ABCMdb

PMID: 26567541

Bosch B, De Boeck K
Searching for a cure for cystic fibrosis. A 25-year quest in a nutshell.
Eur J Pediatr. 2015 Nov 14., [PubMed]

Sentences

No. Mutations Sentence Comment

48 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys Table 1 CF mutation classes and a potential approach for correcting the defect Mutation class CFTR defect result Mutation type Mutation example Potential therapy Mutation class Specific Aspecific I No full-length CFTR Premature stop codon, Large deletions, Out-of-frame deletions or insertions G524X, W1282X Read-through (e.g. ataluren) RNA correction Gene therapy II Processing defect Missense, amino acid deletion F508del, N1303K, 1507del Corrector III Regulation defect Missense G551D Potentiator (e.g. ivacaftor) IV Decreased conductance Missense R117H Potentiator V Reduced synthesis Missense, change in splicing efficiency 3849+10 kb C࢐G, A455E, 5 T Corrector (e.g. VX-809) Potentiator VI Altered channel stability Nonsense, frameshift 4326 delTC, 4279insA Potentiator Proteastasis inhibitor In class I mutation, no protein reaches the plasma membrane as transcription is halted prematurely in the case of premature stop codons or the protein is non-functional in the case of large deletions or out-of-frame deletions or insertions); in class II mutations, a block in protein folding and trafficking leads to protein degradation in the proteasome; class III mutations lead to a protein with defective channel regulation; in class IV, the CFTR channel has an altered conductance; in class V, the amount of CFTR channels synthetized present at the cell membrane is reduced; class VI mutations lead to a functional but less stable protein in the apical cell membrane. Login to comment 105 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Called 'the most important new drug of 2012` and 'a wonder drug`, ivacaftor (Kalydeco&#ae;) indeed decreases sweat chloride concentration by a mean of 50 mmol/L in patients with a class III mutation (e.g. G551D and the less common non-G551D gating mutations) [15, 34]. Login to comment 112 ABCC7 p.Arg117His In clinical trials, some benefit is also proven in patients with the class IV mutation R117H [30] and likely but still to be firmly proven in subjects with mutations associated with residual CFTR function [41]. Login to comment 165 ABCC7 p.Gly551Asp Nutritional status improved in cystic fibrosis patients with the G551D mutation after treatment with ivacaftor. Login to comment 185 ABCC7 p.Gly551Asp De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, Higgins M (2014) Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. Login to comment 216 ABCC7 p.Arg117His Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley SA, Rubenstein RC, Higgins M, VX11-770-110 (KONDUCT) Study Group (2015) Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med 3(7):524-33 31. Login to comment 224 ABCC7 p.Gly551Asp Ramsey BW, Davies J, McElvany TE, Tullis E, Bell SC, Dev&#ed;nek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordo&#f1;ez C, Elborn JS, VX08-770-102 Study Group (2011) A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. Login to comment 230 ABCC7 p.Gly551Asp Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, Sagel SD, Khan U, Mayer-Hamblett N, Van Dalfsen JM, Joseloff E, Ramsey BW, GOAL Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network (2014) Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Login to comment 245 ABCC7 p.Gly551Asp Addition of VX-661 to KALYDECO&#ae; (ivacaftor) Improves lung function in people with CF who are heterozygous for the F508del and G551D mutations in 28-day phase 2 proof-of-concept study. Login to comment