ABCMdb

PMID: 21652558

Rogan MP, Stoltz DA, Hornick DB
Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment.
Chest. 2011 Jun;139(6):1480-90., [PubMed]

Sentences

No. Mutations Sentence Comment

61 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Five Classes of Defective CFTR Protein Processing Based on Gene Mutation Although .1,500 mutations of CFTR have been identified, only four specific mutations besides F508del reach a frequency of 1% to 3%: G551D, W1282X, G542X, and N1303K. Login to comment 63 ABCC7 p.Trp1282* Specific mutations appear to be enriched within ethnic groups.53 For example, the nonsense mutation, W1282X (a PTC in place of tryptophan residue 1282) accounts for slightly .1% of worldwide mutations but for approximately 50% of the those in the Israeli Ashkenazi Jewish population where nonsense mutations nearly exceed the frequency of F508del.54 Ultimately, the majority of CF mutations are rare and have not been functionally characterized. Login to comment 65 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Five Classes of Defective CFTR Protein Processing Based on Gene Mutation Although .1,500 mutations of CFTR have been identified, only four specific mutations besides F508del reach a frequency of 1% to 3%: G551D, W1282X, G542X, and N1303K. Login to comment 66 ABCC7 p.Trp1282* In particular, nonsense mutations, a single point alteration in DNA that creates an in-frame PTC (UAA, UGA, or UAG) in the protein-coding region, have been reported to cause approximately 30% of all human inherited diseases.57 The designation for nonsense mutation ends with an X (eg, W1282X). Login to comment 67 ABCC7 p.Trp1282* ABCC7 p.Trp1282* Specific mutations appear to be enriched within ethnic groups.53 For example, the nonsense mutation, W1282X (a PTC in place of tryptophan residue 1282) accounts for slightly .1% of worldwide mutations but for approximately 50% of the those in the Israeli Ashkenazi Jewish population where nonsense mutations nearly exceed the frequency of F508del.54 Ultimately, the majority of CF mutations are rare and have not been functionally characterized. Login to comment 70 ABCC7 p.Trp1282* In particular, nonsense mutations, a single point alteration in DNA that creates an in-frame PTC (UAA, UGA, or UAG) in the protein-coding region, have been reported to cause approximately 30% of all human inherited diseases.57 The designation for nonsense mutation ends with an X (eg, W1282X). Login to comment 71 ABCC7 p.Trp1282* The Table1-OverviewoftheFiveClassesofCFTRMutations Class ApproximateWorldwide Frequency Predominant MutationType Common Representative Mutations CFTRDomain Location Associated Phenotype Severity CFTRProtein Outcome Functional Consequence RelevantAgentsin ClinicalTrials I?10%(Ashkenazi,50%)Nonsense,spliceG542X,W1282X, 62111G→T NBD1,NBD2, MSD1 HighNoCFTRNoCl2transportPTCread-through (eg,ataluren) II70%MissenseF508del,N1303KNBD1,NBD2HighDefectiveprocessingNoCl2transportCorrectors(eg,VX-809) III2%-3%MissenseG551D,R560TNBD1,NBD1HighDefectiveregulationNoCl2transportPotentiators (eg,VX-770) IVUncertain,,2%MissenseR117H,R347PMSD1,MSD1ReducedAlteredconductanceMinimalexpression&Cl2 transport Potentiators VUncertain,,1%Missense,splice3349110kbC→GIntronReducedReducedsynthesisReducedexpression&Cl2 transport Uncertain CFTR5cysticfibrosistransmembraneconductanceregulator;Cl25chloride;MSD5membranespanningdomain;NBD5nucleotide-bindingdomain;PTC5prematureterminationcodon. Login to comment 73 ABCC7 p.Gly551Asp When F508del-CFTR is rescued and inserted in the plasma membrane, it exhibits defective regulation, characteristic of class III mutations.58 Class III Mutations G551D is the third most common CFTR mutation (occurring in approximately 3% of patients with CF) and provides a representative example of class III mutations. Login to comment 74 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp The G551D missense mutation causes a glycine-to-aspartate substitution at residue 551. Login to comment 75 ABCC7 p.Gly551Asp G551D-CFTR is adequately folded and inserts appropriately into the plasma membrane, but thereafter, it fails to open because of defective regulation. Login to comment 77 ABCC7 p.Gly551Asp When F508del-CFTR is rescued and inserted in the plasma membrane, it exhibits defective regulation, characteristic of class III mutations.58 Class III Mutations G551D is the third most common CFTR mutation (occurring in approximately 3% of patients with CF) and provides a representative example of class III mutations. Login to comment 78 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His The G551D missense mutation causes a glycine-to-aspartate substitution at residue 551. Login to comment 79 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His G551D-CFTR is adequately folded and inserts appropriately into the plasma membrane, but thereafter, it fails to open because of defective regulation. Login to comment 80 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His R117H-CFTR R domain is normally phosphorylated, and the NBD binds ATP, but channel open