ABCMdb

PMID: 7508414

Cuppens H, Marynen P, De Boeck C, Cassiman JJ
Detection of 98.5% of the mutations in 200 Belgian cystic fibrosis alleles by reverse dot-blot and sequencing of the complete coding region and exon/intron junctions of the CFTR gene.
Genomics. 1993 Dec;18(3):693-7., [PubMed]

Sentences

No. Mutations Sentence Comment

14 ABCC7 p.Gly542* Two of these CF alleles were derived from an individual homozygous for the G542X mutation, having a rather mild form of cystic fibrosis, in which only a limited number of exons of the CFTR gene had been analyzed (6). Login to comment 23 ABCC7 p.Trp401* First, a stop at nucleotide position 1258 in the exSi fragment was seen in individuals heterozygous for the W401X mutation, which is located in exon 8. Login to comment 24 ABCC7 p.Trp401* This stop was never seen in non-W401X alleles. Login to comment 25 ABCC7 p.Trp401* The presence of an A at nucleotide position 1335 in the W401X allele may alter the conformation of the ex8i fragment thereby hampering the progression of the T 7 DNA polymerase. Login to comment 31 ABCC7 p.Glu60* The E60X mutation was independently found by Malone et al. (in Ref. 21). Login to comment 32 ABCC7 p.Glu60* The E60X mutation was independently found by Malone et al. (in Ref. 21). Login to comment 35 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Five mutations had a frequency higher than 1% (Table 1) AF508 (72.5%), G542X (5.5%), N1303K (3.5%), 1717-1G --~ A (2.5%), and $1251N (2.0%). Login to comment 36 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Five mutations had a frequency higher than 1% (Table 1) AF508 (72.5%), G542X (5.5%), N1303K (3.5%), 1717-1G --~ A (2.5%), and $1251N (2.0%). Login to comment 39 ABCC7 p.Trp1310* The W1310X mutation and one 2184delA (plus A --~ G at 2183) allele were found in a patient from Turkish descent. Login to comment 40 ABCC7 p.Arg117His ABCC7 p.Trp1310* The W1310X mutation and one 2184delA (plus A --~ G at 2183) allele were found in a patient from Turkish descent. Login to comment 41 ABCC7 p.Arg117His The R117H mutation (8) was found in the non CF individual with the positive trypsin test. Login to comment 42 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Tyr1092* ABCC7 p.Trp401* ABCC7 p.Gly970Arg ABCC7 p.Ile336Lys ABCC7 p.Glu60* ABCC7 p.Trp1310* ABCC7 p.Gly458Val ABCC7 p.Glu730* TABLE 1 Mutations (and Their Frequencies) Identified in This Study Predicted amino Mutation Nucleotide change~ acid change Location Frequencyb Reference E60X G --~ T at 310 (TAGATAGCT) Glu --~ Stop at 60 Malone et al. in (21); this study G --~ A at 482 (GAACACTCT) (8) A --~ C at 622-2 (TTTTCGACT) This study T --~ A at 1139 (AAAAAATTC) This study G --~ A at 1335 (TCTGAGAGG) This study C --~ A at 1496 (TTGGAGGTT) (14) G -~ T at 1505 (GCTGTATCC) (6) Deletion of ATC from 1651 (14); Schwarz et al. (TATC_TTTG) in (21) Deletion of CTT from 1653 145 (13) (TCAT_TGGT) G --~ A at 1717-1 (AATAAGACA) G --~ T at 1756 (TCTTTGAGA) G --~ C at 1898 + 1 (AAAGCTATG) G --~ C at 2014 (TTATCGGAC Deletion of A at 2184; A --~ G at 2183 (AAAAG CAAT) G --~ T at 2320 (TGATTAGCC Deletion of 11 nucleotides from 2721 (TGCT_TAGT) G --~ C at 3040 (AGCACGTAC A --~ G at 3272-26 (TGCAGTGTT) C --~ A at 3408 (TGTAACTGT) Deletion of C at 3659 (CCTA_CAAG) T --~ G at 3837 (TAAGGCCTG G --* A at 3884 (AAGAATACT G --~ A at 3978 (AGTGAAGGA' C --~ G at 4041 (AAAAGTTGG G -~ A at 4061 (CAGTAGAGT Insertion of T after 4218 (CAGTTAAGG) R117H 622-2A --~ C I336K W401X A455E G458V AI507 AF508 1717-1G -~ A G542X 1898+ 1G-~C G628R(G -~ C) 2184delA plus A -~ G