ABCMdb

PMID: 16423550

Ramirez AM, Ramos MD, Jimenez J, Ghio A, de Botelli MM, Rezzonico CA, Marques I, Pereyro S, Casals T, de Kremer RD
Mutational spectrum of cystic fibrosis patients from Cordoba province and its zone of influence: implications of molecular diagnosis in Argentina.
Mol Genet Metab. 2006 Apr;87(4):370-5. Epub 2006 Jan 19., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCC7 p.Gly85Glu ABCC7 p.Arg1066Cys Another four mutations (p.R1066C, c.1811 + 1.6kbA > G, c.711 + 1G > T, and p.G85E) were found based on the microsatellite haplotype-mutation association. Login to comment 9 ABCC7 p.Gly27Arg ABCC7 p.Trp277Arg Finally, 14 mutations were characterized after the CFTR gene scanning, three of them are not previously described (p.G27R, c.622-2A> G, and p.W277R). Login to comment 16 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* The most frequent mutations worldwide (p.F508del, p.G542X, p.G551D, p.N1303K, and p.W1282X) have shown considerable diVerences in their frequencies depending on ethnic origin and geographic areas. Login to comment 44 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Glu60* Mutations (p.F508del, p.N1303K, p.G542X, p.R334W, c.2789 + 5G > A, c.3659delC, p.R553X, c.3849 + 10kbC > T, p.R1162X, c.621 + 1G > T, p.W1282X, p.R117H, c.1078delT, p.E60X, p.R347P, p.A455E, p.I507del, c.1717-1G > A, p.G551D, [c.2183A > G; c.2184delA] and p.S1251N) were analyzed by heteroduplex analysis on polyacrylamide gel electrophoresis [11,12] and by ampliWcation refractory mutation system [13] in all 78 patients. Login to comment 62 ABCC7 p.Gly85Glu ABCC7 p.Arg1066Cys According to the obtained haplotypes, the following mutations were studied: c.2869insG, CFTRdele2.3 (g.24291_29180del21kb), p.R1066C, c.711+1G>T, c.1811+1.6kbA>G, and p.G85E, the last four mutations were detected in seven patients. Login to comment 73 ABCC7 p.Gly27Arg ABCC7 p.Trp277Arg Among these 13 mutations, we detected three novel CFTR mutations (validation of mutations according to HUGO), two missense changes (p.G27R and p.W277R) and one splice site mutation (c.622-2A > G) (Table 3). Login to comment 74 ABCC7 p.Ile148Thr The mutation c.3199_3204delATAGTG has been found in the same allele that the p.I148T, a complex allele previously described. Login to comment 75 ABCC7 p.Ile148Thr More recently, it has been proposed that the p.I148T is a benign polymorphism. Login to comment 77 ABCC7 p.Gly27Arg The p.G27R missense mutation was found in a male patient diagnosed at 2 months and who died at 14 years. Login to comment 79 ABCC7 p.Trp277Arg The p.W277R mutation was identiWed in a patient who carries the p.F508del mutation on the paternal CF allele. Login to comment 85 ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Ile148Thr ABCC7 p.Gly85Glu ABCC7 p.Arg1066Cys ABCC7 p.Arg1283Met ABCC7 p.Trp1089* ABCC7 p.Gly27Arg ABCC7 p.Trp277Arg ABCC7 p.Ser589Ile Haplotype (n D 20) No. of chromosomes (n D 64)a Mutations associated (No. of chromosomes) 23-31 14 p.F508del 17-31 7 p.F508del 17-7 7 p.R1066C (3), p.W277R, c.2789 + 5G > A, c.3120 + 1G > A, c.3849 + 10KbC > T 16-7 6 c.3272-26A > G (2), p.G27R, c.622-2A > G, unknown (2) 16-32 5 p.S589I (2), unknown (3) 16-30 3 IVS8-5T (2), unknown 23-33 2 p.G542X, p.R1283M 23-32 2 p.G542X 23-30 2 p.F508del, p.N1303K 24-31 2 p.N1303K 16-24 2 p.G85E 16-31 3 c.1898 + 1G > A, p.W1089X, unknown 16-46 2 c.1811 + 1.6KbA > G 16-25 1 c.711 + 1G > T 16-33 1 Unknown 16-44 1 c.1898 + 1G > A 16-45 1 p.Y913C 16-47 1 c.4005 + 1G > A 17-30 1 Unknown 23-7 1 [c.3199_3204delATAGTG; p.I148T] Table 2 Frequency of the mutations in the 78 CF Argentinean patients of Córdoba region a IdentiWed novel mutations. Login to comment 86 ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ile148Thr ABCC7 p.Gly85Glu ABCC7 p.Arg1066Cys ABCC7 p.Arg1283Met ABCC7 p.Trp1089* ABCC7 p.Ser589Ile Mutation Exon/Intron CF alleles % p.F508del Exon 10 94 60.26 p.N1303K Exon 21 8 5.13 p.G542X Exon 11 7 4.49 p.R334W Exon 7 3 1.93 p.R1066C Exon 17b 3 1.93 c.2789 + 5G > A Intron 14b 3 1.93 p.G85E Exon 3 2 1.28 c.3659del C Exon 19 2 1.28 c.1811 + 1.6kbA > G Intron 11 2 1.28 c.1898 + 1G > A Intron 12 2 1.28 c.3272-26A > G Intron 17a 2 1.28 p.S589I Exon 12 2 1.28 p.R553X Exon 11 2 1.28 IVS8-5T Intron 8 2 1.28 c.3849 + 10kb C > T Intron 19 1 0.64 c.621 + 1G > T Intron 4 1 0.64 p.R1162X Exon 19 1 0.64 c.711 + 1G > T Intron 5 1 0.64 c.3120 + 1G > A Intron 16 1 0.64 p.Y913C Exon 15 1 0.64 c.4005 + 1G > A Intron 20 1 0.64 p.W1089X Exon 17b 1 0.64 p.R1283M Exon 20 1 0.64 [p.I148T;c.3199_3204del ATAGTG] Exon 4, Exon 17a 1 0.64 p.G27Ra Exon 2 1 0.64 p.W277Ra Exon 6b 1 0.64 c.622-2A > Ga Intron4 1 0.64 Unknown allele - 9 5.77 Wrst year of life he required several internments, for hydroelectric desequilibrium and persistent pulmonary infections causing failure to thrive. Login to comment 89 ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Gly85Glu ABCC7 p.Arg1066Cys ABCC7 p.Ser589Ile Fourteen mutations have a frequency higher than 1%, p.F508del (60.26%), p.N1303K (5.13%), p.G542X (4.49%), and three mutations, p.R334W, p.R1066C, c.2789 + 5G> A (1.93%), and another eight, p.G85E, c.3659delC, c.1811 + 1.6kbA > G, c.1898 + 1G > A, c.3272-26A > G, p.S589I, p.R553X, and 5T (1.28%). Login to comment 98 ABCC7 p.Gly27Glu ABCC7 p.Gly27* ABCC7 p.Gly27Arg About of the novel mutations, our results suggest that p.G27R correlate with a severe phenotype likewise that p.G27X previously described, while another mutation in the same codon, p.G27E, has a milder clinical presentation of CF with late onset of symptoms, diagnosed at 41 years with CBAVD, pancreatic suYciency and mild pulmonary disease [20,21]. Login to comment 103 ABCC7 p.Gly27Arg Novel mutationsa Nucleotide change Exon/ Intron Consequence Haplotype IVS 8CA- IVS17bTA Detection method Clinical datab p.G27R G > A at 211 E.2 Gly > Arg 16-7 SSCA and Seq. Login to comment 105 ABCC7 p.Trp277Arg He is 4 years old, PI, mild lung involvement p.W277R A > G at 961 E.6b Trp > Arg 17-7 SSCA and Seq. Female 5 years old diagnosed at 11 months. Login to comment 107 ABCC7 p.Trp277Arg He is 4 years old, PI, mild lung involvement p.W277R A > G at 961 E.6b Trp > Arg 17-7 SSCA and Seq. Female 5 years old diagnosed at 11 months. Login to comment 111 ABCC7 p.Gly27Arg ABCC7 p.Trp277Arg Missense mutations, p.G27R and p.W277R were identiWed in CF patients with severe phenotype and it