ABCMdb

PMID: 12815607

Scotet V, Barton DE, Watson JB, Audrezet MP, McDevitt T, McQuaid S, Shortt C, De Braekeleer M, Ferec C, Le Marechal C
Comparison of the CFTR mutation spectrum in three cohorts of patients of Celtic origin from Brittany (France) and Ireland.
Hum Mutat. 2003 Jul;22(1):105., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCC7 p.Gly551Asp A high frequency of the c.1652_1655 del3 mutation (F508del: 74.8% to 81.3%) and of the "Celtic" mutation (c.1784G>A (G551D): 3.7% to 9.7%) was observed in each population. Login to comment 7 ABCC7 p.Arg117His ABCC7 p.Asn1303Lys ABCC7 p.Arg560Thr In Brittany, the most common abnormalities were: c.1078delT (3.6%), c.4041C>G (N1303K: 1.4%), c.2670G>A (W846X2: 1.0%) and c.1717-1G>A (1.0%), whereas in the cohort of Dublin, the main mutations were: c.482G>A (R117H: 3.0%), c.1811G>C (R560T: 2.4%) and c.621+1G>T (1.7%). Login to comment 8 ABCC7 p.Arg117His Finally, in the Cork area, only the c.482G>A mutation (R117H) reached a frequency of 1%. Login to comment 9 ABCC7 p.Met1105Arg Two previously-unreported mutations were identified in the Dublin cohort: c.2623-2A>G and c.3446T>G (M1105R). Login to comment 19 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* This spectrum is noteworthy because it includes a main mutation, accounting for 70% of the mutated alleles world-wide (the deletion F508del), four other mutations observed with a frequency over 1% (G542X: 2.4%, G551D: 1.6%, N1303K: 1.3%, W1282X: 1.2%) and a multitude of private abnormalities (Tsui, 2003). Login to comment 44 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg352Gln ABCC7 p.Arg560Thr Firstly, the National Centre for Medical Genetics, Dublin performed an analysis of the most common CFTR mutations, using the ARMS test (Ferrie et al., 1992), which enables the detection of the following mutations: F508del, R117H, I507del, G542X, G551D, R560T, N1303K, R352Q, 1717-1G>A and 621+1G>T. Login to comment 50 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Asn1303Lys ABCC7 p.Arg560Thr Dublin Centre 1262 CF alleles 35 mutations F508del 76.5% G551D 6.5% R117H 3.0% R560T 2.4% 621+1G>T 1.7% Cork Area 278 CF alleles 10 mutations F508del 81.3% G551D 9.7% R117H 1.4% Brittany 778 CF alleles 62 mutations F508del 74.8% G551D 3.7% 1078delT 3.6% N1303K 1.4% W846X2 1.0% 1717-1G>A 1.0% Statistical analysis We determined the spectrum of the CFTR mutations identified in the three cohorts of patients and compared their respective frequencies by a Chi square test. Login to comment 59 ABCC7 p.Gly551Asp Besides the F508del deletion, the G551D mutation was also observed with an elevated frequency in each cohort: it was found in 9.7% of the CF alleles in Cork, in 6.5% in Dublin and in 3.7% in Brittany. Login to comment 61 ABCC7 p.Gly551Asp The G551D mutation was the most frequent molecular anomaly after the deletion F508del in the two Irish cohorts. Login to comment 64 