ABCMdb

PMID: 7520797

Cuppens H, Teng H, Raeymaekers P, De Boeck C, Cassiman JJ
CFTR haplotype backgrounds on normal and mutant CFTR genes.
Hum Mol Genet. 1994 Apr;3(4):607-14., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* With exception of the D7S8 locus, the three most common mutations, AF508, G542X and N1303K, were found on an identical haplotype background. Login to comment 6 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* However, the G542X and N1303K mutations, which have been estimated to be at least 35000 years old, were found to be associated with a single allele at the D7S8 locus. Login to comment 34 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Ser1251Asn ABCC7 p.Ser1251Asn ABCC7 p.Ser1251Asn ABCC7 p.Ser1251Asn ABCC7 p.Ser1251Asn ABCC7 p.Ser1251Asn ABCC7 p.Ser1251Asn ABCC7 p.Ser1251Asn ABCC7 p.Ser1251Asn ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg ABCC7 p.Tyr1092* ABCC7 p.Tyr1092* ABCC7 p.Tyr1092* ABCC7 p.Tyr1092* ABCC7 p.Tyr1092* ABCC7 p.Tyr1092* ABCC7 p.Tyr1092* ABCC7 p.Tyr1092* ABCC7 p.Tyr1092* ABCC7 p.Trp401* ABCC7 p.Trp401* ABCC7 p.Trp401* ABCC7 p.Trp401* ABCC7 p.Trp401* ABCC7 p.Trp401* ABCC7 p.Trp401* ABCC7 p.Trp401* ABCC7 p.Trp401* ABCC7 p.Gly970Arg ABCC7 p.Gly970Arg ABCC7 p.Gly970Arg ABCC7 p.Gly970Arg ABCC7 p.Gly970Arg ABCC7 p.Gly970Arg ABCC7 p.Gly970Arg ABCC7 p.Gly970Arg ABCC7 p.Gly970Arg ABCC7 p.Ile336Lys ABCC7 p.Ile336Lys ABCC7 p.Ile336Lys ABCC7 p.Ile336Lys ABCC7 p.Ile336Lys ABCC7 p.Glu60* ABCC7 p.Glu60* ABCC7 p.Glu60* ABCC7 p.Glu60* ABCC7 p.Glu60* ABCC7 p.Glu60* ABCC7 p.Glu60* ABCC7 p.Glu60* ABCC7 p.Glu60* ABCC7 p.Trp1310* ABCC7 p.Trp1310* ABCC7 p.Trp1310* ABCC7 p.Trp1310* ABCC7 p.Trp1310* ABCC7 p.Trp1310* ABCC7 p.Trp1310* ABCC7 p.Trp1310* ABCC7 p.Trp1310* ABCC7 p.Gly458Val ABCC7 p.Gly458Val ABCC7 p.Gly458Val ABCC7 p.Gly458Val ABCC7 p.Gly458Val ABCC7 p.Gly458Val ABCC7 p.Gly458Val ABCC7 p.Gly458Val ABCC7 p.Gly458Val ABCC7 p.Glu730* ABCC7 p.Glu730* ABCC7 p.Glu730* ABCC7 p.Glu730* ABCC7 p.Glu730* ABCC7 p.Glu730* ABCC7 p.Glu730* ABCC7 p.Glu730* Distribution of alleles at 10 polymorphic loci Locus Allele Normal Mutant Mutations XV2c KM19 D9 1 2 1 2 1 2 58 (0.492) 60 (0.508) 84 (0.622) 51 (0.378) 78 (0.586) 55 (0.414) 146 (0.918) 13 (0.082) 19(0.109) 156 (0.891) 15 (0.085) 161 (0.915) 1001 + llC/T Tn 115 (0.927) R 9 (0.073) 5 7 (0.057) 7 102 (0.836) 9 13 (0.107) M470V C 62 (0.496) R 63 (0.504) 1898+15 2T/A C 84(0.641) R 47 (0.359) T854T Q1463Q D7S8 C 82 (0.636) R 47 (0.364) C 90 (0.692) R 40 (0.308) 1 38 (0.317) 2 82 (0.683) 33 (0.192) 139 (0.808) 0 (0.000) 32 (0.190) 136 (0.810) 156 (0.902) 17 (0.098) 163 (0.926) 13 (0.074) 162 (0.926) 13 (0.074) 162 (0.931) 12 (0.069) 91 (0.569) 69 (0.431) E60X, 622-2A-C, A455E, AF508 (98.3%), 1717-1G-A, G542X, 0.479 63.54 G628R(G-C)/S1235R,2183AA-G, G970R, W1282X, N1303K p<10~ G458V, AI5O7, AF508 (1.7%), 1898 + 1G-C, E73OX, 3272-26A-G, W1310X, 4218insT, UA, UB, UC I336K, W401X, 2T2ldelll, Y1092X, 3659delC, S1251N: not included (5%) E60X, 622-2A-C, W401X, G458V, AF5O8 (1.6%), 1898+ 1G-C, -0.541 90.63 G628R(G-Q/S1235R, E730X, G970R, 3272-26A-G (50.0%), p<10" Y1092X, 3659delC, S1251N, W1310X, UB, UTC A455E, AI507, AF5O8 (98.4%), 1717- 1G-A, G542X, 2183AA-G, 3272-26A-G (50.0%), W1282X, N13O3K, 4218insT, UA 1336K, 2721delU: not included (1%) E60X, 622-2A-C, W401X, G458V, 1898 +1G-C, E730X, G970R, -0.541 90.46 Y1092X, 3659delC, S1251N, W1310X, UB, UC p<10" A455E, AI507, AF508, 1717- 1G-A, G542X, G628R(G-Q/S1235R, 2183AA-G, 3272-26A-G, W1282X, N13O3K, 