsible for 57.31% of cases of CF in France: F508del/F508del (47.75 %), F508del/G542X (3.4%), F508del/N1303K (2.7%), F508del/1717-1G>A (2.02%), and F508del/2789+5G>A (1.43%). Login to comment 102 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Leu206Trp ABCC7 p.Gly85Glu ABCC7 p.Arg1066Cys ABCC7 p.Tyr1092* ABCC7 p.Trp846* Distribution of 310 CF Mutations in France With Respect to Relative Frequencies (Total Number of CF Chromosomes = 7,420) Group Mutations Number of alleles % Cum. % A F508del 4,985 67.18 G542X 212 2.86 N1303K 156 2.10 73.45 1717-1G>A 97 1.31 B G551D 73 0.98 2789+5G>A 72 0.97 W1282X 68 0.91 R553X 66 0.89 I507del 52 0.70 1078delT 49 0.66 7.47 2183AA>G 48 0.64 711+1G>T 33 0.44 R1162X 33 0.44 Y1092X 30 0.40 3849+10kbC>T 30 0.40 C 12 mutationsa 29 to 15 (239) 0.39-0.20 19 mutationsb 14 to 8 (190) 0.19-0.10 11 mutationsc 7 to 6 (71) 0.09-0.08 11 mutationsd 5 (55) 0.06 10.57 15 mutationse 4 (60) 0.05 23 mutationsf 3 (69) 0.04 50 mutationsg 2 (100) 0.02 D 154 mutationsh 1 (154) 0.01 2.07 6,942 93.56 a 3659delC, R347P, 3272-26A>G, R334W, W846X, 621+1G>T, G85E, R1066C, L206W, 394delTT, 4055+1G>A, R347H. Login to comment 103 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Ser1251Asn ABCC7 p.Ile148Thr ABCC7 p.Glu585* ABCC7 p.Gln493* ABCC7 p.Tyr122* ABCC7 p.Ser1235Arg ABCC7 p.Ser945Leu ABCC7 p.Asp1152His ABCC7 p.Lys710* ABCC7 p.Leu558Ser ABCC7 p.Glu60* ABCC7 p.Gly178Arg b 3905insT, 1811+1.6kbA>G, S945L, S1251N, Y122X, 2711delT, R117H, E60X, 2184insA, E585X, L558S, S1235R, D1152H, K710X, Q493X, A455E, G178R, I148T, 574delA. Login to comment 104 ABCC7 p.Gly1244Glu ABCC7 p.Glu831* ABCC7 p.Arg1158* ABCC7 p.Gln220* ABCC7 p.Ile1234Val ABCC7 p.Gly91Arg ABCC7 p.Glu92Lys c 4016insT, G1244E, R1158X, 3120+1G>A, 1677delTA, I1234V, E831X, 5T, Q220X, E92K, G91R. Login to comment 105 ABCC7 p.Gly149Arg ABCC7 p.Ser549Arg ABCC7 p.Gly970Arg ABCC7 p.Ser489* ABCC7 p.Trp1204* ABCC7 p.Arg1066His ABCC7 p.Ser492Phe ABCC7 p.Gln1313* d G149R, S489X, S492F, S549R, 1898+1G>A, 2622+1G>A, G970R, R1066H, W1204X, 3850-1G>A, Q1313X. Login to comment 106 ABCC7 p.Arg792* ABCC7 p.Arg75* ABCC7 p.Arg560Lys ABCC7 p.Leu165Ser ABCC7 p.His1054Asp ABCC7 p.Phe311Leu e M1V, R75X, L165S, F311L, R560K, 1898+1G>C, 1949del84, 2113delA, 2184delA, R792X, W846X2, 3121-1G>A, H1054D, 3737delA, D1270N+R74W. Login to comment 107 ABCC7 p.Pro574His ABCC7 p.Pro205Ser ABCC7 p.Ser549Asn ABCC7 p.Leu1065Pro ABCC7 p.Met1101Lys ABCC7 p.His1085Arg ABCC7 p.Arg117Cys ABCC7 p.Leu1077Pro ABCC7 p.Ile336Lys ABCC7 p.Asp836Tyr ABCC7 p.Glu827* ABCC7 p.Arg709* ABCC7 p.Trp79* ABCC7 p.Leu227Arg f 306insA, W79X, R117C, P205S, L227R, I336K, 1248+1G>A, 1609delCA, 1717-8G>A, S549R(T>G), S549N, 1812-1G>A, P574H, 2176insC, R709X, E827X, D836Y, 3007delG, L1065P, L1077P, H1085R, M1101K, 4021insT. Login to comment 108 ABCC7 