at 2183 E730X 2721de111 G970R 3272-26A --~ G Y1092X 3659delc $1235R $1251N W1282X N1303K W1310X 4218insT Exon 3 2 (1.0%) Arg --~ His at 117 Exon 4 c 3' splice signal Intron 4 1 (0.5%) Ile -~ Lys at 336 Exon 7 1 (0.5%) Trp --~ Stop at 401 Exon 8 2 (1.0%) Ala --~ Glu at 455 Exon 9 2 (1.0%) Gly --* Val at 458 Exon 9 1 (0.5%) Deletion of Ile 507 Exon 10 1 (0.5%) Deletion of Phe 508 Exon 10 (72.5%) 3' splice signal Intron 10 5 (2.5%) Gly --* Stop at 542 Exon 11 11 (5.5%) 5' splice signal Intron 12 1 (0.5%) Gly -~ Arg at 628 Exon 13 1 (0.5%) Frameshift Exon 13 2 (1.0%) Glu --~ Stop at 730 Exon 13 1 (0.5%) Frameshift Exon 14a I (0.5%) Gly --~ Arg at 970 Exon 15 1 (0.5%) 5' splice signal? Login to comment 43 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Tyr1092* ABCC7 p.Trp401* ABCC7 p.Gly970Arg ABCC7 p.Ile336Lys ABCC7 p.Glu60* ABCC7 p.Trp1310* ABCC7 p.Gly458Val ABCC7 p.Glu730* TABLE 1 Mutations (and Their Frequencies) Identified in This Study Predicted amino Mutation Nucleotide change~ acid change Location Frequencyb Reference E60X G --~ T at 310 (TAGATAGCT) Glu --~ Stop at 60 Malone et al. in (21); this study G --~ A at 482 (GAACACTCT) (8) A --~ C at 622-2 (TTTTCGACT) This study T --~ A at 1139 (AAAAAATTC) This study G --~ A at 1335 (TCTGAGAGG) This study C --~ A at 1496 (TTGGAGGTT) (14) G -~ T at 1505 (GCTGTATCC) (6) Deletion of ATC from 1651 (14); Schwarz et al. (TATC_TTTG) in (21) Deletion of CTT from 1653 145 (13) (TCAT_TGGT) G --~ A at 1717-1 (AATAAGACA) G --~ T at 1756 (TCTTTGAGA) G --~ C at 1898 + 1 (AAAGCTATG) G --~ C at 2014 (TTATCGGAC Deletion of A at 2184; A --~ G at 2183 (AAAAG CAAT) G --~ T at 2320 (TGATTAGCC Deletion of 11 nucleotides from 2721 (TGCT_TAGT) G --~ C at 3040 (AGCACGTAC A --~ G at 3272-26 (TGCAGTGTT) C --~ A at 3408 (TGTAACTGT) Deletion of C at 3659 (CCTA_CAAG) T --~ G at 3837 (TAAGGCCTG G --* A at 3884 (AAGAATACT G --~ A at 3978 (AGTGAAGGA' C --~ G at 4041 (AAAAGTTGG G -~ A at 4061 (CAGTAGAGT Insertion of T after 4218 (CAGTTAAGG) R117H 622-2A --~ C I336K W401X A455E G458V AI507 AF508 1717-1G -~ A G542X 1898+ 1G-~C G628R(G -~ C) 2184delA plus A -~ G at 2183 E730X 2721de111 G970R 3272-26A --~ G Y1092X 3659delc $1235R $1251N W1282X N1303K W1310X 4218insT Exon 3 2 (1.0%) Arg --~ His at 117 Exon 4 c 3' splice signal Intron 4 1 (0.5%) Ile -~ Lys at 336 Exon 7 1 (0.5%) Trp --~ Stop at 401 Exon 8 2 (1.0%) Ala --~ Glu at 455 Exon 9 2 (1.0%) Gly --* Val at 458 Exon 9 1 (0.5%) Deletion of Ile 507 Exon 10 1 (0.5%) Deletion of Phe 508 Exon 10 (72.5%) 3' splice signal Intron 10 5 (2.5%) Gly --* Stop at 542 Exon 11 11 (5.5%) 5' splice signal Intron 12 1 (0.5%) Gly -~ Arg at 628 Exon 13 1 (0.5%) Frameshift Exon 13 2 (1.0%) Glu --~ Stop at 730 Exon 13 1 (0.5%) Frameshift Exon 14a I (0.5%) Gly --~ Arg at 970 Exon 15 1 (0.5%) 5' splice signal? Login to comment 47 ABCC7 p.Trp1310* The G628R(G --~ C) and $1235R mutations were found on a single allele; the W1310X allele and one 2184delA (plus A --~ G at 2183) allele were found on a CFTR gene from Turkish descent. Login to comment 48 ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Trp1310* ABCC7 p.Gly458Val The G628R(G --~ C) and $1235R mutations were found on a single allele; the W1310X allele and one 2184delA (plus A --~ G at 2183) allele were found on a CFTR gene from Turkish descent. Login to comment 49 ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Gly458Val For each type mutation, at least one allele was completely sequenced: 14 for AF508, 3 for G542X, 2 for 1717-1G -~ A, 1 for A455E, 1 for G458V, 1 for AI507, 1 for W1282X, 1 for