ABCMdb

PMID: 15618584

Dormer RL, Harris CM, Clark Z, Pereira MM, Doull IJ, Norez C, Becq F, McPherson MA
Sildenafil (Viagra) corrects DeltaF508-CFTR location in nasal epithelial cells from patients with cystic fibrosis.
Thorax. 2005 Jan;60(1):55-9., [PubMed]

Sentences

No. Mutations Sentence Comment

182 ABCC7 p.Arg1283Met Sildenafil also increased DF508-CFTR trafficking in cells from individuals with CF with a single copy DF508 (DF508/4016ins) or with a newly described CF trafficking mutation (R1283M). Login to comment 188 ABCC7 p.Arg1283Met METHODS Patients and cell sampling Airway epithelial cells were obtained by nasal brushing from three non-CF individuals (age 9-22 years) and from six CF individuals (age 6 months to 16 years) undergoing flexible bronchoscopy under sedation as previously described.8 The CF individuals had the following genotypes: four DF508/ DF508, one DF508/4016ins, and one R1283M/E60X. Login to comment 213 ABCC7 p.Gly551Asp This is in agreement with our previous data on the location of CFTR in wild type, DF508/DF508 and DF508/ G551D cells.8 Actions of sildenafil on DF508-CFTR location In DF508/DF508 cells treated with sildenafil (150 mM for 2 h at 37˚C), a marked change in DF508-CFTR location was observed (fig 1C and F) with a significant decrease (p,0.05) in the percentage of cells having a near nuclear location and a significant increase (from 10% to 32%, p,0.05) in cells having DF508-CFTR at the apical membrane. Login to comment 218 ABCC7 p.Arg1283Met ABCC7 p.Glu60* The results are representative of cells from (A) three non-CF individuals, (B, C) four DF508/DF508 CF individuals, and (D, E) one R1283M/E60X individual. Login to comment 219 ABCC7 p.Arg1283Met They show that both DF508- and R1283M-CFTR are predominantly restricted within the cell to a distinct location adjacent to the nucleus (near nucleus) in untreated cells (B, D) whereas, after sildenafil treatment, many cells have an apical location of CFTR (C, E). Login to comment 227 ABCC7 p.Arg1283Met ABCC7 p.Glu60* A new CF trafficking mutation Cells from a CF individual heterozygous for a rare missense mutation, R1283M,13 and a stop mutation, E60X, were also examined (fig 1D-F). Login to comment 243 ABCC7 p.Arg1283Met This is the first description of R1283M as a trafficking mutation and sildenafil was effective in correcting the defect. Login to comment 256 ABCC7 p.Arg1283Met The present studies have also identified a new CFTR trafficking mutation in NBD2 (R1283M) that has not previously been investigated. Login to comment 257 ABCC7 p.Asn1303Lys ABCC7 p.Arg1283Met The only other report of altered trafficking of CFTR with a mutation in NBD2 is N1303K.15 The present results, showing that sildenafil corrects DF508- and R1283M-CFTR location, both mutations in nucleotide binding domains, will provide insights into the mechanism of action of drugs that increase CFTR trafficking. Login to comment