ABCMdb

PMID: 15880796

Kerem E
Pharmacological induction of CFTR function in patients with cystic fibrosis: mutation-specific therapy.
Pediatr Pulmonol. 2005 Sep;40(3):183-96., [PubMed]

Sentences

No. Mutations Sentence Comment

53 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Glu822* This class may include promoter mutations that reduce transcription TABLE 1- Classes of CFTR Mutations1 Class Mutations I Stop codons: W1282X, G542X, R1162X, R553X, E822X Splicing mutations that completely abolish protein synthesis: 1717 À 1G ! Login to comment 58 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly314Glu ABCC7 p.Arg347Cys ABCC7 p.Arg347His ABCC7 p.Arg347Leu ABCC7 p.Asn1303Lys ABCC7 p.Pro205Ser ABCC7 p.Leu206Trp ABCC7 p.Val520Phe ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Gly85Glu ABCC7 p.Ser549Asn ABCC7 p.Arg560Thr ABCC7 p.Arg117Leu ABCC7 p.Thr338Ile ABCC7 p.Leu1065Pro ABCC7 p.Ser549Ile ABCC7 p.Arg560Ser ABCC7 p.Arg1070Gln ABCC7 p.Arg1066Cys ABCC7 p.Ser945Leu ABCC7 p.Asp1152His ABCC7 p.Tyr569Asp ABCC7 p.His1085Arg ABCC7 p.Arg117Cys ABCC7 p.Gly91Arg ABCC7 p.Leu1077Pro ABCC7 p.Arg1070Trp ABCC7 p.Glu92Lys ABCC7 p.Ile336Lys ABCC7 p.Arg553Gly ABCC7 p.Ser492Phe ABCC7 p.Arg117Pro ABCC7 p.Asp565Gly ABCC7 p.Arg334Gln ABCC7 p.Gln98Arg ABCC7 p.His1054Asp ABCC7 p.Gly1061Arg ABCC7 p.Phe311Leu ABCC7 p.Leu346Pro ABCC7 p.Arg1066Met ABCC7 p.Leu88Ser ABCC7 p.Ser945Asp ABCC7 p.Leu227Arg ABCC7 p.Leu927Pro C-D565G II DF508 D1507 S549R S549I S549N S549R S945D S945L H1054D G1061R L1065P R1066C R1066M L1077P H1085R N1303K G85E III G551D S492F V520F R553G R560T R560S Y569D IV R117H, R117C, R117P, R117L D1152H, L88S, G91R, E92K, Q98R, P205S, L206W, L227R, F311L, G314E, R334W, R334Q, I336K, T338I, L346P, R347C, R347H, R347L, R347P, L927P, R1070W, R1070Q V 3849 þ 10 kb C ! Login to comment 59 ABCC7 p.Gly576Ala ABCC7 p.Asp565Gly T, 1811 þ 1.6 kb A >G, 3272 À 26A !G, IVS8-5T, D565G, G576A, c4006 À 1 G À> A, 2789 þ 5 G > A 1 Included are mutations that have been studied in RNA/protein level or having enough experimental data to suggest their molecular mechanism. Login to comment 70 ABCC7 p.Trp1282* In the Ashkenazi Jewish population, W1282X is the most common CF-causing mutation, and together with other nonsense mutations accounts for 64% of all CFTR alleles.78 The phenotype of patients carryingstop mutations is severe, similarto thatof the DF508 mutation.89 It has been known for many years that aminoglycoside antibiotics, in addition to their antimicrobial activity, can suppress premature termination codons by disrupting translational fidelity and allowing the incorporation of an amino acid, thus permitting translation to continue to the normal termination of the transcript.10,11 The susceptibility to suppression by aminoglycosides depends on the stop codon itself and on the sequence context surrounding it. Login to comment 74 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly542* Howard et al. demonstrated in HeLa cells transfected with plasmid vector carrying the CFTR nonsense mutations G542X and R553X that aminoglycosides caused a dose-dependent increase in CFTR expression.14 Subsequently, the same group showed that functional CFTR was restored to the apical membrane, and the relative level of mRNA transcript increased in bronchial cell line IB3-1 expressing the W1282X mutation. Login to comment 75 ABCC7 p.Gly542* Following incubation with aminoglycosides, cAMP-activated chloride conductance and the expression of functional CFTR were restored to the apical membrane.15 Zsembery et al. isolated cholangiocytes from the liver of a patient carrying the G542X mutation and incubated them with gentamicin. Login to comment 77 ABCC7 p.Gly542* ABCC7 p.Gly542* Du et al. daily administered the aminoglycoside antibiotics gentamicin or tobramycin.17 Immunofluorescence staining of intestinal tissues from CftrÀ/À hCFTR-G542X mice revealed that gentamicin treatment resulted in the appearance of CFTR protein at the apical surface of the glands of treated mice. Login to comment 80 ABCC7 p.Gly542* When taken together, these results indicate that gentamicin, and to a lesser extent tobramycin, can restore the synthesis of functional CFTR protein by suppressing the G542X premature stop mutation in vivo. Login to comment 102 ABCC7 p.Trp1282* In this double-blind, crossover, placebo-controlled trial,20 as well as in a previous pilot study,18 all patients in the stop mutation group carried at least one W1282X allele. Login to comment 165 ABCC7 p.Gly551Asp An example of this class is the glycine-to-aspartic acid change at codon 551 (G551D). Login to comment 167 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp The phenotype of patients carrying one DF508 and one G551D allele is characterized by a clinical course as severe as those who are homozygous for DF508, but with a reduced risk of meconium ileus.47 G551D is a class III mutation that produces a protein that is well- synthesized, processed, and correctly inserted in the plasma membrane, but with strongly reduced channel activity.48,49 G551D is localized in the first NBD of CFTR and interferes with ATP hydrolysis.48-50 CFTR Activators Several compounds were found to directly activate both wild-type and mutant CFTR. Login to comment 168 ABCC7 p.Gly551Asp Among them, the most important are alkylxanthines, such as 8-cyclopentyl-1,3-dipropylxanthine (CPX) and genistein.51 The flavonoid genistein is a potent activator of CFTR and can overcome the affected ATP binding to G551D. Login to comment 171 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Genistein restored cAMP-dependent G551D-CFTR activity in vitro and in vivo.52-56 CF subjects bearing at least one G551D allele underwent nasal potential difference testing, in which genistein was superfused following isoproterenol activation of CFTR.57 A modest repolarization of several millivolts on average was observed. Login to comment 172 ABCC7 p.Gly551Asp This degree of chloride transport (17% of that observed in normal subjects) might be augmented overall by increasing the level of G551D expression in nasal mucosa. Login to comment 173 ABCC7 p.Gly551Asp Perfusion of the nasal mucosa with genistein significantly hyperpolarized nasal PD both in G551D CF patients and in healthy subjects, indicative of genistein-induced ClÀ conductance in both groups. Login to comment 198 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro R117H, R334W, and R347P are class IV mutants with reduced single-channel conductance.65 Increases in the overall cell surface content of these mutants might overcome the relative reduction in conductance. Alternatively, restoring native chloride pore characteristics pharmacologically might be effective. Login to comment 199 ABCC7 p.Arg117His Adenosine and its nucleotides were shown to activate wild-type and R117H forms of CFTR in cell cultures through the A2B receptor that is present in human bronchial epithelium.66 Activators of CFTR at the plasma membrane may function by elevating cytosolic cAMP (promoting CFTR phosphorylation), by inhibiting phosphatase activity (blocking CFTR dephosphorylation), and/or by interacting directly with CFTR.67,68 Modulation of CFTR protein-protein interactions, such as with PDZ-binding proteins69,70 and syntaxins,71 may also affect CFTR function. Login to comment 211 ABCC7 p.Gly551Asp ABCC7 p.Pro574His IBMX produced a small, CFTR-related secretory response in the jejunum, cecum, and rectum of G551D mice but had no effect in the nasal epithelium.78 NS-004 restored near-normal channel activity from P574H-CFTR (a mild, trafficking-impaired mutationinNBD1).79 Theseresultssuggestthat,inaddition to their direct effects on CFTR, these drugs may also have other effects that increase the number of channel proteins found in the membrane. Login to comment 234 ABCC7 p.Gly576Ala ABCC7 p.Asp565Gly CLASS V MUTATIONS: REDUCED NUMBER OF ACTIVE CFTR This group includes mutations which generate both aberrantly and correctly spliced transcripts (such as 3849 þ 10 kb C -> T, 3272 À 26 A -> G, IVS8-5T, D565G, and G576A), the levels of which vary among different patients and among different organs of the same patient.85-89 These patients often have a relatively mild phenotype, yet with variable disease expression, from minimal lung disease, pancreatic sufficiency, and male fertility to relatively severe disease with multiorgan involvement.88,89 This variable disease expression is inversely correlated with the level of correctly spliced transcripts, such that lower levels are associated with a severe disease, while higher levels are associated with a milder phenotype. Login to comment 243 ABCC7 p.Arg553* ABCC7 p.Gly542* Quantification studies showed that after aminoglycoside incubation, the amount of full-length CFTR produced is as much as 25% (in the R553X mutation) to 35% (in the G542X mutation) of that observed in cells transfected with a wild-type CFTR complementary DNA (cDNA).14,15 This increase in functional CFTR might be above the threshold required for normal respiratory epithelial cell function. Login to comment 252 ABCC7 p.Gly551Asp Willumsen and Boucher108 found that responses to genistein of nasal PD in G551D CF patients corresponded to 13.6% of normal in terms of Cl current, which may have therapeutic significance. Login to comment