ABCMdb

PMID: 20110398

Bertrand J, Boucherle B, Billet A, Melin-Heschel P, Dannhoffer L, Vandebrouck C, Jayle C, Routaboul C, Molina MC, Decout JL, Becq F, Norez C
Identification of a novel water-soluble activator of wild-type and F508del CFTR: GPact-11a.
Eur Respir J. 2010 Aug;36(2):311-22. Epub 2010 Jan 28., [PubMed]

Sentences

No. Mutations Sentence Comment

45 ABCC7 p.Arg1066Cys ABCC7 p.His1085Arg Human lung tissues were obtained from seven patients: three non-CF males with a mean age of 61 yrs, a non-CF female aged 65 yrs, a F508del/F508del-CFTR male aged 37 yrs, a F508del/R1066C female aged 26 yrs and a F508del/ H1085R-CFTR female aged 23 yrs. Login to comment 116 ABCC7 p.Arg1066Cys The mutation R1066C is a missense mutation in the second transmembrane domain of CFTR [30] and causes a severe CF phenotype. Login to comment 117 ABCC7 p.Arg1066Cys R1066C-CFTR protein is not correctly processed and, unlike F508del-CFTR, this defect can not be corrected in reduced temperature or butyrate-treated cells [31]. Login to comment 118 ABCC7 p.His1085Arg The mutation H1085R is a severe and rare missense mutation identified by MERCIER et al. [32]. Login to comment 119 ABCC7 p.His1085Arg H1085R-CFTR protein presents a trafficking defect which can be corrected by F508del-CFTR corrector [33]. Login to comment 155 ABCC7 p.Arg1066Cys ABCC7 p.His1085Arg Structural determinants for CFTR activation In the chemical structure of GPact-11a (fig. 1b), three main elements can be distinguished: 1) the purine aromatic heterocycles composed of fused pyrimidine and imidazole rings; -15 ΔFx 35 25 15 5 -5 45 CF-KM4 F508del-CFTR HEK-293 CFPACCuFi-1CF15 -5 ΔFx 15 10 5 0 20 F508del/ H1085R F508del/ F508del F508del/ R1066C 0 Activation% 80 60 40 20 100 -2-3-4-5 Log [GPact-11a] M -6-7 Fx 40 20 0 -20 60a) b) c) d) 2015105 Time min GPact-11a CFTRInh-172 0 ● ● ● ● ● ● ● ● ●●●●●●●●●●●●● ●● ●●● ●●●● ● ● ● ● ● ● ●● ● ● ● ● ● FIGURE 5. Login to comment 161 ABCC7 p.Arg1066Cys ABCC7 p.His1085Arg d) Effect of GPact-11a on human bronchial ciliated epithelial cells cells freshly isolated from lungs with different cystic fibrosis genotypes (F508del/F508del-CFTR (n54), F508del/R1066C (n57) and F508del/H1085R-CFTR (n59)). Login to comment