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Pro574His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Arg347Leu ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Arg352Gln ABCC7 p.Gly149Arg ABCC7 p.Gln493* ABCC7 p.Val520Phe ABCC7 p.Ser549Arg ABCC7 p.Gly85Glu ABCC7 p.Tyr122* ABCC7 p.Arg560Thr ABCC7 p.Gln220* ABCC7 p.Tyr1092* ABCC7 p.Ser945Leu ABCC7 p.Asp1152His ABCC7 p.Trp401* ABCC7 p.Gly970Arg ABCC7 p.Ile1234Val ABCC7 p.Gly91Arg ABCC7 p.Tyr563Asn ABCC7 p.Arg1070Trp ABCC7 p.Arg1066His ABCC7 p.Glu60* ABCC7 p.Arg560Lys ABCC7 p.Arg553Gly ABCC7 p.Ser492Phe ABCC7 p.Ser977Phe ABCC7 p.Gly1249Arg ABCC7 p.Ala72Asp ABCC7 p.Phe311Leu ABCC7 p.Met1105Arg ABCC7 p.Gln359Arg ABCC7 p.Leu1335Pro ABCC7 p.Trp79* ABCC7 p.Glu1104* Spectrum of the CFTR Mutations Identified in the Cohorts from Brittany, Dublin Centre, and Cork Area Nucleotide Amino acid change * change Exon Number Frequency Number Frequency Number Frequency 211delG 2 1 0.1% 310G>T E60X 3 5 0.6% 4 0.3% 347C>A A72D 3 1 0.1% 368G>A W79X 3 1 0.1% 386G>A G85E 3 2 0.3% 3 0.2% 403G>A G91R 3 2 0.3% 482G>A R117H 4 4 0.5% 38 3.0% 4 1.4% 498T>A Y122X 4 1 0.1% 574delA 4 1 0.1% 577G>A G149R 4 1 0.1% 621+1G>T int 4 5 0.6% 21 1.7% 790C>T Q220X 6a 1 0.1% 875+1G>C int 6a 1 0.4% 905delG 6b 1 0.1% 1065C>G F311L 7 2 0.3% 1078delT 7 28 3.6% 1132C>T R334W 7 1 0.1% 1172G>A R347H 7 5 0.6% 1172G>T R347L 7 1 0.1% 1172G>C R347P 7 1 0.1% 1187G>A R352Q 7 3 0.2% 2 0.7% 1208A>G Q359R 7 1 0.1% 1154insTC 7 2 0.2% 1221delCT 7 2 0.3% 1248+1G>A int 7 1 0.1% 1249-27delTA int 7 1 0.4% 1334G>A W401X 8 1 0.1% 1461ins4 9 5 0.4% 1471delA 9 2 0.2% 1607C>T S492F 10 2 0.3% 1609C>T Q493X 10 1 0.1% 1648_1653delATC I507del 10 3 0.4% 10 0.8% 1 0.4% 1652_1655del 3 bp F508del 10 582 74.8% 966 76.5% 226 81.3% 1690G>T V520F 10 4 0.3% 1717-1G>A int 10 8 1.0% 9 0.7% 1756G>T G542X 11 5 0.6% 8 0.6% 1779T>G S549R 11 1 0.1% 1784G>A G551D 11 29 3.7% 82 6.5% 27 9.7% 1789C>G R553G 11 1 0.1% 1789C>T R553X 11 3 0.4% 1 0.1% 1806delA 11 1 0.1% 1811G>A R560K 11 2 0.3% 1811G>C R560T 11 30 2.4% 2 0.7% 1819T>A Y563N 12 1 0.1% 1853C>A P574H 12 1 0.1% 1898+1G>A int 12 1 0.1% 2184delA 13 1 0.1% 1 0.1% 2184insA 13 1 0.1% 2622+1G>A int 13 1 0.1% 2 0.2% 2622+1G>T int 13 1 0.1% 2623-2A>G ** int 13 1 0.1% 2670G>A W846X2 14a 8 1.0% 2752-1G>T int 14a 1 0.1% 2752-26A>G int 14a 2 0.2% 2789+5G>A int 14b 6 0.8% 2966C>T S945L 15 2 0.3% 3007delG 15 4 0.3% 3040G>C G970R 15 1 0.1% 3062C>T S977F 16 1 0.1% 3120+1G>A int 16 1 0.1% 3272-26A>G int 17a 4 0.5% 2 0.2% 2 0.7% 3320dupli(CTATG) 17b 1 0.1% 3329G>A R1066H 17b 1 0.1% 3340C>T R1070W 17b 1 0.1% 3408C>A Y1092X 17b 7 0.9% 3442G>T E1104X 17b 1 0.1% 3446T>G ** M1105R 17b 1 0.1% 3586G>C D1152H 18 1 0.1% 3601-17T>C + 1367delC int 18 + 9 1 0.1% 3616C>T R1162X 19 1 0.1% 2 0.2% 3659delC 19 2 0.2% 3832A>G I1234V 19 2 0.3% 3849+4A>G int 19 1 0.1% 3849+10kbC>T int 19 3 0.2% 3877G>A G1249R 20 1 0.1% 3884G>A S1251N 20 1 0.1% 3898insC 20 1 0.1% 3905insT 20 2 0.3% 3978G>A W1282X 20 3 0.4% 4005+1G>A int 20 6 0.8% 4016insT 21 1 0.1% 4041C>G N1303K 21 11 1.4% 5 