ABCMdb

PMID: 17825628

Fichou Y, Genin E, Le Marechal C, Audrezet MP, Scotet V, Ferec C
Estimating the age of CFTR mutations predominantly found in Brittany (Western France).
J Cyst Fibros. 2008 Mar;7(2):168-73. Epub 2007 Sep 6., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCC7 p.Gly551Asp ABCC7 p.Ile1027Thr The W846X2, 1078delT and G551D mutations, as well as the I1027T polymorphism in cis with the ΔF508 mutation (currently referred to as p.F508del) are particularly frequent in this area. Login to comment 16 ABCC7 p.Gly551Asp ABCC7 p.Gly542* Only four additional mutations (i.e., G542X, G551D, Journal of Cystic Fibrosis 7 (2008) 168-173 www.elsevier.com/locate/jcf ☆ Data were presented at The American Society of Human Genetics 56th Annual Meeting, New Orleans, Louisiana, USA, October 9-13, 2006. Login to comment 22 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys doi:10.1016/j.jcf.2007.07.009 W1282X and N1303K) have frequencies N1% in the CF population [5]. Login to comment 24 ABCC7 p.Gly551Asp We have been studying CFTR mutations that are preferentially observed in Brittany, western France [6]: G551D [7], 1078delT [8] and W846X2 [9] mutations, which respective frequencies are 3.7%, 3.8% and 1.1% [10-12]. Login to comment 25 ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr A haplotype we have also been interested in is the ΔF508-I1027T haplotype. Login to comment 26 ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr It consists of the cis-association of the ΔF508 mutation and the I1027T polymorphism. Login to comment 30 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Likewise, the G542X and N1303K mutations were estimated to be N34000 years old [14]. Login to comment 31 ABCC7 p.Gly551Asp In another paper, Cashman et al. [16] calculated 170 generations (N3200 years) for the G551D mutation. Login to comment 39 ABCC7 p.Gly551Asp ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr CF patients Unrelated CF patients (and relatives when available) from Brittany carrying at least one of the following mutations W846X2, 1078delT, G551D and ΔF508-I1027T were selected for the study, accounting for 13, 31, 32 and 10 families, respectively (Table 1). Login to comment 40 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr ABCC7 p.Trp846* ABCC7 p.Trp846* It should be noted that the notations ΔF508, G551D, W846X2 and I1027T should no longer be used and be replaced respectively by p.F508del, p.G551D, p.W846X and p.I1027T at the protein level; and c.1521_1523delCTT, c.1652GNA, c.2538GNA, c.3080TNC, as well as c.946delT for the 1078delT mutation at the DNA level according to the recommended nomenclature (http://www.hgvs.org/mutnomen/). Login to comment 51 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg347His ABCC7 p.Arg347His ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Tyr1092* ABCC7 p.Tyr1092* ABCC7 p.Arg117Cys ABCC7 p.Arg117Cys ABCC7 p.Tyr563Asn ABCC7 p.Tyr563Asn ABCC7 p.Arg1066His ABCC7 p.Arg1066His ABCC7 p.Arg553Gly ABCC7 p.Arg553Gly ABCC7 p.Phe311Leu ABCC7 p.Phe311Leu ABCC7 p.Trp79* ABCC7 p.Trp79* ABCC7 p.Glu60Lys ABCC7 p.Glu60Lys ABCC7 p.Leu610Ser ABCC7 p.Leu610Ser ABCC7 p.Cys225* ABCC7 p.Cys225* Primers amplifying the regions of interest were designed with PrimerQuestSM from Table 1 Genotypes of CF patients W846X2 1078delT G551D Mutation in trans Number Mutation in trans Number Mutation in trans Number ΔF508 6 ΔF508 21 ΔF508 18 R117C 1 1078delTa 2 E60K 1 ΔI507 1 4005+1GNA 2 W79X 1 Y563N 1 L610S 1 C225X 1 1078delTb 1 W846X2 b 1 F311L 1 621+1GNT 1 R1066H 1 R347H 1 2789+5GNA 1 1221delCT 1 G542X 1 3849+4ANG 1 1717-1GNA 1 G551D 1 3659delC 1 R553G 1 S942F 1 Y1092X 1 621+1GNT 1 2789+5GNA 1 4006-1GNA 1 Unidentified 1 Total 13 Total 31 Total 32 a One particular case: in this individual, the two chromosomes 7 are identical by descent. Login to comment 66 ABCC7 p.Gly551Asp ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr Table 3 