ABCMdb

PMID: 24932877

Bell SC, De Boeck K, Amaral MD
New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls.
Pharmacol Ther. 2015 Jan;145:19-34. doi: 10.1016/j.pharmthera.2014.06.005. Epub 2014 Jun 14., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCC7 p.Gly551Asp After several successful clinical trials the potentiator, ivacaftor, is now licenced for use in adults and children (Nsix years), with CF bearing the class III G551D mutation and FDA licence was recently expanded to include 8 additional class III mutations. Login to comment 482 ABCC7 p.Gly551Asp However, the relative frequency of specific CFTR mutations varies greatly between countries and even between regions within countries (Bobadilla et al., 2002), such is the case for G551D which also show heterogeneous geographic distribution (Fig. 1B). Login to comment 492 ABCC7 p.Trp1282* ABCC7 p.Gly542* ABCC7 p.Arg1162* Common mutations in class I include G542X (common in Brittany and Southern France), R1162X (common in Austria and Northern Italy), or W1282X (reaching 48% amongst Ashkenazi Jews) (Bobadilla et al., 2002). Login to comment 493 ABCC7 p.Asn1303Lys ABCC7 p.Arg560Thr ABCC7 p.Arg1066Cys ABCC7 p.Ala561Glu Class II mutations which besides F508del, include R560T (Roxo-Rosa et al., 2006), A561E (Mendes et al., 2003), R1066C (Seibert et al., 1996) and N1303K (Gregory et al., 1991) amongst others, affect CFTR protein processing due to misfolding which is recognized by endoplasmic reticulum (ER) quality control retention and which targets proteins with abnormal conformations to degradation (Amaral, 2004). Login to comment 494 ABCC7 p.Gly551Asp Class III mutations (e.g., G551D) disrupt channel regulation through impaired gating. Login to comment 495 ABCC7 p.Arg334Trp Class IV mutations (e.g., R334W) decrease Cl-ion conductance (i.e. flow) through the Cl-channel. Login to comment 506 ABCC7 p.Arg117His In most CF newborn screening programmes a surplus of "patients" carrying the R117H mutation in trans with F508del were identified (Scotet et al., 2006; Thauvin-Robinet et al., 2009; Lilley et al., 2010) and many of these subjects did not develop phenotypic features of CF. Login to comment 507 ABCC7 p.Arg117His Although R117H by itself somewhat reduces CFTR conductance and gating (Sheppard et al., 1993), it was found that the Table 1 Clinical features of cystic fibrosis. Login to comment 508 ABCC7 p.Arg117His Sinopulmonary Gastrointestinal/hepatobiliary Reproductive and endocrine Salt loss syndromes Other Chronic bronchial infection leading to bronchiectasis Chronic infection with multi-resistant pathogens Haemoptysis Pneumothorax Respiratory failure Allergic bronchopulmonary aspergillosis Chronic rhinosinusitis and nasal polyposis Pancreatic exocrine insufficiency Recurrent acute pancreatitis in those with pancreatic sufficiency Fat soluble vitamin deficiency Distal intestinal obstruction syndrome Intussusception Appendiceal abscess Cirrhosis with portal hypertension Gastroesophageal reflux Constipation Bacterial overgrowth including pseudomembranous colitis Obstructive azoospermia in males Reduced fertility in women Delayed puberty Oligomenorrhea Cystic fibrosis-related diabetes Metabolic bone disease (reduced bone mineral density) Acute dehydration due to heat prostration Hyponatraemic, hypochloraemic metabolic alkalosis Pseudo-Bartter syndrome Difficult vascular access Hypersensitivity reaction to antibiotics CF arthropathy/hypertrophic pulmonary osteoarthropathy Chronic kidney disease Nephrolithiasis/oxalate nephropathy Depression Anxiety number of thymidine (T) repeats in intron 8 (IVS8) in cis with R117H explains the variability of the phenotype. Login to comment 520 ABCC7 p.Gly551Asp Mutation distribution of F508del (A) and G551D (B) - (A) Percent of patients homozygous (dark) or heterozygous (light) for F508del mutation in different countries and regions. Login to comment 521 ABCC7 p.Gly551Asp (B) Percent of patients homozygous (dark) or heterozygous (light) for G551D mutation in different countries and regions. AT: Austria, BE: Belgium, BY: Republic of Belarus, BG: Bulgaria, CH: Switzerland, CZ: Czech Republic, DE: Germany, DK: Denmark, ES: Spain, FR: France, GR: Greece, HU: Hungary, IE: Ireland, IL: Israel, IT: Italy, LV: Latvia, MD: Republic of Moldova, NL: The Netherlands, PT: Portugal, RS: Serbia, SE: Sweden, SI: Slovenia, UK: United Kingdom. AU: Australia, EU: Europe, US: United States of America, BR: Brazil, CA: Canada. Login to comment 544 ABCC7 p.Gly551Asp ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Gly85Glu ABCC7 p.Ala561Glu Mutation Alternative name Allele frequency (% of total known) in ECFSPR 2010 Allele frequency (% of total known mutations) in 2010 ECFSPR F508del 64.5 Most frequent mutation worldwide Southeast to Northwest increasing prevalence in Europe IL 25.5 to DK 82.6 Mutations with an overall EU prevalence above 1% G542X Mediterranean mutation 2.5 GR 6.7, ES 6.0 N1303K Ancient Phoenician mutation 1.9 IT 4.2 W1282X Jewish Ashkenazi mutation 1.2 IL 22.4 G551D Celtic mutation 1.1 IE 7.3 1717-1GNA Italian mutation 1.0 IT 3.7 Mutations with an overall EU prevalence below 0.5% G85E PT 3.5 A455E Dutch mutation NL 3.5 