ABCMdb

PMID: 19903491

Kreindler JL
Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies.
Pharmacol Ther. 2010 Feb;125(2):219-29. Epub 2009 Nov 10., [PubMed]

Sentences

No. Mutations Sentence Comment

396 ABCC7 p.Arg117His For example, patients who have a single R117H CFTR allele (a class IV mutation) have less severe reduction of apical plasma membrane anion permeability (Reddy & Quinton, 2003; Sheppard et al., 1993) and generally have milder disease than CF patients in whom CFTR function is absent, such as those homozygous for a class I or II mutation. Login to comment 405 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Gln1412* Table 1 Classification of CFTR mutations. Class Mutation example Cellular/molecular phenotype I W1282X Absent CFTR production due to nonsense mutations, frameshift mutations, or abnormal mRNA splicing II ΔF508 Improper intracellular processing of CFTR with less than normal amounts of CFTR protein at the apical plasma membrane III G551D Defective regulation of CFTR channels at the apical plasma membrane IV R117H Defective permeation of anions through CFTR channels at the apical plasma membrane V 3849+10KbCNT Reduced synthesis of normal CFTR VI Q1412X Altered apical membrane residence time of CFTR channels with truncated c-termini 4. Login to comment 474 ABCC7 p.Gly551Asp C. For class III mutations such as G551D CFTR that have abnormal channel regulation, there are potentiators, such as VX-770, that increase the chloride conductance of the abnormal channel in the apical plasma membrane (Van Goor et al., 2009). Login to comment 527 ABCC7 p.Gly542* It restored translation of dystrophin with premature stop mutations in human muscle cells in vitro and mdx mice in vivo (Welch et al., 2007), and restored translation of human G542X CFTR in a transgenic CFTR -/- mouse (Du et al., 2008). Login to comment 537 ABCC7 p.Gly551Asp Also, class III mutations, such as G551D, result in expression of CFTR channels with abnormally low sensitivity to cAMP activation. Login to comment 542 ABCC7 p.Gly551Asp The first recognized potentiator of CFTR was 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor that potentiated the cAMP-stimulated Cl- current in Xenopus oocytes injected with either ΔF508 CFTR or G551D CFTR (Drumm et al., 1991) and in CFTR-transfected mouse mammary epithelial cells (Haws et al., 1996). Login to comment 544 ABCC7 p.Gly551Asp The flavonoid compound genistein is a tyrosine kinase inhibitor that potentiates the gating of wild-type (Illek et al., 1995) as well as ΔF508 CFTR (Hwang et al., 1997) and G551D CFTR (Illek et al., 1999). Login to comment 547 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Using combinatorial synthesis with genistein and a benzo[c]quinolizinium potentiator, MPB-07, as lead compounds, Galietta et al. identified 7,8-benzoflavones and fused pyrazolo heterocycles as potentiators of G551D CFTR (Galietta et al., 2001). Login to comment 548 ABCC7 p.Gly551Asp Using a fluorescence-based high-throughput screen, Pedemonte et al. identified sulfonamides as potentiators of ΔF508 and identified phenylglycines as potentiators of ΔF508, G551D, and other mutant CFTR (Pedemonte et al., 2005b). Login to comment 555 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp In Cos-7 cells, G551D CFTR responds differently to genistein than does G551D/G1349D CFTR, suggesting that both NBD sites play a role in the activity of genistein (Melin et al., 2004). Login to comment 560 ABCC7 p.Gly551Asp VX-770, for example, increases the amount of time that wild-type CFTR, G551D CFTR, and ΔF508 CFTR channels are open (Van Goor et al., 2009). Login to comment 561 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp VX-770 also reduces Na+ absorption and increases Cl-secretion in vitro in CF epithelial cells heterozygous for G551D and ΔF508 CFTR mutations to ~50% of cells homozygous for wild-type CFTR (Van Goor et al., 2009). Login to comment 562 ABCC7 p.Gly551Asp In 2008, Vertex and CFF presented the results of a Phase IIb clinical trial of VX-770, reporting that patients with the G551D mutation on at least one CFTR allele who took VX-770 orally for 14 or 28 d had improvement in lung function, NPD, and sweat Cl- values, suggesting that VX-770 successfully addressed the underlying defect in these patients. Login to comment 563 ABCC7 p.Gly551Asp Definitive Phase III clinical trials are currently in progress for patients with at least one G551D CFTR mutation (www.clinicaltrials.gov). Login to comment