ABCMdb

PMID: 7526685

Morral N, Llevadot R, Casals T, Gasparini P, Macek M Jr, Dork T, Estivill X
Independent origins of cystic fibrosis mutations R334W, R347P, R1162X, and 3849 + 10kbC-->T provide evidence of mutation recurrence in the CFTR gene.
Am J Hum Genet. 1994 Nov;55(5):890-8., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Arg1162* 55:890-898, 1994 Independent Origins of Cystic Fibrosis Mutations R334W, R347P, R I 1 62X, and 3849+ 1 OkbC--*T Provide Evidence of Mutation Recurrence in the CFTR Gene Nuria Morral,' Roser Llevadot,' Teresa Casals,' Paolo Gasparini,2 Milan Macek, Jr.,3'4 Thilo Dork,s and Xavier Estivill' 'Molecular Genetics Department, Institut de Recerca Oncol6gica, Hospital Duran Reynals, Barcelona; 2Servizio di Genetica Medica, IRCCS-Ospedale "CSS," San Giovanni Rotondo, Foggia, Italy; 3Center for Medical Genetics, Johns Hopkins Medical Institutions, Baltimore; 4First Medical Faculty of Charles University, Prague; and 5Medizinische Hochschule Hannover, Zentrum Biochemie, Hannover Summary Microsatellite analysis of chromosomes carrying particular cystic fibrosis mutations has shown different haplotypes in four cases: R334W, R347P, R1162X, and 3849+10kbC-).T. Login to comment 5 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg1162* Also in support of recurrence, mutations R334W, R347P, R1162X, and 3849+10kbC--T involve CpG dinucleotides, which are known to have an increased mutation rate. Login to comment 16 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Of all the other mutations, only G542X (Kerem et al. 1990), G551D (Cutting et al. 1990), N1303K (Osborne et al. 1991), and W1282X (Vidaud et al. 1990) have a frequency of 1%-2.5% in the worldwide population (Cystic Fibrosis Genetic Analysis Consortium, in press). Login to comment 19 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg1162* While analyzing microsatellites IVS8CA (Morral et al. 1991), and IVS17BTA,IVS17BCA (Zielenski et al. 1991b; Morral et al. 1992) in CF chromosomes carrying mutations R334W (Gasparini et al. 1991b), R347P (Dean et al. 1990), R1162X (Gasparini et al. 1991b), and 3849+10kbC--T (Highsmith et al., in press), several haplotypes were observed associated with each of these mutations. Login to comment 21 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg1162* Analysis with markers flanking mutations R334W, R347P, R1162X, and 3849+10kbC- T indicated that recurrence was the most probable mechanism. Login to comment 22 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Arg1162* All these mutations involve nucleotide sequences that are prone to mutation; mutations R334W, R1162X, and 3849+10kbC- T result from C--T transitions at 5-methylcytosine (SmC), and mutation R347P results from a G--C change in a CpG dinucleotide. Login to comment 24 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Arg1162* Table I CFTR Microsatellite Haplotypes of Mutations R334W, R347P, R I 162X, and 3849+ 1 OkbC--T Mutation and % No. of Haplotype Normala Chromosomes Origin R334W: 17-46-13 .3 6 Spanish 17-47-13 .2 3 Spanish 16-32-13 7.9 1 Czech 17-7-17b 5.3 2 Russian 17/24-31/35-13c 2 German R347P: 16-45-13 1.5 1 Slovak 16-32-13b 7.9 2 Czech 17-28-13 .07 1 Czech 16-45-13 1.5 1 Czech 17-28-13 .07 2 German 16-32-13 7.9 1 German R1162X: 17-31-13 1.1 37 Italian 17-30-13 .3 2 Italian 16-46-13 . Login to comment 32 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg1162* Fifty-eight chromosomes carried mutation R1162X, 14 carried R334W, 8 carried R347P, and 6 carried 3849+10kbC- oT. Login to comment 35 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg1162* R334W, R347P, and R1162X were analyzed as described elsewhere, by PCR amplification and digestion with the appropriate restriction enzyme (Dean et al. 1990; Gasparini et al. 1991b). Login to comment 36 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg1162* In addition, mutations R334W, R347P, and R1162X were confirmed by