N1303K, and for the remainder, the total number of alleles that were found in this study. Login to comment 51 ABCC7 p.Arg117His c The R117H mutation was not found in a CF patient and is therefore not included. Login to comment 52 ABCC7 p.Arg117His c The R117H mutation was not found in a CF patient and is therefore not included. Login to comment 66 ABCC7 p.Gln1291His A mutation of the last nucleotide of an exon could cause aberrant splicing, as has been shown for the Q1291H mutation in the CFTR gene (12) and, therefore, E528E could still be the basic defect in this CF allele. Login to comment 67 ABCC7 p.Gln1291His A mutation of the last nucleotide of an exon could cause aberrant splicing, as has been shown for the Q1291H mutation in the CFTR gene (12) and, therefore, E528E could still be the basic defect in this CF allele. Login to comment 73 ABCC7 p.Gly628Arg Another G628R CF allele, caused by another nucleotide substitution involving the same nucleotide mutated in G628R(G-~C), has also been observed (10), indicating that this mutation is associated with a defective CFTR protein. Login to comment 74 ABCC7 p.Gly628Arg Another G628R CF allele, caused by another nucleotide substitution involving the same nucleotide mutated in G628R(G-~C), has also been observed (10), indicating that this mutation is associated with a defective CFTR protein. Login to comment 77 ABCC7 p.Ile336Lys The second newly described missense mutation, I336K, is located in the first transmembrane domain and results in the substitution of a neutral amino acid by a basic one. Login to comment 78 ABCC7 p.Ile336Lys The second newly described missense mutation, I336K, is located in the first transmembrane domain and results in the substitution of a neutral amino acid by a basic one. Login to comment 79 ABCC7 p.Lys335Glu It has been shown that mutagenesis of the neighboring amino acid 335 from a basic amino acid to an acidic amino acid (K335E) results in a CFTR protein with altered anion permeability sequence and conductivity sequence properties of the different halides (2). Login to comment 80 ABCC7 p.Lys335Glu ABCC7 p.Ile336Lys It has been shown that mutagenesis of the neighboring amino acid 335 from a basic amino acid to an acidic amino acid (K335E) results in a CFTR protein with altered anion permeability sequence and conductivity sequence properties of the different halides (2). Login to comment 81 ABCC7 p.Ile336Lys The I336K mutation will result in an extra positive charge in the neighborhood of the critical K335 amino acid. Login to comment 82 ABCC7 p.Ile336Lys It could not be excluded that the I336K and 2721de111 mutations were present on a single allele in this individual, as no DNA of the parents was available. Login to comment 83 ABCC7 p.Ile336Lys ABCC7 p.Ile336Lys ABCC7 p.Ile336Lys It could not be excluded that the I336K and 2721de111 mutations were present on a single allele in this individual, as no DNA of the parents was available. Login to comment 84 ABCC7 p.Ile336Lys ABCC7 p.Ile336Lys Subsequent to the identification of the I336K mutation in this individual, an A508/I336K patient with mild CF, who was diagnosed at the age of 12 years, has been iden- tiffed (T. DSrk, pers. Login to comment 86 ABCC7 p.Ile336Lys The presence of the I336K and 2721de111 mutations on a single CFTR allele therefore seems unlikely. Login to comment 87 ABCC7 p.Ile336Lys ABCC7 p.Ile336Lys The presence of the I336K and 2721de111 mutations on a single CFTR allele therefore seems unlikely. Login to comment 88 ABCC7 p.Gly970Arg ABCC7 p.Ile336Lys The I336K mutation