ABCMdb

PMID: 11100963

Choo-Kang LR, Zeitlin PL
Type I, II, III, IV, and V cystic fibrosis transmembrane conductance regulator defects and opportunities for therapy.
Curr Opin Pulm Med. 2000 Nov;6(6):521-9., [PubMed]

Sentences

No. Mutations Sentence Comment

22 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Tyr1092* ABCC7 p.Gln39* ABCC7 p.Arg75* ABCC7 p.Ser1196* ABCC7 p.Glu60* ABCC7 p.Leu719* The nonsense mutations G542X, W1282X, R553X, Q39X, E60X, R75X, L719X, Y1092X, and S1196X significantly reduce the levels of mutant CFTR mRNA to 5 to 30% of wild-type levels [28]. Login to comment 31 ABCC7 p.Trp1282* Interestingly, one patient who carried the W1282X/3849 + 10kbC→T genotype showed complete normalization of chloride transport on NPD following gentamicin administration [31••]. Login to comment 37 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Molecular fate of CFTR protein Type of genetic defect and example Class-specific potential therapeutic approach Specific clinical examples I No synthesis Nonsense G542X Frameshift 394delTT Splice junction 1717-1G→A Aminoglycoside readthrough of premature termination site Gentamicin II Trafficking block AA deletion ∆F508 Missense N1303K Manipulation of intracellular folding environment (chemical or molecular chaperones) Phenylbutyrate, CPX III Block in regulation Missense G551D Stimulation of membrane localized mutant channel Genistein, MPB- compounds IV Altered conductance Missense R117H Augmentation of mutant channel conductance Milrinone, adenosine nucleotides V Reduced synthesis of normal protein Missense A455E Alternative splicing 3849+10kbC→T Maximal activation of decreased but functionally normal channels Stimulation of mRNA and protein synthesis ? Login to comment 52 ABCC7 p.Gly480Cys Since "misfolding" of the ∆F508 CFTR and other class II mutants (eg, G480C) does not completely abolish CFTR chloride conductance [44-46], therapies can be aimed primarily at overcoming the trafficking block, thereby permitting surface expression of the partially active mutant channel. Login to comment 89 ABCC7 p.Gly551Asp G551D is localized at the cell surface but exhibits impaired ATP binding and does not conduct chloride in response to elevated cAMP [71,72]. Login to comment 90 ABCC7 p.Gly551Asp G551D is typically associated with pancreatic insufficiency and a severe phenotype. Login to comment 92 ABCC7 p.Gly551Ser ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Ser1255Pro These mutants, including S1255P, G551S, G1244E, and G1349D, sustain a reduced response to ATP. Login to comment 97 ABCC7 p.Gly551Asp In a small study of five CF patients carrying at least one G551D mutation, perfusion of the nasal mucosa with genistein stimulated chloride-dependent NPD to an average of 16.9% of the responses found in healthy subjects [77••]. Login to comment 106 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly314Glu These CFTR mutants including R117H, G314E, R334W, and R347P demonstrate a reduction in their chloride conductance or abnormal channel gating (see Fig. 2). Login to comment 108 ABCC7 p.Arg117His ABCC7 p.Pro574His ABCC7 p.Arg347Pro R347P affects the rate of chloride flow, whereas R117H and P574H reduce the channel open time. Login to comment 113 ABCC7 p.Gly551Asp Although a recent study failed to demonstrate a significant effect of milrinone on chloride secretion in both ∆F508 and G551D CF patients [83], phosphodiesterase inhibitors such as rolipram, papaverine, and IBMX (3-isobutyl-1- methyxanthine) may still be beneficial for less stringent mutations. Login to comment 114 ABCC7 p.Arg117His In a murine R117H model, milrinone in combination with foskolin resulted in a favorable NPD measurement change [84]. Login to comment 116 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Gly1349Asp Through this mechanism, adenosine indirectly activates wild-type as well as several surface-localized mutant CFTR channels including R117H, A455E, and G1349D. Login to comment 117 ABCC7 p.Gly551Asp Adenosine combined with rolipram or papaverine can also activate G551D CFTR measured by halide efflux to approximately 30% of wild-type activity [86]. Login to comment 124 ABCC7 p.Pro574His ABCC7 p.Ala455Glu Missense mutations that belong to this class include P574H and A455E. Login to comment