sequencing (fmol DNA Sequencing System; Promega). Login to comment 44 ABCC7 p.Arg334Trp Results Mutation R334W This mutation was initially described in a Spanish patient (Gasparini et al. 1991b) and accounts for 1.1% of CF chromosomes in this population (Chillon et al. 1994b). Login to comment 46 ABCC7 p.Arg334Trp Two haplotypes (17-46-13 and 17-47-13) were found associated with R334W (table 1), 17-47-13 being derived from 17-46-13 as a result of slippage at the IVS17BTA locus. Login to comment 47 ABCC7 p.Arg334Trp However, when chromosomes of other ethnic origins were analyzed, the haplotypes observed associated with R334W were different (16-32-13, 17-7-17, and 17/24-31/35-13), depending on the geographic origin of the chromosome (table 2). Login to comment 48 ABCC7 p.Arg334Trp Analysis of other markers flanking the R334W mutation, located in exon 7 of the CFTR gene, showed that either several double recombinations or one recombination and slippage must have occurred to generate these haplotypes from the original. Login to comment 70 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro Table 2 Haplotypes for Mutation R334W and R347P in Exon 7 of CFTR in Several Populations CHROMOSOME ORIGINa Czech Russian German Spanish Czech/Slovak Czech/German Czech/German MARKER (n=-) (n=2) (n=2) (n=9) (n=2) (n=3) (n=3) MetH/Mspl 1 1/2 1 1 XV-2c/TaqI 1/2 1 1 1 1 1 2 KM.19/PstI 2 2 2 1 1 1 1 IVS6aGATT 7 7 6 7 7 7 7 Mutation .R334W R334W R334W R334W R347P R347P R347P IVS8CA .16 17 17/24 17 16 16 17 IVS12/Bc.. 2 2 1 1 1 1 1 T854/AvaII 2 2 1 1 1 1 1 IVS15/NsiI 1 2 1 1 1 1 1 IVS17BTA 32 7 35/31 46-47 45 32 28 IVS17BCA 13 17 13 13 13 13 13 TUB18/Hinfl 1 1 1 1 1 1 Q1463/Hinfl 1/2 1/2 2 2 2 J3.11/Msp. Login to comment 80 ABCC7 p.Arg334Trp Furthermore, R334W is very infrequent in the populations in which the new haplotypes were found (<0.1%, vs. 1.1% in the Spanish population) (Cystic Fibrosis Genetic Analysis Consortium, in press). Login to comment 81 ABCC7 p.Arg334Trp Therefore, the most plausible hypothesis is that R334W arose on at least four separate occasions in different genetic backgrounds. Login to comment 82 ABCC7 p.Arg347Pro Mutation R347P This mutation was first reported on a chromosome of North American origin (Dean et al. 1990), but its highest frequency has been detected in Germany, where it accounts for 1.2%-1.4% of CF chromosomes. Login to comment 84 ABCC7 p.Arg347Pro Analysis of microsatellites on R347P chromosomes from several populations has revealed three different haplotypes among German, Czech, and Slovak chromosomes, suggesting recurrence (table 1). Login to comment 87 ABCC7 p.Arg347Pro Alternatively, mutation R347P could have arisen at least three times. Login to comment 89 ABCC7 p.Arg1162* It is also common in northwestern Spain, where 4.5% of CF chromosomes carry this mutation (Chillon et al. 1994b), and in a Native American population (the Pueblo tribe), where R1162X has been found in 11 of 16 CF chromosomes (Mercier et al., in press). Login to comment 91 ABCC7 p.Arg1162* The analysis of 18 chromosomes of Spanish origin and 40 Italian chromosomes has indicated that R1162X is mainly associated with haplotype 17-31-13 (table 1). Login to comment 92 ABCC7 p.Arg1162* ABCC7 p.Arg1162* ABCC7 p.Arg1162* Slippage of one repeat at the IVS17BTA locus most probably results in haplotype 17-30-13, observed in two chromo- Table 3 Haplotypes for Mutation R I 162X in Exon 19 of CFTR CHROMOSOME ORIGIN Spanish/Italian Spanish Italian MARKER (n=54) (n=3) (n=1) MetH/Taql ............ 1 1 MetH/MspI ........... 1 1 2 XV-2c/TaqI ............ 2 1 2 CS.7/HhaI ............. 2 2 1 KM.19/ScrFI .......... 2 2 2 KM.19/PstI ............ 1 1 1 MP6d-9/MspI ........ 2 2 1 IVS6a GATT ........... 7 6 7 IVS8CA ............. 17 17 16 IVS17BTA ............. 30-31 53 46 IVS17BCA ............. 13 11 13 Mutation ............. R1162X R1162X R1162X Q1463/Hinfl .......... 2 2 2 J3.11/MspI ............. 2 2 2 NOTE.