ABCMdb

PMID: 7689896

Morral N, Nunes V, Casals T, Chillon M, Gimenez J, Bertranpetit J, Estivill X
Microsatellite haplotypes for cystic fibrosis: mutation frameworks and evolutionary tracers.
Hum Mol Genet. 1993 Jul;2(7):1015-22., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* The number of haplotype changes seen for two other common mutations, G542X (haplotype 23-33-13) and N1303K (23 - 31 -13), suggests that they originated at least 35,000 years ago. Login to comment 7 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Microsatellite allele variability associated with AF508, G542X and N1303K demonstrates that slippage and mispairing is the main mechanism generating microsatellite alleles. Login to comment 9 ABCC7 p.Gly551Asp Mutations 1609delCA, 3667del4, A1507 and G551D are all associated with haplotype 1 6 - 7 - 1 7 , which has a frequency of 14.5% in normal chromosomes. Login to comment 11 ABCC7 p.Glu92Lys Haplotype 1 6 - 4 6 - 1 3 is strongly associated with CF mutations E92K and 3601 -111G-C. Login to comment 19 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Gly542* Only 4 non-AF508 mutations (G542X, G551D, W1282X and N13O3K) are present in most geographical and ethnic subgroups with frequencies higher than 1% each, but with considerable variation (5-8). Login to comment 32 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* Only 5 mutations have frequencies of more than 1 % in the sample of chromosomes analysed (AF508, G542X, N1303K, 3601-111G-C, and R1162X), accounting for a total of 63.8% of CF chromosomes; 17 mutations have frequencies of less than 1% each, accounting for 5.4% of CF chromosomes; and 271 chromosomes (30.8%) have as yet uncharacterized mutations (Table 1 and Figure 1). Login to comment 49 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg334Trp ABCC7 p.Arg1162* ABCC7 p.Ile148Thr ABCC7 p.Arg1158* ABCC7 p.Ala120Thr ABCC7 p.Glu92Lys Mutations I148T A120T E92K 621+1G->T R334W 1078delT CFSOKBdeUM G551D G54 AJ507 lDuIKJt AF5O8 2X If*A Iv 1OA 28691m '10X }f)a\OA (G 3601-111G->C R1162X 3860)ns31 R1158X 3€€7deM I W1282X 141303K | | 1 2 3 Exons Markers 6 7 8 8 • b 10 11 12 13 14 15 • t> 16 17 18 19 20 21 22 23 24 IVS8CA IVS17BTA / IVS17BCA Figure 1. Login to comment 58 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg334Trp ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ile148Thr ABCC7 p.Arg1158* ABCC7 p.Ala120Thr ABCC7 p.Lys710* ABCC7 p.Glu92Lys CF mutations identified in the Spanish population Mutation AF5O8 G542X N13O3K 36O1-111G-C R1162X 1609delCA 2869insG W1282X AI507 G551D 1949del84 CF50KBdel tt 1 K710X 621 + 1G-T R334W 1078delT E92K 3667deM R1158X A120T I148T 386Oins31 Unknown Total N 437 73 18 18 14 8 6 6 5 4 3 3 3 2 2 1 1 1 1 1 1 1 271 880 % 49.7 8.3 2.1 2.1 1.6 0.9 0.7 0.7 0.6 0.5 0.3 0.3 0.3 0.2 0.2 0. Login to comment 79 ABCC7 p.Gly542* CFTR microsateDite haplotypes for me three most common CF mutations (AF508, G542X and N13O3K) 16 16 16 16 16 16 16 16 16 17 16 16 16 16 17 23 23 23 4: 3: 30 31 32 29 33 25 35 28 31 31 46 44 45 7 7 33 30 31 18 35 13; 17 49 11: 13 13 13 13 13 13 13 13 14 13 13 13 13 17 17 13 13 13 A A B C 17 52 11: 16 34 83 52 37 26 12 12 11 7 7 6 16 10 6 75 15 12 6 6 16.0 10.0 7.1 5.0 2.3 2.3 2.1 1.3 1.3 1.1 3.0 1.9 1.1 14.5 2.8 2.3 1.1 1.1 15 7 17; 23 7 17; 23 22 17. Login to comment 83 ABCC7 p.Gly542* Haplotypes 8CA 17BTA 17BCA Mutation NCF Chromosomes %CF %Normal 23 23 23 22 24 23 17 17 17 17 18 16 16 16 16 21 23 23 23 23 23 17 16 23 22 24 24 23 31 32 