may postulate that both changes aVect the CFTR activity. Login to comment 112 ABCC7 p.Gly27Arg The p.G27R in the N-terminal region could inXuence the interaction between CFTR and proteins that regulate its expression [23]. Login to comment 113 ABCC7 p.Gly27Arg ABCC7 p.Trp277Arg ABCC7 p.Trp277Arg Missense mutations, p.G27R and p.W277R were identiWed in CF patients with severe phenotype and it may postulate that both changes aVect the CFTR activity. Login to comment 114 ABCC7 p.Gly27Arg The p.G27R in the N-terminal region could inXuence the interaction between CFTR and proteins that regulate its expression [23]. Login to comment 115 ABCC7 p.Trp277Arg Whereas the p.W277R mutation, in the three intracellular loop, may aVect the interaction with the NB1 domain [24]. Login to comment 117 ABCC7 p.Trp1282* ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Other most signiWcant diVerences were that in Buenos Aires, besides the p.F508del, only Wve mutations showed frequencies higher than 1%, being their percentages the following ones: p.F508del 58.64%, p.G542X 4.1%, p.W1282X 2.73%, p.N1303K 2.73%, and the last two ones p.R334W and c.1717-1G > A with 1.14%. Login to comment 118 ABCC7 p.Trp1282* It is interesting to note that p.W1282X and c.1717-1G> A mutations, two of the most common in Buenos Aires study, were not found in our patients. Login to comment 119 ABCC7 p.Trp1282* ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Other most signiWcant diVerences were that in Buenos Aires, besides the p.F508del, only Wve mutations showed frequencies higher than 1%, being their percentages the following ones: p.F508del 58.64%, p.G542X 4.1%, p.W1282X 2.73%, p.N1303K 2.73%, and the last two ones p.R334W and c.1717-1G > A with 1.14%. Login to comment 120 ABCC7 p.Trp1282* It is interesting to note that p.W1282X and c.1717-1G> A mutations, two of the most common in Buenos Aires study, were not found in our patients. Login to comment 121 ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1066Cys ABCC7 p.Arg1066Cys ABCC7 p.Arg1283Met ABCC7 p.Trp1089* ABCC7 p.Tyr913Cys ABCC7 p.Trp277Arg ABCC7 p.Ser589Ile In addition, it is important to denote that in our series the most frequent mutations found were p.F508del, p.N1303K, p.G542X, p.R334W, p.R1066C, and c.2789+5G>A, however, the last two ones were rare in Buenos Aires series (p.R1066C, 0.23%) and others were not found (p.S589I, c.3272-26A>G, c.1898+1G>A, c.711+1G>T, c.3199_ 3204delATAGTG, p.W1089X, p.R1283M, p.Y913C, c.4005+1G>A, c.3120 +1G >A, p.G27R, p.W277R, and c.622-2A>G). Login to comment 123 ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1066Cys ABCC7 p.Arg1066Cys ABCC7 p.Arg1283Met ABCC7 p.Trp1089* ABCC7 p.Tyr913Cys ABCC7 p.Trp277Arg ABCC7 p.Ser589Ile In addition, it is important to denote that in our series the most frequent mutations found were p.F508del, p.N1303K, p.G542X, p.R334W, p.R1066C, and c.2789+5G>A, however, the last two ones were rare in Buenos Aires series (p.R1066C, 0.23%) and others were not found (p.S589I, c.3272-26A>G, c.1898+1G>A, c.711+1G>T, c.3199_ 3204delATAGTG, p.W1089X, p.R1283M, p.Y913C, c.4005+1G>A, c.3120 +1G >A, p.G27R, p.W277R, and c.622-2A>G). Login to comment