-Allele designations are as in table 2. somes of Italian origin. Login to comment 93 ABCC7 p.Arg1162* However, two other haplotypes were observed, one on three Spanish chromosomes and the other on one Italian chromosome, suggesting either the independent origin of this mutation or a recombination event between exon 19, where R1162X is located, and the IVS17B locus. Login to comment 94 ABCC7 p.Arg1162* The analysis of several markers within and flanking the CFTR gene shows that either a recombination has occurred independently on two chromosomes (one Spanish and one Italian) within a region of <20 kb or that R1162X occurred independently three times (table 3). Login to comment 95 ABCC7 p.Arg1162* ABCC7 p.Arg1162* The common R1162X haplotype 17-31-13 is also associated with all the chromosomes from the Pueblo tribe carrying this mutation, which suggests an introduction of Spanish chromosomes into the native population, rather than recurrence of R1162X in this population (Mercier et al., in press). Login to comment 105 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Mutations that have a relatively high worldwide frequency (AF508, G542X, and N1303K) and that are also ancient have a small proportion of chromosomes associated with haplotypes different from the original, which can be explained by slippage of the DNA polymerase at one microsatellite during replication. Login to comment 106 ABCC7 p.Arg117His ABCC7 p.Arg75Gln ABCC7 p.Arg31Cys ABCC7 p.Arg117Cys ABCC7 p.Arg75* ABCC7 p.Arg31Leu ABCC7 p.Arg75Leu Slippage usually results in the addition or subtraction of one repeat unit either side Table 5 CpG Dinucleotides in CFTR Gene That Have More than One Mutational Event Position Change Mutation Reference 223 ......... CT R31C Ghanem et al. 1994 224 ......... GT R31L Zielenski et al., in press 355 ........ C- >T R75X Dork et al., in press 356 ......... G--*T R75L B. Costes, personal communication 356 ......... G-aA R75Q' Zielenski et al. 1991b 481 ......... CT R117C D6rk et al., in press 482 ......... G-oA R117H Dean etal. Login to comment 107 ABCC7 p.Arg347Cys ABCC7 p.Arg347His ABCC7 p.Arg117Leu 1990 G--*-T R117L G. Novelli, personal communication 1171 ......... CT R347C C. Ferec, personal communication 1172 ......... G--A R347H Cremonesi et al. 1992 G I. Login to comment 108 ABCC7 p.Arg553* ABCC7 p.Arg347Pro ABCC7 p.Arg347Leu ABCC7 p.Arg1070Gln ABCC7 p.Arg1070Gln ABCC7 p.Arg1066Cys ABCC7 p.Arg553Gln ABCC7 p.Arg1066Leu ABCC7 p.Arg1070Trp ABCC7 p.Arg1066His ABCC7 p.Arg553Gly )-.T R347L Audrezet et al. 1993 G--S-C R347P Dean et al. 1990 1789 ......... C--.G R553G C. Ferec, personal communication CI-T R553X Cutting et al. 1990 1790 ......... G---A R553Q Dork et al.1991a 3328 ......... C-OT R1066C Fanen et al. 1992 3329 ......... G-.A R1066H Ferec et al. 1992 GT R1066L Mercier et al. 1993 3340 ......... CT R1070W M. Macek, Jr., unpublished data 3341 ......... G-A R1070Q Mercier et al. 1993 a This change is a polymorphism, not a disease mutation. Login to comment 112 ABCC7 p.Gly1244Glu ABCC7 p.Gly1244Glu ABCC7 p.Ser549Asn ABCC7 p.Ser549Asn ABCC7 p.Arg560Thr ABCC7 p.Arg560Thr ABCC7 p.Met1101Lys ABCC7 p.Met1101Lys ABCC7 p.Arg1283Met ABCC7 p.Arg1283Met ABCC7 p.Met1101Arg ABCC7 p.Met1101Arg ABCC7 p.Tyr563Asn ABCC7 p.Tyr563Asn ABCC7 p.Glu92Lys ABCC7 p.Glu92Lys ABCC7 p.Arg560Lys ABCC7 p.Arg560Lys ABCC7 p.Arg1283Lys ABCC7 p.Arg1283Lys ABCC7 p.Tyr563Asp ABCC7 p.Tyr563Asp ABCC7 p.Glu92* ABCC7 p.Glu92* ABCC7 p.Gly628Arg ABCC7 p.Gly628Arg ABCC7 p.Gly628Arg ABCC7 p.Gly628Arg ABCC7 p.Gly1244Val ABCC7 p.Gly1244Val CT................... 3863: G--oA .................. G-.T ................... 