ABCMdb

PMID: 15891431

Rubenstein RC
Novel, mechanism-based therapies for cystic fibrosis.
Curr Opin Pediatr. 2005 Jun;17(3):385-92., [PubMed]

Sentences

No. Mutations Sentence Comment

23 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly542* Such mutations are relatively infrequent in the general CF population (G542X, 2.4%; R553X, 0.9%; W1282X, 1.4% of mutant alleles in the 2003 Cystic Fibrosis Foundation Patient Registry). Login to comment 24 ABCC7 p.Trp1282* The W1282X allele is highly prevalent in the Ashkenazi Jewish population; in Israeli CF patients, its allele frequency is >50% [6,7]. Login to comment 25 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Arg1162* Treatment of cells expressing these 'X` mutations with aminoglycoside antibiotics such as gentamicin or G418 (Geneticin, Life Technologies, Inc., Gaithersburg, MD, USA) causes expression of a full-length, functional CFTR protein from G542X [8], R553X [8], R1162X [9], and W1282X [9] alleles. Login to comment 27 ABCC7 p.Gly542* Similar effects were noted in a murine cftr(ÿ/ÿ) knockout model where the G542X allele was expressed under control of an intestine-specific promoter. Login to comment 41 ABCC7 p.Asn1303Lys CFTR`s most common mutation, the deletion of phenylalanine 508 (DF508, ;70% of mutant alleles), is the most common Class II mutation, with N1303K (1.2% of mutant alleles) being next in prevalence. Login to comment 68 ABCC7 p.Gly551Asp These mutations are typically missense changes in regulatory regions of CFTR [46], with the most common being G551D (;2.2% of mutant alleles). Login to comment 69 ABCC7 p.Gly551Asp G551D is within CFTR`s first nucleotide binding domain and is associated with a severe CF phenotype [3]. Login to comment 70 ABCC7 p.Gly551Asp Genistein, an isoflavone that is present in milligram per kilogram quantities in tofu and soy, enhances chloride channel activity of wild-type and mutant CFTRs [47], including G551D [48]. Login to comment 71 ABCC7 p.Gly551Asp Perfusion of genistein onto the nasal epithelia increased chloride transport, as assessed by NPD, in non-CF subjects, as well as in subjects with the G551D mutation [48]. Login to comment 75 ABCC7 p.Arg117His There are a number of less common missense mutations of CFTR, such as R117H, that have normal intracellular localization and reduced chloride transport function [54]. Login to comment 80 ABCC7 p.Asn1303Lys DF508 has reduced channel open probability [17,55], although others have not observed this [56], whereas N1303K has aberrant CFTR gating [57]. Login to comment 89 ABCC7 p.Arg117His Mutations associated with milder clinical phenotypes and pancreatic sufficiency, such as R117H, maintain some ability to regulate Clÿ and HCO3 ÿ transport [63]. Login to comment 90 ABCC7 p.Ile148Thr However, I148T, which is associated with a severe CF phenotype and pancreatic insufficiency, is defective in regulation of HCO3 ÿ transport, but transports Clÿ with similar efficiency to wild-type CFTR [63]. Login to comment 95 ABCC7 p.Gly551Asp DF508 [70,77,78•] and G551D [65,79] do not regulate ENaC appropriately. Login to comment 96 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp We hypothesized that augmentation of DF508 and G551D function with a potentiator would improve regulatory interactions between ENaC and these mutant CFTRs, and observed that genistein significantly improved the regulatory interactions of ENaC with DF508 [70] and G551D [80] in Xenopus oocytes. Login to comment