p.Gly544Ser ABCC7 p.Thr338Ile ABCC7 p.Arg560Ser ABCC7 p.His199Tyr ABCC7 p.Trp401* ABCC7 p.Tyr569Asp ABCC7 p.Arg1066Leu ABCC7 p.Gln890* ABCC7 p.Val232Asp ABCC7 p.Arg1070Trp ABCC7 p.Ser1196* ABCC7 p.Arg851* ABCC7 p.Glu116Lys ABCC7 p.Asp110His ABCC7 p.Gly673* ABCC7 p.Ser977Phe ABCC7 p.Gly1061Arg ABCC7 p.Val562Ile ABCC7 p.Trp57* ABCC7 p.Gly1249Arg ABCC7 p.Ala561Glu ABCC7 p.Gln452Pro ABCC7 p.His199Arg ABCC7 p.Ile502Thr ABCC7 p.Ile175Val ABCC7 p.Leu137Arg ABCC7 p.Cys225* ABCC7 p.Glu292* ABCC7 p.Gln290* ABCC7 p.Gly314Val ABCC7 p.Asp44Gly g D44G, 300delA, W57X, 405+1G>A, D110H, E116K, 541del4, 542del7, L137R, 621+2T>G, I175V, H199R, H199Y, C225X, V232D, Q290X, E292X, G314V, T338I, 1221delCT, W401X, Q452P, I502T, 1716+2T>C, G544S, R560S, A561E, V562I, Y569D, 1898+3A>G, 1898+5G>A, G628R(G>A), 2143delT, G673X, R851X, Q890X, S977F, 3129del4, 3154delG, 3271+1G>A, G1061R, R1066L, R1070W, 3601-17T>C, S1196X, 3732delA, G1249R, 3898insC, 4374+1G>A, del25kb. Login to comment 109 ABCC7 p.Ser1255Pro ABCC7 p.Arg347Leu ABCC7 p.Arg352Gln ABCC7 p.Arg75Gln ABCC7 p.Pro67Leu ABCC7 p.Arg117Leu ABCC7 p.Asn1303His ABCC7 p.Ile1005Arg ABCC7 p.Gln39* ABCC7 p.Gly27Glu ABCC7 p.Phe508Cys ABCC7 p.Gly576Ala ABCC7 p.Arg31Cys ABCC7 p.Asp443Tyr ABCC7 p.Arg764* ABCC7 p.Arg1162Leu ABCC7 p.Tyr563Asn ABCC7 p.Trp1089* ABCC7 p.Ile506Thr ABCC7 p.Ala141Asp ABCC7 p.Asp1445Asn ABCC7 p.Cys225Arg ABCC7 p.Asp979Val ABCC7 p.Arg1283Lys ABCC7 p.Arg553Gly ABCC7 p.Ala1067Thr ABCC7 p.Arg117Pro ABCC7 p.Thr1246Ile ABCC7 p.Gly241Arg ABCC7 p.Leu206Phe ABCC7 p.Cys866Tyr ABCC7 p.Asn1303Ile ABCC7 p.Gln1238* ABCC7 p.Ser364Pro ABCC7 p.Asp993Tyr ABCC7 p.Gln98Arg ABCC7 p.Trp361Arg ABCC7 p.Lys716* ABCC7 p.Gly628Arg ABCC7 p.Gly576* ABCC7 p.Met152Val ABCC7 p.Trp1098* ABCC7 p.Phe1286Ser ABCC7 p.Val920Met ABCC7 p.Ala72Asp ABCC7 p.Tyr569Cys ABCC7 p.Trp1063* ABCC7 p.Ser466* ABCC7 p.Glu1104* ABCC7 p.Glu664* ABCC7 p.His139Arg ABCC7 p.Thr1086Ile ABCC7 p.Gln1238Arg ABCC7 p.Asp192Asn ABCC7 p.Trp216* ABCC7 p.Tyr913Cys ABCC7 p.Leu732* ABCC7 p.Arg600Gly ABCC7 p.Ser1206* ABCC7 p.Trp882* ABCC7 p.Cys491Arg ABCC7 p.Leu610Ser ABCC7 p.Lys698Arg ABCC7 p.Gln237Glu ABCC7 p.Glu292Lys ABCC7 p.Glu193* ABCC7 p.Ala559Glu ABCC7 p.His939Arg ABCC7 p.Thr501Ala ABCC7 p.Thr582Ile ABCC7 p.Ser776* ABCC7 p.Tyr569* ABCC7 p.Asn186Lys ABCC7 p.Trp19* ABCC7 p.Lys14* ABCC7 p.Tyr304* ABCC7 p.Tyr569His ABCC7 p.Gln689* ABCC7 p.Asp985His ABCC7 p.Arg1128* ABCC7 p.Gln1382* ABCC7 p.Ser434* ABCC7 p.His939Asp h M1K, K14X, W19X, 211delG, G27E, R31C, 237insA, 241delAT, Q39X, 244delTA, 296+2T>C, 297-3C>T, W57X+F87L, 306delTAGA, P67L, A72D, 347delC, R75Q, 359insT, 394delT, 405+4A>G, Q98R, 457TAT>G, R117H+5T, R117H+I1027T, R117L, R117P, H139R, A141D, M152V, N186K, D192N, D192del, E193X, 711+1G>A, 711+3A>G, 712-1G>T, L206F, W216X, C225R, Q237E, G241R, 852del22, 876-14del12, 905delG, 