ABCMdb

PMID: 16436643

Elahi E, Khodadad A, Kupershmidt I, Ghasemi F, Alinasab B, Naghizadeh R, Eason RG, Amini M, Esmaili M, Esmaeili Dooki MR, Sanati MH, Davis RW, Ronaghi M, Thorstenson YR
A haplotype framework for cystic fibrosis mutations in Iran.
J Mol Diagn. 2006 Feb;8(1):119-27., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCC7 p.Asn1303Lys ABCC7 p.Lys1177* The next most frequent mutations were c.1677del2 (p.515fs) at 7.5%, c.4041C>G (p.N1303K) at 5.6%, c.2183AA>G (p.684fs) at 5%, and c.3661A>T (p.K1177X) at 2.5%. Login to comment 32 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Gly542* Only four (p.G542X, p.N1303K, p.G551D, and p.W1282X) have overall frequencies greater than 1%.12 Intriguingly, p.G542X and p.N1303K are found on the same haplotype background as ⌬F508, suggesting that they arose in the same population.13 Two previous reports of CFTR mutations in Iran have been published. Login to comment 91 ABCC7 p.Lys1177* ABCC7 p.Pro1013Leu Two of the mutations were only recently reported, one affecting an amino acid alteration, c.3170CϾT (p.P1013L), and another creating a stop codon, c.3661AϾT (p.K1177X). Login to comment 94 ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly85Glu ABCC7 p.Thr338Ile ABCC7 p.Ile506Thr ABCC7 p.Leu467Phe The mutation p.G85E has been shown to reduce gene activity by altering the tertiary structure of the CFTR channel;31 p.R334W leads to loss of conductivity of the large conductance channel of CFTR;32 p.T338I is a mutation in the sixth transmembrane segment of the MSD1 domain; p.L467F and p.I506T are mutations in the first nucleotide binding domain (NBD1); and p.N1303K is a mutation in the second nucleotide binding domain (NBD2) of the CFTR protein. Login to comment 95 ABCC7 p.Arg334Trp ABCC7 p.Thr338Ile ABCC7 p.Pro1013Leu ABCC7 p.Asp110His ABCC7 p.Leu467Phe Both domains are conserved in the ATP-binding cassette transporters.33 In addition, mutations p.D110H, p.R334W, p.T338I, p.L467F, and p.P1013L altered predicted exon splicing enhancer motifs in the CFTR gene, suggesting that they may have a deleterious effect on splicing. Login to comment 98 ABCC7 p.Asn1303Lys ABCC7 p.Lys1177* The next most frequent mutations were c.1677del2 (p.515fs) at 7.5%, c.4041CϾG (p.N1303K) at 5.6%, c.2183AAϾG (p.684fs) at 5%, and c.3661AϾT (p.K1177X) at 2.5%. Login to comment 105 ABCC7 p.Ile148Thr ABCC7 p.Glu1194Ala Six were exonic polymorphisms that were either silent for an amino acid change or demonstrated to have little or no effect on protein function (p.E92E, p.I148T, p.M470V, p.E1194A, p.P1290P, and p.Q1463Q). Login to comment 106 ABCC7 p.Glu1194Ala Two of the variants that altered an amino acid (p.M470V and p.E1194A) were observed in at least one patient with two other mutations, adding credence to their assignment as neutral polymorphisms (however, see below). Login to comment 107 ABCC7 p.Glu1194Ala The CF chromosome carrying p.E1194A also carried the common p.515fs mutation, because the patient was homozygous for the latter. Login to comment 109 ABCC7 p.Ile148Thr A third variant (p.I148T) was confirmed as a neutral polymorphism by a recent report.34 However, p.M470V may not be strictly neutral.21,35 It was found that the M470 protein matured more slowly and had increased intrinsic chloride channel activity compared with the V470 protein.35 In addition, the V470 allele was shown to reduce CFTR protein activity when present in combination with H1352.21 M470V may also affect exon 9 skipping during splicing processes.35,36 Its incidence in non-cystic fibrosis CFTR-related diseases also suggests that M470V has a role in those diseases.36,37 M470V in phase with the T5 allele of the polymorphic Tn locus was suggested to be a disease-causing allele in a Korean cystic fibrosis patient.38 The extent to which this allele may have contributed to the disease Table 1. Login to comment 111 ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Gly85Glu ABCC7 p.Thr338Ile ABCC7 p.Gln1412* ABCC7 p.Ile506Thr ABCC7 p.Lys1177* ABCC7 p.Pro1013Leu ABCC7 p.Asp110His ABCC7 p.Ser466* ABCC7 p.Leu467Phe ABCC7 p.Tyr563* of Patients Total alleles* Associated haplotype Global distributionHom Het Exon 1 c.134TϾC M1T 1 1 Rare Exon 3 c.386GϾA G85E 1 1 Global Exon 4 c.460GϾC D110H 1 1 H2 Europe Exon 7 c.1132CϾT R334W 1 1 H2 Global Exon 7 c.1145CϾT T338I 1 1 Europe Intron 9 c.1525-1GϾA Mis-splicing 1 1 H8 Pakistan Exon 10 c.1529CϾG S466X 1 2 H4 Germany Exon 10 c.1531CϾT L467F 1 1 Rare Exon 10 c.1649TϾC I506T 1 2 H8 Lebanon Exon 10 