further substantiates the observation that mutations in the first transmembrane regions result in a mild CF phenotype (8, 19). Login to comment 89 ABCC7 p.Gly970Arg Finally, the G970R mutation is located in the second transmembrane region. Login to comment 91 ABCC7 p.Gln1291His However, this mutation involves the last nucleotide of an exon and could result in aberrant splicing, as has been shown for the Q1291H mutation (12), resulting in a truncated protein. Login to comment 92 ABCC7 p.Gln1291His However, this mutation involves the last nucleotide of an exon and could result in aberrant splicing, as has been shown for the Q1291H mutation (12), resulting in a truncated protein. Login to comment 93 ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly458Val No additional mutations, except for some polymorphisms, in the CF patient homozygous for the G542X mutation, as well as in her CF cousin, who was a compound heterozygote for the G458V and G542X mutations (6), could be found. Login to comment 94 ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly458Val ABCC7 p.Gly458Val No additional mutations, except for some polymorphisms, in the CF patient homozygous for the G542X mutation, as well as in her CF cousin, who was a compound heterozygote for the G458V and G542X mutations (6), could be found. Login to comment 95 ABCC7 p.Gly458Val ABCC7 p.Gly458Val One of the polymorphisms on the G458V allele was a valine at amino acid position 470 in exon 10. Login to comment 96 ABCC7 p.Gly458Val G458V is located in exon 9 in one of the most important regions of the first nucleotide binding fold. Login to comment 103 ABCC7 p.Gly458Val The G458V allele carried seven thymidines in its poly- (T) tract, which suggests that the proportion of 9-CFTR transcripts of this allele will not be very low. Login to comment 104 ABCC7 p.Gly542* ABCC7 p.Gly458Val ABCC7 p.Gly458Val The G458V allele carried seven thymidines in its poly- (T) tract, which suggests that the proportion of 9- CFTR transcripts of this allele will not be very low. Login to comment 105 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Gly542* ABCC7 p.Tyr1092* ABCC7 p.Gly458Val The fact that the G458V/G542X individual has CF suggests that the alternatively spliced 9- CFTR mRNA transcript cannot compensate for the basic defect of the CFTR protein in this CF patient. Login to comment 106 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Tyr1092* This was also seen in another CF patient, who was a compound heterozygote for the A455E and Y1092X mutations, A455E also being located in exon 9. Login to comment 107 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Tyr1092* The A455E allele carried nine thymidines in its poly-(T) tract. Login to comment 108 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Tyr1092* The parent of the A455E/Y1092X compound heterozygote, carrying the A455E allele, carried five thymidines in the poly-(T) tract on the normal CFTR allele (data not shown). Login to comment 111 ABCC7 p.Trp1282* The 875 + 40A --~ G polymorphism was found on a W1282X allele. Login to comment 112 ABCC7 p.Trp1282* The 875 + 40A --~ G polymorphism was found on a W1282X allele. Login to comment 113 ABCC7 p.Phe508Cys Four F508C alleles were found in this study, which all turned out to carry the $1251N mutation and a second missense mutation polymorphism (M470V). Login to comment 114 ABCC7 p.Phe508Cys Four F508C alleles were found in this study, which all turned out to carry the $1251N mutation and a second missense mutation polymorphism (M470V). Login to comment