993del5, E292K, Y304X, F311del, 1161delC, R347L, R352Q, W361R, 1215delG, S364P, S434X, D443Y, S466X, C491R, T501A, I506T, F508C, I507del+F508C, F508del+L467F, 1774delCT, R553G, 1802delC, 1806delA, A559E, Y563N, 1833delT, Y569C, Y569H, Y569X, G576X, G576A, T582I, 1898+3A>G+186-13C>G, 1918delGC, R600G, L610S, G628R, 2043delG, 2118del4, E664X, 2174insA, Q689X, K698R, K716X, L732X, 2347delG, 2372del8, R764X, 2423delG, S776X, 2634insT, 2640delT, C866Y, 2752-1G>T, W882X, Y913C, V920M, 2896insAG, H939D, H939R, D979V, D985H, D993Y, 3120G>A, I1005R, 3195del6, 3293delA, 3320ins5, W1063X, A1067T, 3359delCT, T1086I, W1089X, Y1092X+S1235R, W1098X, E1104X, R1128X, 3532AC>GTA, 3548TCAT>G, M1140del, 3600G>A, R1162L, 3667ins4, 3732delA+K1200E, S1206X, 3791delC, S1235R+5T, Q1238R, Q1238X, 3849+4A>G, T1246I, 3869insG, S1255P, R1283K, F1286S, 4005+1G>T, 4006-8T>A, 4015delA, N1303H, N1303I, 4172delGC, 4218insT, 4326delTC, Q1382X, 4375-1C>T, 4382delA, D1445N, CF40kbdel4-10, Cfdel17b. Login to comment 113 ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Ala1067Thr Eleven mutations were reported as ''complex alleles,`` particularly in chromosomes carrying the 5T allele, although several changes (G576A, R668C, A1067T) are considered as neutral polymorphisms (CFGAC). Login to comment 115 ABCC7 p.Arg117His ABCC7 p.Asp1152His ABCC7 p.Asp443Tyr The most frequent were F508del (21.75%), the 5T allele (16.31%), and R117H (4.37%), followed by D1152H (1.19%), and D443Y (0.93%). Login to comment 119 ABCC7 p.Arg117His ABCC7 p.Arg117His Compound heterozygosity was the rule, but 10 patients were found to be homozygotes for one CFTR mutation [5T/5T (n=7), R117H/R117H (n=2), R74W+D1270N/R74W+ FIGURE 2. Geographic distribution of the most common mutations responsible for CF in 12 regions in France, as given by the area of residence of parents and/or grandparents. Login to comment 120 ABCC7 p.Asp1270Asn D1270N (n=1)]. Login to comment 124 ABCC7 p.Arg117His The most common compound heterozygous genotypes were F508del/5T (28.44%) and F508del/R117H (5.6%). Login to comment 129 ABCC7 p.Ser1235Arg ABCC7 p.Ala800Gly ABCC7 p.Ala1067Thr ABCC7 p.Thr1053Ile ABCC7 p.Gly550Arg Six sequence changes listed as mutations (CFGAC or personal communication) were detected on a chromosome carrying the 5T allele (G550R, A800G, T1053I, A1067T, S1235R, and 1717- 3T>G). Login to comment 130 ABCC7 p.Arg117His All R117H alleles whose data at locus IVS8(T)n were communicated to us were found on a 7T background. Login to comment 140 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Glu831* ABCC7 p.Arg1158* ABCC7 p.Arg560Ser ABCC7 p.Tyr1092* ABCC7 p.Ser945Leu ABCC7 p.Tyr569Asp ABCC7 p.Ile1234Val ABCC7 p.Leu1077Pro ABCC7 p.Glu92Lys ABCC7 p.Gly178Arg ABCC7 p.Val562Ile ABCC7 p.Leu227Arg ABCC7 p.Gln1313* ABCC7 