time and thus chloride transport are reduced.60 Additionally, the degree of R117H-CFTR function depends on the length of the polythymidine tract in intron 8 on the same chromosome (which influences splicing efficiency) such that the longer thymidine tracts (9T.7T.5T) produce more functional R117H-CFTR. Login to comment 81 ABCC7 p.Arg117His Clinical disease typically requires the R117H mutation in cis with 5T.61 Class V Mutations Found in ,1% of patients with CF, class V mutations produce normal plasma membrane CFTR. Login to comment 82 ABCC7 p.Arg117His R117H, among the most common class IV mutations, occurs at a worldwide frequency approaching 0.5% (www.genet.sickkids.on.ca). Login to comment 83 ABCC7 p.Arg117His ABCC7 p.Arg117His The R117H missense mutation causes an arginine-to-histidine substitution at residue 117. Login to comment 84 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His R117H-CFTR R domain is normally phosphorylated, and the NBD binds ATP, but channel open time and thus chloride transport are reduced.60 Additionally, the degree of R117H-CFTR function depends on the length of the polythymidine tract in intron 8 on the same chromosome (which influences splicing efficiency) such that the longer thymidine tracts (9T.7T.5T) produce more functional R117H-CFTR. Login to comment 85 ABCC7 p.Arg117His Clinical disease typically requires the R117H mutation in cis with 5T.61 Class V Mutations Found in ,1% of patients with CF, class V mutations produce normal plasma membrane CFTR. Login to comment 123 ABCC7 p.Trp1282* Although NPD changes were not detected, the promising data for VX-809 provide support for more clinical trials.105 Potentiators of Mutant CFTR Protein Potentiator compounds increase chloride ion flow of PKA-activated mutant CFTR proteins that are Ataluren, developed by PTC Therapeutics, Inc (South Plainfield, New Jersey), is an orally bioavailable small molecule that proved superior to gentamicin in in vitro assays at inducing ribosomal read-through of in-frame nonsense PTCs to produce full-length proteins.76 Ataluren does not exhibit any antibiotic activity, and studies in transgenic CF mouse possessing hG542X- CFTR revealed that ataluren is capable of enhancing production of the full-length CFTR protein.84 Ataluren also passed requisite tolerability studies in healthy non-CF human volunteers apart from a mild elevation of hepatic transaminases with repeated dosing.85 In a subsequent phase II prospective trial in Israel where nonsense CFTR mutations are prevalent (eg, W1282X), 23 adult patients with CF exhibiting mainly heterozygous nonsense mutations were administered ascending doses of ataluren in two 2-week cycles (with a 2-week interval washout). Login to comment 127 ABCC7 p.Trp1282* Although NPD changes were not detected, the promising data for VX-809 provide support for more clinical trials.105 Potentiators of Mutant CFTR Protein Potentiator compounds increase chloride ion flow of PKA-activated mutant CFTR proteins that are Ataluren, developed by PTC Therapeutics, Inc (South Plainfield, New Jersey), is an orally bioavailable small molecule that proved superior to gentamicin in in vitro assays at inducing ribosomal read-through of in-frame nonsense PTCs to produce full-length proteins.76 Ataluren does not exhibit any antibiotic activity, and studies in transgenic CF mouse possessing hG542X- CFTR revealed that ataluren is capable of enhancing production of the full-length CFTR protein.84 Ataluren also passed requisite tolerability studies in healthy non-CF human volunteers apart from a mild elevation of hepatic transaminases with repeated dosing.85 In a subsequent phase II prospective trial in Israel where nonsense CFTR mutations are prevalent (eg, W1282X), 23 adult patients with CF exhibiting mainly heterozygous nonsense mutations were administered ascending doses of ataluren in two 2-week cycles (with a 2-week interval washout). Login to comment 133 ABCC7 p.Gly551Asp Such treatments that repair a flawed protein due to specific gene mutations may realize the concept of personalized medicine: subsets of patients with CF specifically selected for targeted therapy based on CFTR genotype information (eg, G551D mutation).112 Ultimately, enthusiasm for this novel class of treatments must be balanced by the reality that long-term efficacy and safety data have yet to be established, and it could take several more years before any of these agents become part of the therapeutic arsenal in CF. Login to comment 137 ABCC7 p.Gly551Asp Such treatments that repair a flawed protein due to specific gene mutations may realize the concept of personalized medicine: subsets of patients with CF specifically selected for targeted therapy based on CFTR genotype information (eg, G551D mutation).112 Ultimately, enthusiasm for this novel class of treatments must be balanced by the reality that long-term efficacy and safety data have yet to be established, and it could take several more years before any of these agents become part of the therapeutic arsenal in CF. Login to comment