4218insT, UA I336K, 2721delll: not included (1%) E60X, 622-2A-C, I336K, W401X, G458V, AI507, 1717- 1G-A, -0.726 155.94 1898 + 1G-C, G628R(G-C)/S1235R, 2183AA-G, E730X, 2721delll, p< 10" G970R, 3272-26A-G, Y1092X, 3659delC, S1251N, W1282X, W1310X, 4218insT, UA, UB, UC A455E, AF5O8, G542X, N13O3K E60X, 622-2A-C, I336K, W401X, G458V, AI507, 1717-1G-A, 1898 + 1G-C, G628R(G-C)/S1235R, 2183AA-G, E730X, 2721delll, G970R, 3272-26A-G, Y1092X, 3659delC, S1251N, W1282X, W1310X, 4218insT, UA, UB, UC A455E, AF5O8, G542X, N13O3K A455E, AI5O7, AF508, 1717-1G-A, G542X, G628R(G-Q/S1235R, 2183AA-G, 3272-26A-G, W1282X, N13O3K, 4218insT, UA E60X, 622-2A-C, W401X, G458V, 1898 + 1G-C, E730X, G970R, Y1092X, 3659delC, S1251N, W1310X, UB, UC 1336K, midclll: not included (1%) E60X, 622-2A-C, W401X, A455E, G458V, AF508 (99.2%), G542X, 1898 + 1G-C, 2183AA-G, E730X, G970R, Y1092X, 3659delC, S1251N, N1303K, W1310X, UB, UC AI507, AF5O8 (0.8%), 1717-1G-A, G628R(G-Q/S1235R, 3272-26A-G, W1282X, 4218insT, UA I336K, 2721delU: not included (1%) E60X, 622-2A-C, W401X, A455E, G458V, AF508 (99.2%), G542X, 1898+1G-C, 2183AA-G, E730X, G970R, Y1092X, 3659delC,S1251N, N13O3K, W1310X, UB, UC AI507, AF508 (0.8%), 1717-1G-A, G628R(G-C)/S1235R, 3272-26A-G, W1282X, 4218insT, UA 1336K, midelll: not included (1%) E60X, 622-2A-C, W401X, A455E, G458V, AF5O8 (99.2%), G542X, G628R(G-Q/S1235R, 2183AA-G, E730X, G970R, Y1092X, 3659delC, S1251N,N1303K, W1310X, UC AI507, AF5O8 (0.8%), 1717-1G-A, 1898 + 1G-C, 3272-26A-G, W1282X, 4218insT 1336K, 2721del11. Login to comment 35 ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Gly542* ABCC7 p.Ser1251Asn ABCC7 p.Ser1235Arg ABCC7 p.Tyr1092* ABCC7 p.Trp401* ABCC7 p.Gly970Arg ABCC7 p.Glu60* ABCC7 p.Trp1310* ABCC7 p.Gly458Val ABCC7 p.Glu730* UA, UB: not included (2%) A455E, AF508 (61.2%), 1717-1G-A (66.7%), G542X, G628R(G-C)/S1235R, 3272-26A-G, S1251N, W1282X, W1310X E60X, 622-2A-C, W401X, G458V, AJ507, AF5O8 (38.8%), 1717- 1G-A (33.3%), 1898 +1G-C, 2183AA-G, E730X, G970R, Y1092X, 3659delC, N13O3K, 4218insT, UA, UB, UC 1336K, 2721delll: not included (1%) -0.694 139.81 p<10~ 0.452 60.83 p<10" 0.355 38.77 p<10" 0.360 39.44 p<10~7 0.314 29.91 0.250 17.54 p<10"4 The observed CFTR genes associated with a particular allele are given, proportions are given between brackets. Not all the mutations were informative for each of the tested loci, which were therefore not included. For the Tn locus the standardized linkage disequilibrium coefficient was calculated for the group of the non-T9 alleles and the T9 alleles. Login to comment 37 ABCC7 p.Gly542* Standardized linkage disequilibrium coefficient at ten polymorphic loci for all mutant CFTR genes and for individual AF5O8, G542X and N13O3K CFTR genes. Login to comment 45 ABCC7 p.Gly542* At the D7S8 locus, a higher value of A was found for G542X CFTR genes than for AF508 CFTR genes. Login to comment 46 ABCC7 p.Gly542* All G542X CFTR genes (9 genes studied) were associated with allele 1, while only about 60% of AF508 CFTR genes (116 genes studied) were associated with this allele. Login to comment 47 ABCC7 p.Asn1303Lys The 5 studied N1303K CFTR genes were associated with allele 2, which resulted in a A value of opposite sign. Login to comment 59 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* These mutations are also the most common mutations worldwide, such as the G542X, "N1303K, 1717- 1G-A and W1282X mutations. Login to comment 72 ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Gly542* ABCC7 p.Ser1235Arg