ABCMdb

PMID: 20622033

Sermet-Gaudelus I, Boeck KD, Casimir GJ, Vermeulen F, Leal T, Mogenet A, Roussel D, Fritsch J, Hanssens L, Hirawat S, Miller NL, Constantine S, Reha A, Ajayi T, Elfring GL, Miller LL
Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis.
Am J Respir Crit Care Med. 2010 Nov 15;182(10):1262-72. Epub 2010 Jul 9., 2010-11-15 [PubMed]

Sentences

No. Mutations Sentence Comment

136 ABCC7 p.Gly542* Patients with end-of-treatment total chloride transport hyperpolarization in either cycle were more likely to show both intrinsic and stimulated chloride transport changes; such changes are demonstrated in an example of pretreatment and end-of-treatment nasal TEPD tracings from a 14-year-old female patient with a G542X/DF508 genotype and a UGA premature stop codon type who received the higher dose of ataluren in Cycle 1 (Figure 2). Login to comment 138 ABCC7 p.Gly542* Of these genotypes, G542X was the most common; in the 14 patients with this genotype, 6 (43%) met the criterion for a total chloride transport response and 7 (50%) showed hyperpolarization of total chloride transport. Login to comment 139 ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Arg1162* An examination of the data in the two patients who were homozygous for stop mutations in both alleles (one with G542X/G542X and one with R1162X/ R1162X) did not suggest that these patients were more likely to have an improvement in total chloride transport than patients who were heterozygous for a nonsense mutation in only one allele. Login to comment 148 ABCC7 p.Trp882* An example of paired pretreatment and second-cycle end-of- treatment immunostaining images are shown for a 17-year-old female patient with a W882X/DF508 genotype and a UAG premature stop codon type who received the low-to-high dose sequence of ataluren (Figure 4); these images correspond to the patient denoted in Figure 3. Login to comment 154 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gln493* ABCC7 p.Trp846* ABCC7 p.Glu1104* ABCC7 p.Gln1313* ABCC7 p.Trp882* BASELINE PATIENT CHARACTERISTICS Characteristic N 5 30 Age, median, yr (range) 12 (6 to 18) Sex, n Male 16 Female 14 BMI, median % predicted*(range) 35 (,1 to 97) Sweat test chloride concentration, median, mEq/L† (range) 104 (84 to 140) TEPD Total chloride transport, median, mV‡ (range) 20.3 (24.6 to 114.6) Pulmonary function, mean % predictedx FEV1 (range) 90 (40 to 133) FVC (range) 99 (52 to 131) Pathologic bacterial/fungal colonization, n 30 Staphylococcus aureus 26 Pseudomonas aeruginosa 9 Hemophilus influenzae 3 Alcaligenes xylosoxidans 1 Stenotrophomonas maltophilia 1 Pancreatic insufficiency, n 30 Exocrine 30 Endocrine 2 Liver enzyme abnormalities, n 15 Alkaline phosphatase 7 Lactate dehydrogenase 6 g-Glutamyltransferase 4 Alanine aminotransferase 4 Aspartate aminotransferase 2 Bilirubin 1 Nonsense mutation genotype (premature stop codon type), n G542Xk (UGA) 14 W1282X (UGA) 4 Q493X (UAG) 3 R553X (UGA) 2 E1104X (UGA) 2 R1162Xk (UGA) 2 W846X (UGA) 1 W882X (UAG) 1 Q1313X (UAA) 1 Definition of Abbreviations: BMI 5 body mass index; TEPD 5 transepithelial potential difference. Login to comment 159 ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Arg1162* k Two patients were homozygous for nonsense mutations (G542X/G542X, n 5 1; R1162X/R1162X, n 5 1). Login to comment 189 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Gln493* ABCC7 p.Trp846* ABCC7 p.Glu1104* ABCC7 p.Gln1313* ABCC7 p.Trp882* TOTAL CHLORIDE TRANSPORT RESPONSE AND HYPERPOLARIZATION BY NONSENSE MUTATION TYPE Nonsense Mutation Type Responses* n/N† % Response Rate Hyperpolarizations‡ n/N† % Hyperpolarization Rate Q493X (UAG) 1/3 33 1/3 33 G542X (UGA) 8/14 57 7/14 50 R553X (UGA) 1/2 50 1/2 50 W846X (UGA) 0/1 0 0/1 0 W882X (UAG) 1/1 100 1/1 100 E1104X (UGA) 1/2 50 0/2 0 R1162X (UGA) 1/2 50 2/2 100 W1282X (UGA) 2/4 50 2/4 50 Q1313X (UAA) 0/1 0 0/1 0 * At least a 25 mV total chloride transport improvement in either cycle. Login to comment 190 ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Arg1162* † Patients with nonsense mutations in both cystic fibrosis transmembrane conductance regulator alleles are counted only once (G542X/G542X, n 5 1; R1162X/R1162X, n 5 1). Login to comment 234 ABCC7 p.Trp1282* ABCC7 p.Gly542* However, our data do extend the range of nonsense mutations studied beyond the three responsive nonsense mutation genotypes (G542X, W1282X, and 3849110 kB C/T) evaluated in adults with CF (29). Login to comment 235 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Gln493* ABCC7 p.Glu1104* ABCC7 p.Trp882* Our findings indicate that multiple genotypes (Q493X, G542X, R553X, W882X, E1104X, R1162X, and W1282X) can be responsive to ataluren therapy. Login to comment