p.Ile175Val ABCC7 p.Gly314Val Non-F508del Mutations Found as Homozygous in a Sample of 3,710 Patients With Cystic Fibrosis Mutation n 711+1G>T 8 G542X 7 N1303K 7 2183delAA>G 5 W1282X 4 G551D 3 3905insT 3 R334W 2 R347P 2 1078delT 2 1811+1.6kbA>G 2 2113delA 2 Y1092X 2 R1162X 2 306insA 1 E92K 1 G178R 1 L227R 1 1677delTA 1 1717-1G>A 1 1717-8G>A 1 R553X 1 S549R(T>G) 1 R560S 1 V562I 1 Y569D 1 2711delT 1 S945L 1 R1158X 1 I1234V 1 3849+10kbC>T 1 Q1313X 1 del25kb 1 E831X 1 I175V 1 G314V 1 L1077P 1 produce a small quantity of functional protein as a result of a variable proportion of normal CFTR mRNA transcripts in addition to the abnormal ones (class V); 3) they are located in sites known to generate less severe mutants (external loops, residues lining the pore); and/or 4) they have been observed in CF with pancreatic sufficiency, CBAVD, and/or CF-related attenuated phenotypes only. Login to comment 141 ABCC7 p.Pro574His ABCC7 p.Ala455Glu Some mutants are misprocessed (class II) but generate channels that retain significant activity which is sufficient to confer a milder clinical phenotype (for instance, A455E or P574H). Login to comment 143 ABCC7 p.Asn1303Ile Some mutants remained undefined because available information sources were inadequate, particularly when we found them both in severe CF and CBAVD but correlations with the genotype have not been published yet (for instance, N1303I). Login to comment 152 ABCC7 p.Ala455Glu ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Ile1027Thr ABCC7 p.Val232Asp ABCC7 p.Arg851Leu ABCC7 p.Arg1066His ABCC7 p.Ile980Lys ABCC7 p.Ala1067Thr ABCC7 p.Thr908Asn ABCC7 p.Asp110His ABCC7 p.Asn1303Ile ABCC7 p.Asp1154Gly ABCC7 p.Leu90Ser ABCC7 p.Arg117Gly ABCC7 p.His939Arg ABCC7 p.Asp1377His Twenty-four non F508del mutations were found associated with the 9T allele: 394delTT, L90S, D110H, R117G, 621+1G>T, V232D, A455E, G542X, R851L, T908N, 2789+5G>A, 2896insAG, H939R, 3007delG, I980K, I1027T, R1066H, A1067T, D1154G, 3737delA, R74W+D1270N, N1303I, N1303K, D1377H. Login to comment 153 ABCC7 p.Arg347His ABCC7 p.Leu206Trp ABCC7 p.Asp1152His Four mutations were detected on a 7T or a 9T background: L206W, R347H, D1152H, 3272-26A>G. Login to comment 158 ABCC7 p.Gly542* Distribution of Mutations Within the CFTR Gene Due to the high frequencies of F508del and G542X, 75.22% of French CF alleles were mutated in exons 10 and 11, encoding for the first nucleotide binding domain of CFTR (NBD1) or their flanking intronic sequences (Fig. 5). Login to comment 166 ABCC7 p.Gly551Asp ABCC7 p.Arg553* Considering the prevalence of some mutations in different regions, the northern part appears subdivided into at least three zones, from West to East: Brittany, colored by a Celtic settlement (G551D); Nord-Pas-de-Calais, settled by Scandinavians (394delTT); and, in the northeast, a Germanic area (R553X). Login to comment 171 ABCC7 p.Arg117His ABCC7 p.Pro574His ABCC7 p.Arg347His ABCC7 p.Arg347His ABCC7 p.Arg347His ABCC7 p.Arg347Leu ABCC7 p.Gly542* ABCC7 p.Leu206Trp ABCC7 p.Thr338Ile ABCC7 p.Ser1235Arg ABCC7 p.Asp1152His ABCC7 p.Asp443Tyr ABCC7 p.Arg117Cys ABCC7 p.Arg1070Trp ABCC7 p.Arg1066His ABCC7 p.Thr1246Ile ABCC7 p.Val920Met ABCC7 p.Tyr569Cys CFTR Mutation Genotypes Identified Both in Cystic Fibrosis (CF) and in Congenital Bilateral Absence of the Vas Deferens (CBAVD) CF CBAVD F508del/5T 3 143 F508del/2789+5G>A 53 1 F508del/3272-26A>G 17 4 F508del/R117H* 10 39 F508del/R117C 2 2 F508del/L206W 12 4 F508del/R347H 10 5 F508del/R347L 1 1 F508del/D443Y 1 5 F508del/Y569C 1 1 F508del/P574H 3 1 F508del/G628R(G>A) 2 1 F508del/V920M 1 1 F508del/R1070W 2 3 F508del/D1152H 6 8 F508del/S1235R 3 1 F508del/T1246I 1 1 F508del/D1270N+R74W 2 3 F508delN1303I 1 1 3659delC/R347H 1 1 G542X/T338I 2 2 R347H/R1066H 1 1 *The only case with CF whose alleles at IVS8(T)n were reported had mutation R117H associated with a 5T allele. Login to comment 172 ABCC7 p.Arg117His In the group of CBAVD patients, 26 were reported with a 7T allele associated with mutation R117H. Login to comment 175 ABCC7 p.Gly542* 1.6kbA>G) is markedly different from the rest of France whereas the Mediterranean coast (G542X) shows similarity between the western and eastern parts,withsomedifferencefromthecentralpart.This study demonstrates that even within one country, wide variations exist among the frequencies of spe- cificmutations.OtherEuropeancountriesshowmore substantial genetic homogeneity than France [Cuppensetal.,1993;Bonizzatoetal.,1995;Schwarz et al., 1995; Tümmler et al., 1996]. Login to comment 213 ABCC7 p.Tyr1092* Since CFTR is intrinsically a chloride channel when properly anchored in the cell membrane, its activity is best measured by patch- clampanalysisorothersimilarytediousmethodsthat are rarely used by molecular geneticists to confirm the identity of putative mutations. An example of the difficulties in defining missense mutations and polymorphismsisS1235R.Thisvariantwasoriginally describedasamutation[Cuppensetal.,1993].However, as it has been detected in a patient who also hadastopmutation(Y1092X)elsewhereinthegene (Claustresetal.,unpublishedresults),itismostlikely misclassified as a missense mutation. Login to comment 214 ABCC7 p.Ser1235Arg This observation does not excude that S1235R could be, in combination with some polymorphisms affecting splicing (such as 5T), responsible for a CF or CBAVD-related phenotype. Login to comment 215 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp Mutations D1270N and R74W have been independently reported elsewhere to be CF alleles [Anguiano et al., 1992; Claustres et al., 1993]. Login to comment