ABCC7 p.Gly970Arg ABCC7 p.Glu60* ABCC7 p.Trp1310* ABCC7 p.Gly458Val Extragenic (XV2c/KM19/D9) haplotypes Haplotype Normal Mutant Mutations 111 211 121 112 212 122 222 23 (0.204) 43 (0.381) 2 (0.018) 6 (0.053) 0 (0.000) 22 (0.195) 17 (0.150) 4 (0.026) E60X, 622-2A-C, G970R 6 (0.039) G458V, 1898+1G-C, E73OX, W1310X, UB, UC 0 (0.000) 3 (0.019) AF5O8 (1.7%), G628R(G-Q/S1235R 1 (0.006) 3272-26A-G (50.0%) 134 (0.870) A455E, AF508 (96.5%), 1717-1G-A, G542X, 2183AA-G, W1282X, N13O3K 6 (0.039) AI507, AF508 (1.8%), 3272-26A-G (50.0%), 4218insT, UA p<10"3 p<10"7 p<10~7 p<10"2 The observed CFTR genes associated with a particular haplotype are given, proportions are given between brackets. Login to comment 73 ABCC7 p.Ser1251Asn ABCC7 p.Tyr1092* ABCC7 p.Trp401* ABCC7 p.Ile336Lys The I336K, W401X, 2721delll, Y1092X, 3659delC and S1251N mutations, contributing for 5% of all mutant CFTR genes, are not included. Login to comment 84 ABCC7 p.Trp1282* The 875+40A-G mutation was found on the W1282X chromosome. Login to comment 95 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* With the exception of the D7S8 locus, the three most common mutations AF508, G542X, and N1303K shared the same haplotype background. Login to comment 96 ABCC7 p.Trp1282* The 1717-1G-A and W1282X mutations shared the same haplotype at the centromeric site of the CFTR gene, but differed in the intragenic regions of the CFTR gene, except for the M470V locus. Login to comment 99 ABCC7 p.Ser1235Arg Other mutations found to be associated with haplotype backgrounds not present among normal CFTR genes were the G628R(G-C)/S1235R and the 2183AA -G mutations. Login to comment 103 ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Ser1251Asn ABCC7 p.Ser1235Arg ABCC7 p.Tyr1092* ABCC7 p.Trp401* ABCC7 p.Gly970Arg ABCC7 p.Glu60* ABCC7 p.Trp1310* ABCC7 p.Gly458Val ABCC7 p.Glu730* CFTR haplocypes I II ma mb rv V VI Haplotype C7RCCC 211C7RCCC1 111C7RCCC1 /11C7RCCC1 211C7RCCC2 111C7RCCC2 /11C7RCCC2 122C7RCCC2 121C7RCCC2 C5CRRR 122C5CRRR1 211C5CRRR2 222C5CRRR2 C7CRRR 122C7CRRR1 222C7CRRR1 212C7CRRR1 122C7CRRR2 222C7CRRR2 122C7CRRR/ C9CRRR 211C9CRRR1 R9CCCC 122R9CCCC1 222R9CCCC1 /22R9CCCC1 112R9CCCC1 122R9CCCC2 222R9CCCC2 112R9CCCC2 R9CRRR 122R9CRRR1 C7CRRC 112C7CRRC1 112C7CRRC2 C9CRRC 211C9CRRC1 C7CCCC 211C7CCCC1 222C7CCCC1 122C7CCCC2 C7RCCR 211C7RCCR2 Normal 0.524 (43) 0.085 0.073 0.195 0.146 0.012 0.012 0.049 (4) 0.012 0.024 0.012 0.220 (18) 0.024 0.073 0.000 0.073 0.049 0.012 (1) 0.012 0.073 (6) 0.000 0.000 0.000 0.061 0.012 0.000 0.000 (0) 0.000 0.061 (5) 0.000 0.061 0.012 (1) 0.012 0.037 (3) 0.012 0.024 0.000 0.012 (1) 0.012 Mutant 0.080 (IS) 0.005 0.000 0.020 0.015 0.020 0.020 0.000 0.000 0.000 (0) 0.000 0.000 0.000 Mutations p<10"7 W1310X S1251N G458V, E730X, UC E60X, 622-2A-C, G970R W401X, Y1092X, 3659delC 0.055 (9) p<10"2 0.017 0.005 0.005 0.008 0.010 0.010 0.000 (0) 0.000 1717-1G-A (66.7%) 50.0% of 3272-26A-G 50.0% of 3272-26A-G 1717-1G-A(33.3%) AI507, 4218insT W1282X 0.819 (130) p<10~7 0.466 0.007 0.010 0.007 0.312 0.007 0.007 0.005 (1) 0.005 0.005 (1) 0.005 0.000 0.000 (0) 0.000 0.010 (2) 0.000 0.000 0.010 0.005 (1) 0.005 56.7% of AF508, G542X 1% of AF5O8 A455E 1% of AF5O8 38.1% of AF508, N1303K 1.0% of AF5O8 1% of AF508 1% of AF508 G628R(G-Q/S1235R 2183AA-G 1898+1G-C The proportion of CFTR genes associated with a particular haplotype, and the mutations found to be associated with that haplotype are given. Login to comment 104 ABCC7 p.Asp36Lys The D36K, 2721delll, UA and UB