Estimation of the age of the CFTR mutations Mutation Number of chromosomes Age in generations [95% CI] Age in yearsa [95% CI] Assumed ancestral haplotypeb W846X2 13 25 [15;41] 625 [375;1025] 201-123-195-275-306-250-Mut-226-318-277-243 1078delT 32 40 [30;53] 1000 [750;1325] 199-123-201-279-310-250-Mut-228-308-281-243 G551D 33 48 [36;62] 1200 [900;1550] 207-113-197-275-302-264-Mut-224-322-293-239 ΔF508 45 115 [91;148] 2875 [2275;3700] 209-117-201-283-308-256-Mut-224-308-281-243 I1027T 10 24 [13;44] 600 [325;1100] 209-123-203-271-308-256-Pol-228-308-289-243 Mut and Pol respectively indicate the relative position of the mutation and the polymorphism within each haplotype of interest. Login to comment 87 ABCC7 p.Gly551Asp CFTR mutations All available DNAs from CF patients carrying mutations W846X2, 1078delT or G551D, and relatives had been previously genotyped in the laboratory (Table 1). Login to comment 88 ABCC7 p.Gly551Asp A total of 13 chromosomes were studied for the W846X2 mutation, 32 for 1078delTand 33 for G551D (one homozygous patient for the two latter mutations). Login to comment 89 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp As expected, the ΔF508 mutation is the most associated in trans with the three other mutations of interest (45/75, 60.0% of the total associated mutations): 6/13 (46.2%), 21/31 (67.7%) and 18/32 (56.3%) with W846X2, 1078delT and G551D, respectively. Login to comment 91 ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr Among these chromosomes, 2/45 (4.4%) carry the I1027T polymorphism in CFTR exon 17a. Login to comment 92 ABCC7 p.Gly551Asp ABCC7 p.Ile1027Thr An additional set of ΔF508 chromosomes was screened for the polymorphism, accounting for a total of ten chromosomes carrying the ΔF508-I1027T haplotype. Login to comment 93 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp In this latter cohort, the ΔF508 and G551D alleles are respectively carried in trans by eight (8/10) and two (2/10) patients. Login to comment 94 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Three other mutations were found twice: 621+1GNT (trans-associated with W846X2 and G551D), 2789+5GNA (with W846X2 and G551D) and 4005+1GNA (with 1078delT). Login to comment 101 ABCC7 p.Gly551Asp ABCC7 p.Ile1027Thr The G551D and 1078delT mutations are assumed to be appeared in Brittany at the end of the First Millenium while W846X2 and I1027T are very likely the most recent (~600 years). Login to comment 102 ABCC7 p.Gly551Asp ABCC7 p.Ile1027Thr The G551D and 1078delT mutations are assumed to be appeared in Brittany at the end of the First Millenium while W846X2 and I1027T are very likely the most recent (~600 years). Login to comment 105 ABCC7 p.Gly551Asp ABCC7 p.Ile1027Thr Although relatively rare, W846X2, 1078delT, G551D and I1027T are found at higher frequency in the population from Brittany than in the other French regions. Login to comment 106 ABCC7 p.Gly551Asp ABCC7 p.Ile1027Thr Although relatively rare, W846X2, 1078delT, G551D and I1027T are found at higher frequency in the population from Brittany than in the other French regions. Login to comment 108 ABCC7 p.Ile1027Thr The W846X2 mutation as well as the I1027T polymorphism were estimated to be ~600 years old, while 1078delT was found to be older (~1000 years old) in Brittany. Login to comment 109 ABCC7 p.Ile1027Thr The W846X2 mutation as well as the I1027T polymorphism were estimated to be ~600 years old, while 1078delT was found to be older (~1000 years old) in Brittany. Login to comment 116 ABCC7 p.Gly551Asp The G551D mutation is commonly found in Caucasian populations from Scotland [24], Wales [25], Ireland [12,26], Australia and the USA (www.genet.sickkids.on.ca/cftr/). Login to comment 117 ABCC7 p.Gly551Asp The G551D mutation is commonly found in Caucasian populations from Scotland [24], Wales [25], Ireland [12,26], Australia and the USA (www.genet.sickkids.on.ca/cftr/). Login to comment