ABCMdb

PMID: 24561283

Ikpa PT, Bijvelds MJ, de Jonge HR
Cystic fibrosis: toward personalized therapies.
Int J Biochem Cell Biol. 2014 Jul;52:192-200. doi: 10.1016/j.biocel.2014.02.008. Epub 2014 Feb 20., [PubMed]

Sentences

No. Mutations Sentence Comment

1592 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Just four other mutations, notably G551D (class III), W1282X, G542X (class I), and N1303K (class II) have a worldwide prevalence of 1-3% each, whereas only 20 mutations have a frequency above 0.1%. Login to comment 1620 ABCC7 p.Gly480Cys ABCC7 p.Asn287Tyr Most CFTR trafficking mutants, including F508del, with a few exceptions (e.g. G480C; N287Y), show additional defects in channel gating function, and most PCs and PRs identified thus far only partially normalize the channel conformational defect. Login to comment 1640 ABCC7 p.Gly551Asp 2.3.4. Improvement of CFTR gating by potentiators Most CFTR class III gating mutations, including the most common "Keltic" mutation, G551D (frequency ~3%) are localized in the ABC signature sequence or in the Walker A or B motif of the two ATP binding pockets (ABP1 and ABP2) of the NBDs (cf. Login to comment 1644 ABCC7 p.Gly551Asp This non-conventional gating mechanism could be reproduced in purified G551D-CFTR inserted in planar lipid bilayers and proteoliposomes, confirming that VX-770 binds directly to the CFTR protein, most plausibly to the MSDs rather than the NBDs (Eckford et al., 2012). Login to comment 1646 ABCC7 p.Arg117His This new gating model may explain why VX-770 increases the open probability of both WT CFTR and all 10 class III gating mutants tested (Yu et al., 2012), as well as numerous other CFTR forms with missense mutations or deletions, including F508del and R117H (Rowe and Verkman, 2013; Van Goor et al., 2014). Login to comment 1647 ABCC7 p.Gly551Asp In several phase III trials oral VX-770 treatment of G551D patients led to rapid, dramatic and sustained improvements in FEV1 and body weight, and a strong reduction of sweat chloride and pulmonary exacerbations (reviewed in Rowe and Verkman, 2013). Login to comment 1650 ABCC7 p.Gly551Asp However recent studies on human bronchial cells suggest an alternative explanation: in these cells, chronic exposure to VX-770 resulted in a dramatic increase in endocytosis and lysosomal degradation of WTand F508del-CFTR, but not of G551D channels (Cholon DM, 2013). Login to comment 1653 ABCC7 p.Gly551Asp The isoflavone genistein, a major component of soya-rich food, potentiates G551D- and F508del-CFTR channels by binding to the NBDs and promoting ATP-dependent gating (French et al., 1997; Sohma et al., 2013), but also enhances CFTR phosphorylation at basal cAMP levels (Pyle et al., 2011) and inhibits CFTR endocytosis through an ill-defined mechanism (Lim et al., 2007). Login to comment 1655 ABCC7 p.Gly551Asp As predicted from their distinct mechanism of action, the combined application of genistein and curcumin in a low concentration range (5-10 òe;M) synergistically restored the gating defect of G551D of up to ~50% of the WT level (Sohma et al., 2013). Login to comment 1658 ABCC7 p.Gly551Asp Toward individualized therapies The success of VX-770 monotherapy in G551D patients and improved insights into the mechanism of action of CFTR potentiators and correctors have greatly boosted attempts to develop more potent and specific CFTR modulators targeting a specific class of mutant CFTR. Login to comment 1675 ABCC7 p.Arg117His Such a strategy may be particularly important to identify corrector effects in biopsies carrying very mild mutations (e.g. R117H) that are associated with < 80% loss of CFTR function. Login to comment 1687 ABCC7 p.Ala455Glu Normalized non-corrected FIS rates differed greatly between different CFTR genotypes (non-CF > class V (A455E) > class II (F508del) > class I), and, perhaps less evident, between individuals carrying the same alleles (i.e. F508del/F508del). Login to comment