mutations, contributing for 2% of all mutant CFTR genes, were not included. Login to comment 123 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* The three most common CFTR mutations share a similar haplotype background The 3 most common mutations, AF5O8, G542X, N1303K, shared a very similar haplotype background. Login to comment 127 ABCC7 p.Gly542* A complete association of allele 1 with G542X CFTR genes (Fisher Exact Test, p < 10~4 ) was found. Login to comment 128 ABCC7 p.Gly542* Given the facts that the Q1463Q and D7S8 loci are in linkage equilibrium (ANorma] = -0.032, AMua« = -0.018) and that the G542X mutation has been estimated to be at least 35000 years old (16), this complete association is surprising. Login to comment 131 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Absence of recombination between the Q1463Q and D7S8 loci was also observed among particular normal CFTR genes: no normal CFTR genes having haplotype background Ilia (haplotype background ma was associated with the AF508, G542X and N1303K mutations), and certain genes with haplotype background IV (Table 4), carried allele 1 at the D7S8 locus. Login to comment 134 ABCC7 p.Ala455Glu The 3 most frequent mutations together with the A455E mutation were associated with allele R, all other CFTR mutations were associated with allele C. Login to comment 150 ABCC7 p.Ala455Glu The 4 mutations that were also associated with the R allele at the 1001 + 11C/T locus were associated with the 9T allele, i.e. the three most common CF mutations and the A455E mutation. Login to comment 151 ABCC7 p.Ala455Glu The A455E mutation is located in exon 9 itself, in which only a limited number of mutations have been identified. Login to comment 152 ABCC7 p.Gly458Val The G458V mutation, which is also located in exon 9 of the CFTR gene, carried 7 T nucleotides in its poly-T tract. Login to comment 153 ABCC7 p.Ala455Glu ABCC7 p.Gly458Val A major difference between these two mutations is that G458V is considered as a severe mutation (23), while A455E is known as a mild mutation with regard to pancreatic involvement (10). Login to comment 155 ABCC7 p.Arg117His The R117H mutation can result in either a CF or a CBAVD (congenital bilateral absence of the vas deferens) mutant CFTR gene, depending on the allele present at the Tn locus. Login to comment 162 ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg Of the two missense mutations allele, G628R(G-Q and S1235R, S1235R is located in the second nucleotide binding fold. Login to comment 164 ABCC7 p.Ser1251Asn ABCC7 p.Phe508Cys However the S1251N mutation is associated with the F508C polymorphism which is, like M470V, located in exon 10 of the CFTR gene (5). Login to comment 180 ABCC7 p.Trp1282* These conclusions were drawn from the observation that of the 7 studied mutations that shared the same haplotype background at the centromeric region of the CFTR gene, 2 of them, 1717- 1G- A and W1282X, shared a different intragenic haplotype. Login to comment 181 ABCC7 p.Trp1282* We also found here that of the mutations that shared haplotype background 122 (XV2c/KM19/D9), the 1717- 1G-A, 2183AA-G and W1282X CFTR genes did not share identical alleles at several intragenic polymorphic loci. Login to comment 184 ABCC7 p.Trp1282* In fact, within the group of 122 (XV2c/KM19/D9) mutant CFTR genes, of all 6 intragenic polymorphic loci tested, this was the only common allele that was even shared by the 1717- 1G-A and W1282X mutant CFTR genes. Login to comment