ABCMdb

PMID: 25404111

Cutting GR
Cystic fibrosis genetics: from molecular understanding to clinical application.
Nat Rev Genet. 2015 Jan;16(1):45-56. doi: 10.1038/nrg3849. Epub 2014 Nov 18., [PubMed]

Sentences

No. Mutations Sentence Comment

55 ABCC7 p.Arg1070Trp ABCC7 p.Arg1070Trp Intriguingly, introduction of the disease-associated p.Arg1070Trp (legacy R1070W)29 variant in CL4 and correction of NBD1 misfolding using synthetic suppressor mutations could restore processing to F508delߛCFTR28,30,31 . Login to comment 73 ABCC7 p.Gly542* The level and/or content of CFTR transcripts can be affected by disease-causing variants in the promoter (for example, c.-234T࢐A (also known as -102T࢐A in legacy nomenclature))140 and splice sites (for example, c.3717ߙ+ߙ12191ߙC࢐T (legacy 3849ߙ+ߙ10ߙkb C࢐T))141 , or by variants that introduce a premature termination codon (PTC) and that lead to RNA decay (for example, p.Gly542X; (legacy G542X)142 . Login to comment 74 ABCC7 p.Asn287Tyr ABCC7 p.Asn287Tyr The processing of CFTR can be altered by variants that cause aberrant folding of the protein, leading to degradation (for example, p.Phe508del (legacy F508del))18 , or by variants that cause reduced membrane stability as a result of increased rates of endocytosis (for example, p.Asn287Tyr (legacy N287Y))143 . Login to comment 76 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp Disease-causing variants cause reduction in activity (for example, p.Gly551Asp (legacy G551D)144 or changes in the conduction properties of the chloride channel (for example, p.Arg334Trp (legacy R334W))144 . Login to comment 83 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp The Cftr gene in mice has been extensively manipulated to derive lines that do not express CFTR and lines that express CFTR bearing variants equivalent to those observed in humans (for example, F508del and p.Gly551Asp (legacy G551D))43 . Login to comment 212 ABCC7 p.Gly551Asp A promising compound termed ivacaftor (also known as VXߛ770 and Kalydeco (Vertex Pharmaceuticals)) increased chloride transport of primary airway cells bearing the G551D variant up to ~50% of wild-type level96 . Login to comment 215 ABCC7 p.Gly551Asp Indeed, Phase III clinical trials over 4ߛweek and 48ߛweek intervals demonstrated that ivacaftor improved lung function (by 10% on average) and reduced sweat chloride concentration (to an average concentration below the diagnostic threshold of 60ߙmM) in individuals with cystic fibrosis carrying the G551D variant15,99 (FIG. 3a). Login to comment 266 ABCC7 p.Gly551Asp Although F508del and G551D account for a large fraction of cystic fibrosis alleles, ~7% of patients with cystic fibrosis carry neither variant. Login to comment 275 ABCC7 p.Gly551Asp As noted for the G551D variant, ivacaftor treatment of immortalized cells expressing CFTR bearing each of these variants increased chloride transport from 21% to 157% of normal levels108 , thereby predicting that clinical response should occur in individuals carrying these variants (FIG. 3c). Login to comment 305 ABCC7 p.Gly551Asp ABCC7 p.Gly542* Nature Reviews | Genetics * * * G542X G551D 3849+10kbC࢐T Clinical response Clinical response Clinical response Clinical response Function Quantity Function Quantity Function Quantity Function Quantity F508del F508del a b c d Function Quantity Therapy Ivacaftor P5 Potentiators PTC suppressor Splicing corrector Lumacaftor C4 Expression Correctors Figure 3 | Molecular treatments for cystic fibrosis. Login to comment 310 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp a | Single-drug strategies for G551D (also known as p.Gly551Asp) and F508del (also known as p.Phe508del) are shown. Login to comment 311 ABCC7 p.Gly551Asp CFTR bearing the G551D variant is found at normal levels in the cell membrane but cannot be activated. Login to comment 320 ABCC7 p.Gly551Asp As this functional defect is similar to that caused by G551D,eachvariantistestedforresponsetoivacaftorincell-basedstudies. Login to comment 323 ABCC7 p.Gly542* Suppression of the cryptic splice sitecanincreaseCFTRproteinlevelsabove10%ofnormal145 .Thenonsense variant G542X (also known as p.Gly542X) introduces a premature termination codon (PTC) that causes severe reduction in mRNA levels and anabsenceoftheCFTRprotein.UseofPTCsuppressorsincreasestranscript andproteinlevels,leadingtoamodestrecoveryofCFTRfunctionthatfalls short of a clinical response. Login to comment