c.1652del3† ⌬F508 6 7 19 H5 Global Exon 10 c.1677delTA 515fs 4 1 9 H1 Europe Exon 11 c.1756GϾT G542X 1 1 H5 Global Exon 12 c.1821CϾA Y563X 2 2 Europe Exon 13 c.2183AAϾG 684fs 3 6 H3 Europe Exon 17a c.3170CϾT P1013L 1 1 Turkey Exon 19 c.3616CϾT R1162X 2 2 H2 Germany Exon 19 c.3661AϾT K1177X 1 1 3 H2 Bahrain Intron 20 c.4005ϩ1GϾA Mis-splicing 1 2 H2 Europe Exon 21 c.4041CϾG N1303K 3 1 7 H5 Global Exon 23 c.4363CϾT Q1412X 1 1 Rare *A total of 64 (53%) of the 120 expected alleles were observed. Login to comment 115 ABCC7 p.Glu1194Ala Four novel polymorphisms were observed in the Iranian CF patients, including c.297-75CϾA, c.408AϾG (p.E92E), c.1716ϩ8AϾG, and c.3713AϾC (p.E1194A). Login to comment 123 ABCC7 p.Lys1177* One of the haplotypes associated with the mutation p.K1177X was also probably recombined. Login to comment 128 ABCC7 p.Ile148Thr ABCC7 p.Glu1194Ala Putative Polymorphism in the CFTR Gene of Iranian CF Patients Genomic position* Polymorphism designation Location in gene Effect on protein Minor allele frequency DB-SNP number 42296936 c.185ϩ45AϾG Intron 1 1% 42325703 c.297-75CϾA Intron 2 6% 42347645 c.408AϾG Exon 4 E92E 1% 42347812 c.575TϾC Exon 4 I148T 2% 42352195 c.875ϩ40AϾG Intron 6a 2% 42353259 c.876-33delTTGA Intron 6a 45% rs4148700 42353428 c.1001ϩ11CϾT Intron 6b 30% rs1800503 42376147 c.1525-61AϾG Intron 9 35% 42376223 c.1540AϾG Exon 10 M470V 45% rs213950 42376407 c.1716ϩ8AϾG Intron 10 1% 42423325 c.3041-92GϾA Intron 15 15% 42423346 c.3041-71GϾC Intron 15 1% 42423539 c.3271ϩ42AϾT Intron 16b 1% 42427170 c.3272-93TϾC Intron 16b 3% 42444201 c.3601-65CϾA Intron 18 14% rs213989 42444378 c.3713AϾC Exon 19 E1194A 1% 42459334 c.4002AϾG Exon 20 P1290P 3% rs1800130 42459458 c.4005ϩ121delTT Intron 20 2% 42469386 c.4006-200GϾA Intron 20 16% rs214164 42469496 c.4006-90delC Intron 20 2% 42483798 c.4521GϾA Exon 24 Q1463Q 19% rs1800136 *Genomic reference sequence NT_007933. Login to comment 159 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* These are c.1525-1GϾA found in Pakistan, c.1649TϾC found in Lebanon, c.3170CϾT found in Turkey, and c.3661AϾT found in Bahrain.39 - 42 Two mutations that were common in the rest of the world, p.G551D and p.W1282X, were not found in this group of Iranian CF patients.43,44 This suggests that there has been some divergence in the CFTR mutation spectrum in recent human history and has implications for mutation screening in West Asia and North Africa. Login to comment 167 ABCC7 p.Tyr563* Haplotypes Observed in Iranian CF Patients and a European Control Group Haplotype c.876-33 (delTTGA) c.1001ϩ11 (C/T) c.1540 (A/G) c.3601-65 (C/A) c.4006-200 (G/A) c.4521 (G/A) Iranian CF patients (%) European controls (%) H0 7 C A C G A 1 2 H1 7 C G C G A 7 2 H2 7 C G C G G 25 39 H3 7 C A C G G 9 - H4 6 C A C G G 3 - H5 6 T A C G G 36 - H3, H4, H5 - - A C G G (48) 35 H6 7 C A A G G 3 0 H7 7 C G A G G 2 0 H8 7 C A C A G 3 0 H9 7 C A A A A 7 14 H10 7 C G A A A 5 9 Europe before it was introduced by migration, possibly from the Middle East.4,45 As for patients of European, Bashkortostanian, and Turkish descent, the vast majority (18 of 19) of the ⌬F508 alleles were associated with allele 6 of the TTGA repeat in intron 6b.9,46,47 All ⌬F508 mutations were found on the same SNP haplotype background, consistent with a report that ⌬F508 had extensive allele sharing of STR haplotypes in a French population48 and its complete linkage with a single variant of the intron 9 splice site polymorphism.49 All other CFTR mutations found on more than one chromosome, except p.Y563X, could be assigned to a single haplotype (Table 1). Login to comment 175 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Lys1177* Specifically, the four most common Turkish mutations were found in Iran, including ⌬F508, c.1677delTA, p.G542X, and c.2183AAϾG.9,29 The p.G542X "Mediterranean mutation," purported to be of Phoenician origin, was found on only one Iranian chromosome, whereas it was relatively frequent (3.6%) among the Turkish CF chromosomes.6,51 Another common mutations in Iran, p.K1177X, was not found in Turkey but was reported in Bahrain.39 In contrast, three mutations commonly found in Europe, including p.W1282X, p.G551D, and c.1717-1GϾA,12 were not found in Iran. Login to comment 177 ABCC7 p.Ser549Arg ABCC7 p.Arg75* Six additional mutations reported in at least two other Arab populations, including c.711ϩ1GϾA, p.R75X, c.1548delG, c.3120ϩ1GϾA, c.3199del6, and p.S549R,30,42,53-56 could have been detected in our assay but were not found in Iran. Login to comment