ABCMdb

PMID: 17347447

Clancy JP, Rowe SM, Bebok Z, Aitken ML, Gibson R, Zeitlin P, Berclaz P, Moss R, Knowles MR, Oster RA, Mayer-Hamblett N, Ramsey B
No detectable improvements in cystic fibrosis transmembrane conductance regulator by nasal aminoglycosides in patients with cystic fibrosis with stop mutations.
Am J Respir Cell Mol Biol. 2007 Jul;37(1):57-66. Epub 2007 Mar 8., [PubMed]

Sentences

No. Mutations Sentence Comment

50 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Tyr1092* ABCC7 p.Glu60* GENOTYPE AND DEMOGRAPHIC INFORMATION OF STUDY SUBJECTS Age (yr) Sex Genotype Premature stop mutation subjects 16 Male 621ϩ1G-T/E60X 16 Male ⌬F508/G542X 22 Male ⌬F508/G542X 12 Female ⌬F508/G542X 22 Female ⌬F508/G542X 11 Male ⌬F508/R553X 15 Female 621ϩ1G-T/R553X 27 Female ⌬F508/R553X 32 Female ⌬F508/Y1092X 28 Male ⌬F508/R1162X 11 Female ⌬F508/W1282X Mean yr (SD) 20.2 (8.9) M:F 5:6 (six separate stop alleles represented) Control subjects 8 Male ⌬F508/⌬F508 14 Male ⌬F508/⌬F508 16 Female ⌬F508/⌬F508 16 Female ⌬F508/⌬F508 16 Male ⌬F508/⌬F508 18 Female ⌬F508/⌬F508 18 Male ⌬F508/⌬F508 20 Male ⌬F508/⌬F508 20 Female ⌬F508/⌬F508 20 Male ⌬F508/⌬F508 24 Female ⌬F508/⌬F508 32 Female ⌬F508/⌬F508 35 Male ⌬F508/⌬F508 42 Female ⌬F508/⌬F508 29 Male ⌬F508/G551D 59 Female ⌬F508/2789ϩ5G-T 16 Male ⌬F508/3905InsT 15 Female ⌬F508/N1303K Mean yr (SD) 23.2 (12.3) M:F 9:9 ⌬F508/⌬F508: 14:18 were provided (with 25% overfill) at Days 0, 7, 42, and 49 for the premature stop group, and at Days 0 and 7 for the control group. Login to comment 165 ABCC7 p.Gly542* (B) Low-power fields of nasal cells obtained from a normal subject, a patient with CF homozygous for the ⌬F508 CFTR mutation, and a subject with CF possessing a premature stop mutation (G542X/⌬F508). Login to comment 168 ABCC7 p.Gly542* The final panel demonstrates minimal CFTR staining (G542X/⌬F508 subject). Login to comment 176 ABCC7 p.Gly542* Figure 4 provides examples of cytoplasmic and surface CFTR staining of nasal cells brushed from normal control subjects, perinuclear CFTR staining from a ⌬F508/⌬F508 subject with CF, and sparse staining from a subject with CF heterozygous for a premature stop mutation (G542X/⌬F508; all staining shown was from cells isolated from subjects off of treatment). Login to comment 212 ABCC7 p.Trp1282* The majority of premature stop subjects were homozygous for stop mutations (n ϭ 11/19), and all possessed at least one copy of the W1282X CFTR mutation. Login to comment 213 ABCC7 p.Trp1282* In contrast, no subject in our study had two copies of premature stop mutations, and only 1 of 11 subjects carried the W1282X CFTR mutation. Login to comment 215 ABCC7 p.Trp1282* Furthermore, in vitro studies completed in our laboratory have demonstrated that W1282X CFTR can retain partial function that is enhanced after stop codon suppression (28). Login to comment 216 ABCC7 p.Trp1282* Thus, increased activity of W1282X CFTR might be predicted in the context of higher expression levels. Login to comment 220 ABCC7 p.Trp1282* Thus, genetic differences in NMD between the Israeli and American populations with CF may account in part for differences in treatment effects (particularly in the context of the W1282X CFTR mutation). Login to comment 230 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Arg1162* The four most common stop mutations (G542X, R553X, R1162X, W1282X CFTR) all contain a UGA codon, and all have been shown to be suppressed by aminoglycoside treatment in vitro using heterologous expression systems. Login to comment 231 ABCC7 p.Tyr1092* ABCC7 p.Glu60* The less common stop mutations found in our study subjects (E60X, Y1092X) are produced by other codons (UAG or UAA, respectively) that are frequently less sensitive to suppression than the UGA codon (20). Login to comment