30 31 31 31 32 31 33 41 32 31 30 31 7 7 33 32 34 31 37 33 32 31 31 31 32 30 13 13 13 13 13 14 13 13 13 13 13 13 13 14 17 17 13 13 13 13 13 13 13 13 13 13 13 13 AF5O8 (49.7) Total G542X (8.396) Total N13O3K (2.1%) Total 106 2 2 2 2 1 34 29 2 3 1 1 1 1 1 2 190 36 18 4 1 1 1 1 62 10 3 2 1 1 17 55.7 1.1 1.1 1.1 1.1 0.5 17.9 15.3 1.1 1.5 0.5 0.5 0.5 0.5 0.5 1.1 100.0 58.0 29.0 6.5 1.6 1.6 1.6 1.6 100.0 58.8 17.6 11.8 5.9 5.9 100.0 1.1 0.4 1.1 - 0.2 - - 1.1 0.2 - - 10.0 16.0 1.3 14.5 0.2 31.4 2.3 0.4 0.6 1.1 - 0.2 7.1 11.7 1.1 - 0.2 0.2 1.1 2.6 N CF, number of CF chromosomes; CF, cystic fibrosis; (), frequency of CF mutations. Login to comment 103 ABCC7 p.Gly542* The three most common CF mutations are associated with the same haplotype subgroup About 90% of G542X chromosomes are associated with haplotypes 23-33-13 or 23-32-13, which account for 2.3% and 0.4% of normal chromosomes, respectively. Login to comment 104 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Haplotype distribution for each allelic system and the haplotype frequency G542X N1303K Figure 3. Login to comment 105 ABCC7 p.Gly542* Parsimonious tree of evolution for haplotypes carrying mutations AF5O8, G542X and N13O3K. Login to comment 112 ABCC7 p.Gly542* The most parsimonious tree for G542X would suggest a hypothetical haplotype 17-32-13 or 16-33-13, which would explain haplotype 17-33-13. Login to comment 113 ABCC7 p.Gly542* However, these haplotypes probably each derive independently from the most common G542X haplotypes 23-33-13 and 23-32 - 13, respectively. Login to comment 115 ABCC7 p.Gly542* show that G542X originally arose with allele 23 for the IVS8CA locus, and 13 for the IVS17BCA. Login to comment 116 ABCC7 p.Gly542* IVS17BTA alleles 32 and 33 are found in two haplotypes each; the highfrequencyof haplotype 23-33-13 makes it most likely that this haplotype is the original wherein G542X arose. Login to comment 117 ABCC7 p.Gly542* Haplotypes 16-32-13 or 17-33-13 could be derived independently from the two most common G542X haplotypes by a deletion of 6 and 7 dinucleotides respectively at the IVS8 locus (Table 3 and Figure 3). Login to comment 118 ABCC7 p.Asn1303Lys Analysis of haplotypes for the N1303K mutation shows that this mutation arose in haplotype 23-31 - 13 (Table 3 and Figure 3). Login to comment 120 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* The only difference between haplotype 23-31 -13 (AF508 and N1303K) and 23-33-13 (G542X) is two TA repeats at the IVS17BTA locus. Login to comment 124 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Age of mutations AF508, G542X and N1303K The current knowledge on mutations generating new alleles at microsatellite loci suggests a mutation rate of about 1 x 10~4 (ref. 26). Login to comment 131 ABCC7 p.Gly542* ABCC7 p.Gly542* For the G542X chromosomes the mean number of mutations of the three microsatellites, according to the reconstructed tree (Figure 3), is 0.451, representing about 1,350 generations or 34,000 years as the minimum age of G542X. Login to comment 132 ABCC7 p.Gly542* For N13O3K there are 17 chromosomes that would give a result very similar to that of G542X (at least 35,000 years), which, nonetheless, must be considered with caution because of the low sample size. Login to comment 135 ABCC7 p.Gly551Asp Mutations 1609delCA, 3667del4, AI507 and G551D are all associated with haplotype 16-7-17, which has a frequency of 14.5% in normal chromosomes and of 10.6% in the as yet unknown CF mutation