0.4% 4136T>C L1335P 22 1 0.1% 1 0.4% 4279insA 23 1 0.1% Unidentified Unidentified - 3 0.4% 41 3.2% 11 4.0% Total 778 100.0% 1262 100.0% 278 100.0% * All nucleotide changes correspond to cDNA numbering. Login to comment 71 ABCC7 p.Gly551Asp Despite a similar high frequency of the F508del and G551D mutations, the other most common mutations observed in each region were not the same (Table 1, Figure 1). Login to comment 72 ABCC7 p.Asn1303Lys In Brittany, the four mutations found with a frequency above 1% were: 1078delT (3.6%), N1303K (1.4%), W846X2 (TGGàTGA) (1.0%) and 1717-1G>A (1.0%). Login to comment 73 ABCC7 p.Arg117His ABCC7 p.Arg560Thr In the cohort from Dublin, the three mutations presenting a frequency greater or equal to 1% were different: R117H (3.0%), R560T (2.4%) and 621+1G>T (1.7%). Login to comment 74 ABCC7 p.Gly551Asp ABCC7 p.Arg117His In the cohort from Cork, only one mutation other than F508del and G551D reached a frequency of 1%: R117H (1.4%). Login to comment 75 ABCC7 p.Arg560Thr Finally, the main differences observed between these cohorts were the high frequency of the 1078delT mutation in Brittany (3.6%) and of the R560T in the Dublin cohort (2.4%). Login to comment 76 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Tyr1092* ABCC7 p.Glu60* Number Frequency Number Frequency 1652_1655del 3 bp F508del 384 75.6% 196 73.1% 582 74.8% 1784G>A G551D 17 3.3% 12 4.5% 29 3.7% 1078delT 25 4.9% 3 1.1% 28 3.6% 4041C>G N1303K 3 0.6% 8 3.0% 11 1.4% 2670G>A W846X2 7 1.4% 1 0.4% 8 1.0% 1717-1G>A 5 1.0% 3 1.1% 8 1.0% 3408C>A Y1092X 1 0.2% 6 2.2% 7 0.9% 2789+5G>A 2 0.4% 4 1.5% 6 0.8% 4005+1G>A 5 1.0% 1 0.4% 6 0.8% 310G>T E60X 3 0.6% 2 0.7% 5 0.6% 621+1G>T 2 0.4% 3 1.1% 5 0.6% 1172G>A R347H 5 1.0% 5 0.6% 1756G>T G542X 4 0.8% 1 0.4% 5 0.6% 482G>A R117H 3 0.6% 1 0.4% 4 0.5% 3272-26A>G 2 0.4% 2 0.7% 4 0.5% 1648_1653delATC I507del 1 0.2% 2 0.7% 3 0.4% 1789C>T R553X 3 0.6% 3 0.4% 3978G>A W1282X 2 0.4% 1 0.4% 3 0.4% Unidentified Unidentified 3 0.6% 3 0.4% Total Total 508 100.0% 268 100.0% 778 100.0% Basse-Bretagne Haute-Bretagne Brittany * Amino acid change Nucleotide change Table 3: Distribution of the Main CFTR Nutations Observed in the Irish Cohorts (Dublin and Cork) The 62 mutations detected in Brittany combined to give 81 different genotypes in CF patients. Login to comment 81 ABCC7 p.Gly551Asp Just three genotypes were responsible for two thirds of CF cases in this region: F508del/F508del (57.6%), F508del/G551D (4.9%) and F508del/1078delT (4.6%). Login to comment 83 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg560Thr The other most frequent genotypes were: F508del/G551D (9.5%), F508del/R117H (3.5%) and F508del/R560T (2.7%). Login to comment 84 ABCC7 p.Gly551Asp ABCC7 p.Arg117His Finally, in the Cork area, about 70.0% of patients were homozygous for the main mutation, 13.7% were F508del/G551D and 2.9% were F508del/R117H. Login to comment 85 ABCC7 p.Gly551Asp The frequency of the F508del/G551D genotype differed