ABCMdb

PMID: 7513293

Chillon M, Casals T, Gimenez J, Ramos MD, Palacio A, Morral N, Estivill X, Nunes V
Analysis of the CFTR gene confirms the high genetic heterogeneity of the Spanish population: 43 mutations account for only 78% of CF chromosomes.
Hum Genet. 1994 Apr;93(4):447-51., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCC7 p.Gly542* This indicates that, in the Spanish population, with the exception of AF508 (50.6%) and G542X (8%), the mutations are not concentrated in a few exons of the gene nor are there any predominating mutations. Login to comment 22 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* We have previously analysed the three most frequent mutations in our population (AF508, G542X and N1303K), and the association between CF Spanish chromosomes and their intragenic microsatellites IVSCA8-IVS17BTA-IVS 17BCA (Nunes et al. 1991; Casals et al. 1992; Morral et al. 1993; Chilldn et al. 1993). Login to comment 30 ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* There are seven mutations with a frequency higher than 1%, viz. AF508 (50.6%), G542X (8.0%), N1303K (2.3%), 3601-111G---~C (1.9%), Rl162X (1.8%, 711+IG--+T (1.2%) and R334W (1.1%), whereas the other 36 mutations have a frequency lower than 1% and account for only about 11% of CF chromosomes. Login to comment 31 ABCC7 p.Arg553* ABCC7 p.Ser1255Pro ABCC7 p.Arg347Pro ABCC7 p.Val520Phe ABCC7 p.Tyr122* ABCC7 p.Arg560Thr ABCC7 p.Gln552* ABCC7 p.His1085Arg ABCC7 p.Ile1234Val ABCC7 p.Tyr563Asn ABCC7 p.Gln1291His ABCC7 p.Arg1066His ABCC7 p.Arg560Lys ABCC7 p.Ala1067Thr At present, we have not detected any Spanish CF chromosomes bearing any of the following mutations: 394delTA, Y122X, 556delA, 852de122, R347P, $492F, 1677delTA, V520F, Q552X, R553X, L559S, R560K, R560T, Y563N, P564H, 2043delG, 3320ins5, R1066H, A1067T, H1085R, 3732delA, 3737delA, I1234V, S1255P, 3898insC, Q1291H or 4005+ 1G---~A. Login to comment 34 ABCC7 p.Gly542* A non-uniform distribution had previously been observed in the Spanish population for the AF508 and G542X mutations (Casals et al. 1993) but this had not been shown for any other mutations. Login to comment 35 ABCC7 p.Arg334Trp We studied the distribution of the other five more commun mutations (N 1303K, 3601-111 G--~C, R 1162X, 711 + 1G--~T, R334W), since studies with less frequent mutations did not give significant values (data not shown). Login to comment 37 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* When we analysed the Spanish CF population in subsets (Fig. 1), we found typical mutations; in the Mediterranean subset, G542X and N1303K (11.8% and 4.5%, respectively); in the Arab-Andalusian subset, 3601-111G---~ C (5.6%); in the Gallician subset, Rl162X and 711+1 G---~T (8.5% and 6.4%, respectively); in the Canary islands, because of the founder effect, we observed only a few mutations but with high frequencies, whereas we only found the AF508 mutation and none of the other six most common mutations in the Basques. Login to comment 40 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Gly85Glu ABCC7 p.Arg1066Cys Frequencies of CF mutations in the Spanish population Mutation Exon/intron N~chro- % mosomes Known (43) 760 78.18 AF508 Exon 10 492 50.61 G542X Exon 11 78 8.02 N1303K Exon 21 23 2.36 3601-111 G---~C Intron 18 19 1.95 R1162X Exon 19 18 1.85 711+1 G---~T Exon 5 12 1.23 R334W Exon 7 11 1.13 1609 del CA Exon 10 9 0.92 G85E Exon 3 8 0.82 2789+5 G---~A Intron 14b 7 0.72 2869 ins G Exon 15 7 0.72 R1066C Exon 17b 7 0.72 W1282X Exon 20 6 0.62 AI507 Exon 10 5 0.51 3272-26 A---~G Intron 17a 5 0.51 G551D Exon 11 4 0.41 1812-1 G---~A Intron 11 4 0.41 2184 de! Login to comment 41 ABCC7 p.Arg347His ABCC7 p.Pro205Ser ABCC7 p.Ile148Thr ABCC7 p.Glu585* ABCC7 p.Leu206Trp ABCC7 p.Arg1158* ABCC7 p.Ala120Thr ABCC7 p.Tyr1092* ABCC7 p.His199Tyr ABCC7 p.Gln30* ABCC7 p.Lys710* ABCC7 p.Glu92Lys ABCC7 p.Trp1098* ABCC7 p.Thr582Arg ABCC7 p.Gln1100Pro A Exon 13 4 0.41 621-1 G--~T Intron 4 3 0.31 P205S Exon 6a 3 0.31 936 del TA Exon 6b 3 0.31 1949 del 84 Exon 13 3 0.31 K710X Exon 13 3 0.31 CF del #1 Exon 4-7/11-18 3 0.31 L206W Exon 6a 2 0.20 R347H Exon 7 2 0.20 Y1092X Exon 17b 2 0.20 Q1100P Exon 17b 2 0.20 Q30X Exon 2 1 0.10 E92K Exon 4 1 0.10 A120T Exon 4 1 0.10 I148T Exon 4 1 0.10 H199Y Exon 6a 1 0.10 1078 del T Exon 7 1 0.10 1717-1 G--+A Intron 10 1 0.10 T582R Exon 12 1 0.10 E585X Exon 12 1 0.10 1898+3 A~---G Intron 12 1 0.10 W1098X Exon 17b 1 0.10 R1158X Exon 19 1 0.10 3667 del 4 Exon 19 1 0.10 3860 ins 31 Exon 20 1 0.10 3905 ins T Exon 20 1 0.10 Unknown 212 21.81 The Basque subset The Basques have a different genetic background with respect to other ethnic groups (Pancorbo et al. 1989) as they are the only pre-Indoeuropean group in Spain. Login to comment 42 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Thus, of the seven most common mutations, they only have the G542X 4/47=8.5% MUTATION )/39=0% N1303K 0/47=0% MUTATION D/39=0% 3601-111G>CMUTATION )/47=0% _oI~=O% 10/260:3.8% )4" 26/220=11.8% I~7/49=14.3%~Qr ~lP,m. Login to comment 43 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* 5/260=1.9%41~4," p- I0/220=4,5% 1/49:2.0%CT !