ABCMdb

PMID: 10834512

Kambouris M, Banjar H, Moggari I, Nazer H, Al-Hamed M, Meyer BF
Identification of novel mutations in Arabs with cystic fibrosis and their impact on the cystic fibrosis transmembrane regulator mutation detection rate in Arab populations.
Eur J Pediatr. 2000 May;159(5):303-9., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ORIGINAL PAPER M. Kambouris á H. Banjar á I. Moggari á H. Nazer á M. Al-Hamed á B. F. Meyer Identi®cation of novel mutations in Arabs with cystic ®brosis and their impact on the cystic ®brosis transmembrane regulator mutation detection rate in Arab populations Received: 18 December 1998 / Accepted: 14 May 1999 Abstract The cystic ®brosis transmembrane regulator (CFTR) gene in Arab patients with cystic ®brosis (CF) (sweat chloride >60 mmol/l) from 61 unrelated families was screened for mutations in exons 3, 4, 5, 7, 10, 11, 16 and 19 and for mutations W1282X, N1303K and 3849 + 10kbC ® T. Login to comment 5 ABCC7 p.His139Leu The comparative frequencies of the most common mutations are: 1548delG> I123V DF508 3120 + 1G ® A > H139L. Login to comment 43 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys Mutation analysis All patients were screened for known mutations 3849 + 10KbC ® T (intron 19), W1282X (exon 20) and N1303K (exon 21) by restriction enzyme digestion analysis with enzymes Mnl I, Bst OI and Hph I respectively according to standard protocols [23]. Login to comment 63 ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Ser549Arg ABCC7 p.Ile1234Val ABCC7 p.Arg75* ABCC7 p.Ala141Asp Of more than 850 known CFTR mutations (http:// www.genet.sickkids.on.ca/cftr-cgi-bin/Mutation Table), only 9 were encountered in this study: R75X, A141D, 1249G ® A, DF508, S549R, R553X, 3120 + 1G ® A, I1234V and N1303K. Login to comment 64 ABCC7 p.His139Leu ABCC7 p.Phe533Leu CFTR exons 4, 10, 11 from 100 normal individuals (200 chromosomes) were screened to evaluate whether the novel missense mutations found in these exons (H139L in exon 4 and F533L in exon 11) were neutral polymorphisms rather than pathogenic mutations. Login to comment 65 ABCC7 p.His139Leu ABCC7 p.Phe533Leu Neither the H139L (exon 4) nor the F533L (exon 11) mutations were detected among the normal individuals suggesting that they indeed represent pathogenic sequence changes. Login to comment 70 ABCC7 p.Ile148Thr One with the I148T (585C ® T) mutation in exon 4 and the other with DF508 in exon 10. Login to comment 80 ABCC7 p.Ile1234Val These are: DF508, the most common mutation in Caucasians, 3120 + 1G ® A, the most common mutation in Africans and I1234V which has been reported previously as a ``familial'' mutation in the South of France [3]. Login to comment 81 ABCC7 p.His139Leu The last of the common Arab mutations (H139L) is a novel missense mutation that has not been seen in any other ethnic group. Login to comment 88 ABCC7 p.His139Leu ABCC7 p.Phe533Leu Two mutations resulted in amino acid substitutions (H139L and F533L). Login to comment 93 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys In that study, three mutations, DF508 (37.5%), W1282X (15.6%), and N1303K (9.4%) collectively accounted for 62.5% of the CF alleles. Login to comment 94 ABCC7 p.Trp1282* W1282X was not encountered at all in our study while the incidence of the other two mutations was signi®cantly lower among the families we examined. Login to comment 100 ABCC7 p.Asn1303Lys This is highlighted by the absence of families with the DF508 mutation which is present in 13% of our study group including