3980: G-jA .................. G--)T.................... 4374+1: G-A .................. G--oT.................... L88S L88X L88X G. Malone, personal communication Savov et al. 1994b Macek et al. 1992 406-1G--.C Bonizzato et al. 1992 406-1G- T T. Bienvenu, personal communication E92K Nunes et al. 1993 E92X Will et al. 1994 S549N Cutting et al. 1990 S5491 Kerem et al. 1990 R560K Ferec et al. 1992 R560T Kerem et al. 1990 Y563D A. Hamosh, personal communication Y563N Kerem et al. 1990 1898+1CG-.A Strong et al. 1992 1898+1GC-.C Cuppens et al. 1993 1898+3A-)C W. Lissens, personal communication 1898+3A--4G Cremonesi et al. 1992 G628R G628R 2183AA- G 2184delA 2184insA M1101K M1101R 3667del4 3667ins4 3791delC T12201 G1244E G1244V R1283K R1283M Fanen et al. 1992 Cuppens et al. 1993 Bozon et al. 1994 Dork et al., in press N. Kilin, personal communication Zielenski et al. 1993 Mercier et al. 1993 Chillon et al. 1994a Sangiuolo et al. 1993 M. Macek, Jr., personal communication Ghanem et al. 1994 Devoto et al. 1991 Savov et al. 1994a Chevalier et al., in press Cheadle et al. 1992 4374+1G-*A Fanen et al. 1992 4374+1G--iT Dork et al. 1993 of the most common allele. Login to comment 116 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg1162* Mutations R334W, R347P, R1162X, and 3849+10kbC- T have been found associated with more than one haplotype. Login to comment 117 ABCC7 p.Arg334Trp ABCC7 p.Arg1162* Among these mutations, R334W and R1162X are relatively frequent in specific populations. Login to comment 118 ABCC7 p.Arg334Trp ABCC7 p.Arg1162* ABCC7 p.Arg1162* Therefore, it is expected that more than one haplotype could be associated with each of these two mutations, because of slippage at one of the microsatellite loci (for R334W, haplotypes 17- 46-13 and 17-47-13; and, for R1162X, haploytpes 17-3113 and 17-30-13). Login to comment 122 ABCC7 p.Arg334Trp ABCC7 p.Arg1162* It is not surprising that mutations R334W, R1162X, and 3849+10kbC- ~T have arisen more than once, since they are the result of CT transitions within a CpG dinucleotide. Login to comment 123 ABCC7 p.Arg347Pro In addition, mutation R347P consists of a G- >C substitution in a CpG dinucleotide (positions 1171 and 1172 of the CFTR cDNA). Login to comment 124 ABCC7 p.Arg347Cys ABCC7 p.Arg347His ABCC7 p.Arg347Leu Two other mutations (R347H and R347L) (Cremonesi et al. 1992; Audrezet et al. 1993) have occurred at nucleotide 1172 (G--A and G--T), and another one (R347C) has occurred at nucleotide 1171, which consists of a C-*T transition (C. Ferec, personal communication). Login to comment 125 ABCC7 p.Arg1162* ABCC7 p.Arg1162Leu The CpG at which mutation R1162X occurred has also been involved in a G-o*T change to produce mutation R1162L (Fanen et al. 1992). Login to comment 140 ABCC7 p.Arg553* (1991) suggested an independent origin of mutation R553X in chromosomes of American Black and German origin. Login to comment 141 ABCC7 p.Arg553* (1991) suggested an independent origin of mutation R553X in chromosomes of American Black and German origin. Login to comment 142 ABCC7 p.Arg553* (1994, and in press) have suggested recurrence of R553X as well as of mutations 2184insA, 3272-26A-*G, and 3849+10kbC-)T. Login to comment 143 ABCC7 p.Arg117His ABCC7 p.Arg553* Mutation R117H has also been reported to have originated in two different genetic backgrounds, giving a different clinical status of CF in each (Kiesewetter et al. 1993). Login to comment 144 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Arg1162* ABCC7 p.His199Tyr ABCC7 p.Leu558Ser A collaborative study involving the analysis of 94 mutations in the CFTR gene has shown that mutations R117H, H199Y, R347H, R347P, L558S, 2184insA, R1162X, 3272-26A--G, and 3849+10kbC-)T have arisen more than once in different genetic backgrounds (authors' unpublished data). Login to comment 145 ABCC7 p.Arg117His ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Arg1162* ABCC7 p.His199Tyr ABCC7 p.Leu558Ser A collaborative study involving the analysis of 94 mutations in the CFTR gene has shown that mutations R117H, H199Y, R347H, R347P, L558S, 2184insA, R1162X, 3272-26A--G, and 3849+10kbC-)T have arisen more than once in different genetic backgrounds (authors' unpublished data). Login to comment