CFTR dele 2,3 Slavic mutation CZ 5.2, BY 6.7 394delTT Nordic mutation SE 7.9, DK 2.0 3905insT Swiss mutation CH 2.4 R1162X Italian mutation IT 7.8 A561E Portuguese mutation PT 3.2 Abbreviations ECFSPR - European Cystic Fibrosis Society Patient Registry. Login to comment 547 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Gly551Ser ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Ser1255Pro ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Ser549Arg ABCC7 p.Gly85Glu ABCC7 p.Ser549Asn ABCC7 p.Arg560Thr ABCC7 p.Arg1066Cys ABCC7 p.Gly970Arg ABCC7 p.Gly178Arg ABCC7 p.Ala561Glu Class Type of defect List of mutations attributed to this class Class I Defective protein production Nonsense mutations: G542X, R1162X, RW1282X Deletions and insertions: CFTRdele2,3; 1078delT; 1717-1G ࢐ A; 3659delC; 621+1G N T Class II Defective protein processing G85E, F508del, I507del, R560T, A561E, R1066C, N1303K Class III Defective protein regulation (gating) G178R, S549N, S549R, G551D, G551S, G970R, G1244E, S1251N, S1255P, G1349D Class IV Defective protein conductance R334W, R347P, R117H Class V Reduced amount of functioning protein 2789+5G ࢐ A, 3272-26ANG, 3849+10KbC ࢐ T, A455E Class VI Reduced cell surface stability Rescued F508del, c.120del23 Unclassified All other mutations, including those unknown a F508del-CFTR pocket (at NBD1:ICL4 interface) (Farinha et al., 2013). Login to comment 553 ABCC7 p.Gly551Asp Class III: CFTR channel activators, which are termed potentiators (Moran & Zegarra-Moran, 2005), such as VX-770 (ivacaftor) which following demonstration of success in vitro (Van Goor et al., 2009) and in clinical trials with patients having at least one G551D mutation were already approved for the clinic by both FDA and EMA. Login to comment 567 ABCC7 p.Arg117His Another example is R117H which could be classified as class IV due to a slight decrease in channel conductance but is not a CF-causing mutation per se (Thauvin-Robinet et al., 2009; de Nooijer et al., 2011). Login to comment 569 ABCC7 p.Arg117His So the "real CF-causing mutation" is the complex allele R117H-5 T which can be considered as a class IV/V mutation. Login to comment 577 ABCC7 p.Gly542* Class I mutations, which abrogate protein production, often include mutations that generate premature stop codons, class Ia (e.g. G542X) that lead to mRNA degradation by nonsense-mediated decay or those affecting canonical splice sites class Ib (e.g. 1717 - 1GNA). Login to comment 579 ABCC7 p.Gly551Asp Class III mutants affect channel regulation, impairing channel opening (e.g. G551D). Login to comment 580 ABCC7 p.Arg334Trp Class IV mutants exhibit reduced conduction: that is, decreased flow of ions (e.g. R334W). Login to comment 627 ABCC7 p.Gly551Asp Ivacaftor has proven efficacy in children over six year of age and adults (Accurso et al., 2010; Ramsey et al., 2011; J.C. Davies et al., 2013) with CF and at least one G551D mutation. Login to comment 629 ABCC7 p.Gly551Asp Ivacaftor treatment improved lung clearance index (LCI, a measure of ventilation homogeneity) and further improved FEV1 in patients with G551D who have preserved lung function (J. Davies et al., 2013). Login to comment 630 ABCC7 p.Gly551Asp In "Named Patient Programs" ivacaftor also improved lung function in many of the subjects with G551D mutation who had advanced lung disease and very low FEV1 (b40%) who had been previously excluded from participation in the randomized clinical trials (Hebestreit et al., 2013; Barry et al., 2014). Login to comment 631 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp In a cross-over study the efficacy of ivacaftor has also been proven in subjects who carry gating mutations other than G551D where the increase in FEV1% predicted was in line with the G551D trials (de Boeck et al., 2013b). Login to comment 632 ABCC7 p.Gly551Asp Furthermore, in patients with G551D, who have so far the longest ivacaftor treatment exposure, the long term benefit can be explored: treatment benefit seems to be sustained and the impact of treatment on acquisition of P. aeruginosa on the rate of decline of FEV1 and on the occurrence of CF complications is being explored during continuous prospective open label follow up (McKone et al., 2013; Rowe et al., 2013). Login to comment 640 ABCC7 p.Arg117His In a randomized controlled trial including 69 children and adults with the R117H mutation (a class IV CFTR mutation), which is the most frequent mutation with residual function, the primary endpoint of improvement in FEV1 was not met (www.ccf.org, 2014). Login to comment 642 ABCC7 p.Gly551Asp The efficacy and safety of ivacaftor are also currently being evaluated in children with G551D aged 2 to 5 years and in subjects with splicing and missense mutations (NCT01685801) associated with residual function. Login to comment 777 ABCC7 p.Gly551Asp As the prevalence of the CF mutation, G551D, varies from country to country, the financial impact on the CF health budget varies. Login to comment 786 ABCC7 p.Gly551Asp Ivacaftor, the first of these therapies, has demonstrated 'proof-of-principle` for CFTR modulators and is now licenced for global use in patients with the G551D CFTR mutation. Login to comment