significantly between the cohorts (χ²=12.2 - p=0.0022). Login to comment 89 ABCC7 p.Gly551Asp This study highlights, on one hand, the common background of these populations with a common origin, through the high frequency of the "Celtic" mutation (G551D) resulting from the expansion of the Celts which was at its height between the IVth and IIIth centuries BC, and, on the other hand, the specificities of each cohort, reflecting the influence of their own history. Login to comment 98 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg352Gln ABCC7 p.Val520Phe ABCC7 p.Gly85Glu ABCC7 p.Arg560Thr ABCC7 p.Glu60* Number Frequency Number Frequency 1652_1655del 3 bp F508del 966 76.5% 226 81.3% 1192 77.4% 1784G>A G551D 82 6.5% 27 9.7% 109 7.1% 482G>A R117H 38 3.0% 4 1.4% 42 2.7% 1811G>C R560T 30 2.4% 2 0.7% 32 2.1% 621+1G>T 21 1.7% 21 1.4% 1648_1653delATC I507del 10 0.8% 1 0.4% 11 0.7% 1717-1G>A 9 0.7% 9 0.6% 1756G>T G542X 8 0.6% 8 0.5% 1187G>A R352Q 3 0.2% 2 0.7% 5 0.3% 1461ins4 5 0.4% 5 0.3% 4041C>G N1303K 5 0.4% 5 0.3% 310G>T E60X 4 0.3% 4 0.3% 1690G>T V520F 4 0.3% 4 0.3% 3007delG 4 0.3% 4 0.3% 3272-26A>G 2 0.2% 2 0.7% 4 0.3% 386G>A G85E 3 0.2% 3 0.2% 3849+10kbC>T 3 0.2% 3 0.2% Unidentified Unidentified 41 3.2% 11 4.0% 52 3.4% Total Total 1262 100.0% 278 100.0% 1540 100.0% Dublin cohort Cork cohort Ireland Amino acid change Nucleotide change We noted similar high frequencies of the F508del and G551D mutations in the three cohorts studied. Login to comment 101 ABCC7 p.Gly551Asp We, in collaboration with others, have shown by studying the haplotypes for three intragenic microsatellites markers (IVS8CA, IVS17bTA and IVS17bCA) that the G551D alleles of Irish, Scottish, English, Breton and Czech subjects were associated with a unique haplotype (marker names 16-7-17). Login to comment 104 ABCC7 p.Gly551Asp Besides the F508del and G551D mutations, disparities appeared in the spectrum of mutations between the three cohorts, reflecting the influence of the past of each population, with their own populations` movements, genetic drifts, founder effects, … (Tables 2 and 3). Login to comment 109 ABCC7 p.Arg560Thr The R560T, frequent in this cohort, has also been found in Northern Ireland (2.6%) (Bobadilla et al., 2002), whereas the 621+1G>T has also been observed with an abnormally high frequency in Saguenay-Lac-Saint-Jean, Quebec (23%), giving evidence of a founder effect (Rozen et al., 1992). Login to comment 115 ABCC7 p.Gly551Asp ABCC7 p.Asn1303Lys ABCC7 p.Tyr1092* We concluded that western Brittany presented a specific mutation spectrum (1078delT, G551D, 4005+1G>A, W846X2), whereas the eastern part of the region showed a spectrum of mutations more similar to that generally observed in France (N1303K, Y1092X, 2789+5G>A, etc). Login to comment 124 ABCC7 p.Gly551Asp The spectrums of CFTR mutations show disparities, even if G551D is the most frequent mutation after the deletion F508del in each of the studied cohorts. Login to comment