Saudi Arabs. The study lists only three common mutations among Arab: the ®rst (3120 + 1A ® G) was found in three families while the other two (N1303K and 1548delG), in only two families. Login to comment 103 ABCC7 p.His139Leu Two of the six ``common Arab'' mutations, namely 1548delG and H139L have not been observed in any Caucasian chromosomes, suggesting that they are derived from the native Arab population. Login to comment 108 ABCC7 p.Arg75* ABCC7 p.Gln98His aa amino acids CFTR position Mutation DNA Consequence Number of families Number and percentage of alleles Exon 3 355C ® T R75X ± protein truncation 1a [1548delG] 1 (private mutation) Exon 4 425del42 Q98H and deletion of the following 14 aa 1a [?] Login to comment 109 ABCC7 p.Ser549Arg ABCC7 p.Ile1234Val ABCC7 p.His139Leu ABCC7 p.Ala141Asp 1 (private mutation) 475G ® T G115X ± protein truncation 1 2 1a [I1234V] 1 Total: 2 2.5% 536C ® T A141D 1 2 (private mutation) 548A ® T H139L 3 6 1a [S549R] 1 Total: 4 6% Exon 5 711 + 1G ® A Splice site 1 2 1a [?] Login to comment 111 ABCC7 p.Asn1303Lys ABCC7 p.Arg75* 1 (private mutation) Exon 10 1548delG Frame shift 8 16 Altered residues at aa 473; stop codon at 526 1a [R75X] 1 1a [1811 + 2 T ® C] 1 1a [N1303K] 1 2a [?] Login to comment 113 ABCC7 p.Phe533Leu 2 Total: 8 12% Exon 11 1729T ® C F533L 1a [?] Login to comment 114 ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Ser549Arg ABCC7 p.His139Leu 1 (private mutation) 1779T ® G S549R 1 2 1a [H139L] 1 Total: 2 2.5% 1789C ® T R553X ± protein truncation 1a [3120 + 1G ® A] 1 (private mutation) 1811 + 2T ® C Splice site 1a [1548delG] 1 (private mutation) Exon 16 3120 + 1G ® A Splice site 5 10 1a [R533X] 1 1a [N1303K] 1 1a [?] Login to comment 115 ABCC7 p.Asn1303Lys ABCC7 p.Ile1234Val ABCC7 p.Phe533Leu ABCC7 p.Lys1177* 1 Total: 8 11% Exon 19 3661A ® T K1177X ± protein truncation 1 2 (private mutation) 3832A ® G I1234V 7 14 1a [G115X] 1 Total: 8 12.5% Exon 21 4041C ® G N1303K 1a [1548delG] 1 1a [3120 + 1G ® A] 1 Total: 2 1.5% Undetected 11 22 1a [425del42] 1 1a [711 + 1G ® A] 1 2a [1548delG] 2 2a [DF508] 2 1a [F533L] 1 1a [1249 + 1G ® A] 1 1a [3120 + 1G ® A] 1 Total: 20 25% a Indicates a compound heterozygous family. Login to comment 117 ABCC7 p.His139Leu ABCC7 p.Phe533Leu aa amino acids CFTR position Mutation Consequence Exon 4 425del42 In-frame 42 bp deletion [426-467] that predicts the removal of 14 aa [99-112] from the CFTR protein and a Gln ® His substitution at aa residue 98 [deletion point] 475G ® T [G115X] G ® T transversion at nucleotide 475 that results in Glu ® Stop codon at aa 115 548A ® T[H139L] A ® T transition at nucleotide 548 that results in a His ® Leu substitution at aa 139 Exon 5 711 + 1G ® A G ® A transition at nucleotide 711 + 1 causing a splice site defect Exon 10 1548delG Deletion of a ``G'' at nucleotide1548 which predicts a frameshift mutation that alters the aa sequence starting at residue 473 and results in translation termination at residue 526 Exon 11 1729T ® C [F533L] T ® C transition at nucleotide 1729 that results in a Phe ® Leu at aa 533 1811 + 2T ® C T ® C transversion at nucleotide 1811 + 2 causing a splice site defect Exon 19 3361A ® T [L1177X] A ® T transition at nucleotide 3361 that results in a Lys ® Stop codon at aa 1177 Fig. 1 MDE heteroduplex analysis and sequencing of amplicons containing novel CFTR mutations identi®ed in Arabs. Login to comment 125 ABCC7 p.His139Leu Arab CF patients carry CFTR mutations that have not been reported in other populations (1548delG and H139L). Login to comment