chromosomes. Login to comment 138 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg334Trp ABCC7 p.Arg1162* ABCC7 p.Ile148Thr ABCC7 p.Ala120Thr ABCC7 p.Lys710* ABCC7 p.Glu92Lys CFTR mjcrosatellhe haplotypes for 19 CF mutations Haplotypes 8CA 16 17 23 14 16 17 16 16 16 17 17 16 21 22 17BTA 7 7 7 31 31 31 44 43 46 45 46 - 31 30 17BCA 17 17 17 13 13 13 13 13 13 13 13 - 13 13 Mutation 1609delCA (0.9) AI507 (0.6) G551D (0.5) 3667del4 (0.1) W1282X (0.7) R1158X(0.1) I148T (0.1) 1949del84 (0.3) K710X (0.3) 1078ddT (0.1) R1162X (1.6) 2869insG (0.7) 3601-111G-C (2.1) E92K (0.1) 3860ins31 (0.1) R334W (0.2) CF50KBdel#l (0.3) Chromosomes CF Number 8 5 4 1 5 1 1 3 2 1 7 5 1 18 1 1 2 3 621 + 1G-T (0.2)1 A120T (0.1) 1 % Normal 14.5 2.9 0.6 - 10.0 1.1 1.9 - 3.0 - 0.2 - 0.4 - CF cystic fibrosis; ( ) frequency of mutation in the population. Login to comment 140 ABCC7 p.Glu92Lys In the initial analysis only one mutation (E92K) was found associated with haplotype 16-46-13, yet 18 other CF chromosomes have this haplotype (representing about 9% of CF chromosomes with unknown mutations), which is present injust 3% of normal chromosomes. Login to comment 142 ABCC7 p.Asn1303Lys 3601 -111G-C is a possible splicing mutation accounting for about 2% of CF chromosomes and may have a recent origin as compared to N1303K, for which a similar number of chromosomes were analysed (M.Chilldn, unpublished). Login to comment 180 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* The variability observed for G542X and N1303K haplotypes also suggests an ancient origin of, more than 35,000 years ago, for these two mutations. Login to comment 187 ABCC7 p.Trp1282* Other mutations which are also relatively common (3601 -111G-C, 1609delCA, Rl 162X, W1282X, and AI5O7) were always found associated with the same respective haplotype, which suggests that they have arisen quite recently in the population. This association allows us to use microsatellite haplotypes as frameworks for mutation analysis in populations with a high level of mutation heterogeneity. Login to comment 188 ABCC7 p.Trp1282* ABCC7 p.Gly542* Therefore, mutation analysis can be performed, firstly by screening only for the most common mutations (i.e. AF508 and G542X, in the case of the Spanish population); then, having the microsatellite haplotypes allows us to conduct a specific search for known mutations pertaining to each framework (i.e. 17-7-17 with mutations W1282X or Rl 158X, 14-31 -13 with 1949del84, etc); finally, the negative cases are analysed by searching for the unknown molecular defects. Login to comment 200 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg334Trp ABCC7 p.Arg1162* ABCC7 p.Arg1158* ABCC7 p.Glu92Lys Several mutations were analysed by digestion with restriction enzymes: R1162X/£WeI, 1609delCA/£WeI, N13O3K/D<ieI, KllOX/Xmnl, 3667del4/AfariI, R1158X/§SJNI, G551D/tfincII, W1282X/M/iII, 2869insG/AftoI, 3601-lllG-C/Afa«III, E92K/£coNI, R334W/AftpI and 621 + 1G-T/Miefl. Login to comment 201 ABCC7 p.Gly542* G542X was analysed by restriction site-generation PCR and digestion with ScrFl (36). Login to comment 202 ABCC7 p.Ile148Thr ABCC7 p.Ala120Thr Mutations I148T, A120T, and 1078deIT were analysed by SSCP analysis. Login to comment 213 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* As at the departure point the mutations AF508, G542X and N1303K occurred each in a single haplotype, all the mutations at the microsatellite loci have accumulated in the genealogy. Login to comment