/248=1.2% 13/'232=5.6% ~=0% R1162XMUTATION t/47=8.S% ~I3/49--6.1%(I" f-it*" 711+1G>T 5/47=6A% MUTATION 0~9=0% <7" Fig.1.DistributionoftheG542X,N1303K,3601-111G---~C,R1162X,7tI+IG--)Tand R334WmutationsinthedifferentsubsetsoftheSpanishpopulation.Onlythe615chro- mosomesforwhichtheethnicorigincouldbeestablishedhavebeenincluded.Subsets withahighfrequencyforagivenmutationareshaded.TheMediterraneansubsethasa R334WMUTATION 1/47=2.1% highfrequencyforG542XandN1303K;theArab-Andalusiansubsetfor3601-111G---) C;theGalliciansubsetforG542X,R1162Xand711+1G---)C;theCanariansubsetfor G542X,RlI62XandR334W,whereasnoneofthesesixmutationsispresentinthe Basquesubset4~ ~D AF508 mutation (76.9% compared with 50.6% for the rest of Spain). Login to comment 46 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* The Mediterranean subset The Mediterranean subset shows high frequencies of the mutations G542X and N1303K. Login to comment 48 ABCC7 p.Gly542* The G542X mutation has been postulated to have arisen in a population of Semitic origin (Phoenicians and Jews) in the Neolithic Age, and to have been introduced into Spain, via the Mediterranean Sea, by Phoenicians (Casals et al. 1993); this would explain its high frequency in this subset (11.8%) with respect to the rest of Spain (3.8%) (~2 = 10.1, P < 0.001). Login to comment 49 ABCC7 p.Asn1303Lys On the other hand, analysis of the frequency of the N1303K mutation in different populations (Osborne et al. 1992) suggests that its origin was in a population of the Mediterranean area, since this mutation is significantly more common in Southern European populations than in Northern European populations. Login to comment 50 ABCC7 p.Asn1303Lys Similarly, in countries with a Mediterranean coast (France and Italy), the incidence of the N1303K mutation is higher in Mediterranean coastal regions that in non-coastal regions. Login to comment 51 ABCC7 p.Asn1303Lys This can also be observed in the Spanish population in which the N1303K mutation is mainly distributed in the Mediterranean subset with a frequency of 4.5%, instead of 1.9% for the rest of Spain. Login to comment 59 ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Thus, we have found AF508 (46.9%), G542X (14.3%), Rl162X (6.1%), R334W (4.0%) and N1303K (2.0%) but we have not found 3601-111G--->C, 711+IG-~T or any of the other 36 less frequent mutations. Login to comment 61 ABCC7 p.Asn1303Lys Mutations Rl162X and 711+IG--->T have a high frequency (8.5% and 6.4%, respectively), whereas mutations N1303K and 3601-111G--->C are not present. Login to comment 66 ABCC7 p.Arg334Trp Association of R334W with the intragenic polymorphisms (IVS8CA-IVS17BCA-IVS17BTA) suggests that it is a recurring mutation and that is distribution in the different subsets could be the result of several independent origins (N.Morral, unpublished). Login to comment 69 ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* There are seven mutations with a frequency higher than 1% (AF508, G542X, N1303K, 3601-111G-->C, Rl162X, 711+IG---~T and R334W), whereas another 36 less frequent mutations account for only 11% of the CF chromosomes. Login to comment 70 ABCC7 p.Gly542* These results show that the Spanish population [like other Southern and Mediterranean European populations (Nunes et al. 1991)] has a marked genetic heterogeneity, since the CF mutations are not confined to a few exons and there are no predominant mutations (except for AF508 and G542X). Login to comment 75 ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Arg1162* Thus, the Basque subset has the AF508 mutation but none of the other 6 mutations; the Mediterranean subset has a high frequency of G542X and N1303K (as in South European populations); the Arab-Andalusian subset has a high frequency of 3601-111G---~C, which we propose has an Arab origin; the Canarian Islands has a founder effect, where we find high frequencies of the G542X, Rl162X and R334W mutations, and the Gallician subset has a high frequency of G542X, R1162X and 711+1G---~C. Login to comment