ABCMdb

PMID: 7539891

Gan KH, Veeze HJ, van den Ouweland AM, Halley DJ, Scheffer H, van der Hout A, Overbeek SE, de Jongste JC, Bakker W, Heijerman HG
A cystic fibrosis mutation associated with mild lung disease.
N Engl J Med. 1995 Jul 13;333(2):95-9., [PubMed]

Sentences

No. Mutations Sentence Comment

28 ABCC7 p.Arg117His ABCC7 p.Pro574His ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Since the gene for cystic fibrosis was cloned, there have been several studies on associations between the genotype and the phenotype in cystic fibrosis.5-8 A number of mutations (R117H, R334W, R347P , A455E, and P574H) appear to be associated with pancreatic sufficiency9 and residual transmembrane transport of chloride.10,11 The most common mutation, F508, is associated with pancreatic insufficiency and severe pulmonary disease.5,6 There is great variation in the severity of lung disease, but until now no mutation associated with mild pulmonary disease has been found. Login to comment 29 ABCC7 p.Arg117His ABCC7 p.Pro574His ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Since the gene for cystic fibrosis was cloned, there have been several studies on associations between the genotype and the phenotype in cystic fibrosis.5-8 A number of mutations (R117H, R334W, R347P, A455E, and P574H) appear to be associated with pancreatic sufficiency9 and residual transmembrane transport of chloride.10,11 The most common mutation, ⌬F508, is associated with pancreatic insufficiency and severe pulmonary disease.5,6 There is great variation in the severity of lung disease, but until now no mutation associated with mild pulmonary disease has been found. Login to comment 30 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu Recently, we noted that a group of Dutch patients with cystic fibrosis who carried the A455E mutation had significantly better lung function than patients homozygous for the ⌬F508 mutation.12 An association between this mutation and exocrine pancreatic sufficiency has already been described.9,11 In addition, A455E appears to be associated with residual secretion of chloride in electrophysiologic studies of rectal-biopsy specimens.11 Among our patients the A455E mutation is relatively common and is associated with an older age at diagnosis.11,13 Because of the older age at diagnosis and the mutation-dependent residual chloride secretion associated with A455E, we hypothesized that the presence of this mutation could result in milder lung disease. Login to comment 33 ABCC7 p.Ala455Glu Among the patients screened, 151 were found to be homozygous for the F508 mutation and 39 were found to have compound heterozygosity for the A455E mutation. Login to comment 34 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Glu60* Among the patients screened, 151 were found to be homozygous for the ⌬F508 mutation and 39 were found to have compound heterozygosity for the A455E mutation. Login to comment 35 ABCC7 p.Ala455Glu ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Glu60* In the A455E compound heterozygotes, the following mutations were found on the other allele: ⌬F508 (27 patients), 1717-1G→A (4 patients), E60X (4 patients), G542X (2 patients), R553X (1 patient), and an unknown mutation (1 patient). Login to comment 36 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu The other mutations found in A455E heterozygotes are all associated with pancreatic insufficiency and have been classified as severe cystic fibrosis mutations,8 predicted to produce no functioning CFTR.14 Therefore, all patients with an A455E allele were analyzed together. Login to comment 37 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu The other mutations found in A455E heterozygotes are all associated with pancreatic insufficiency and have been classified as severe cystic fibrosis mutations,8 predicted to produce no functioning CFTR.14 Therefore, all patients with an A455E allele were analyzed together. Login to comment 38 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu One patient, whose genotype was A455E/ ⌬F508, has been described elsewhere.15 This patient died at the age of 71 and could not be matched with a ⌬F508 homozygote because of her advanced age. Login to comment 39 ABCC7 p.Ala455Glu No other data on deceased A455E compound heterozygotes were available, and therefore no data on deceased patients were included in the analysis of matched pairs. Login to comment 40 ABCC7 p.Ala455Glu Analysis for the F508 mutation was carried out by direct polyacrylamide-gel electrophoresis of the CFTR exon 10 product of the polymerase chain reaction16 or as part of a multiplex amplification refractory mutation system.17 For the analysis of the A455E mutation, a specific amplification refractory mutation system was developed (Scheffer H, et al.: unpublished data). Login to comment 41 ABCC7 p.Ala455Glu Analysis for the ⌬F508 mutation was carried out by direct polyacrylamide-gel electrophoresis of the CFTR exon 10 product of the polymerase chain reaction16 or as part of a multiplex amplification refractory mutation system.17 For the analysis of the A455E mutation, a specific amplification refractory mutation system was developed (Scheffer H, et al.: unpublished data). Login to comment 42 ABCC7 p.Ala455Glu For A455E compound heterozygotes, the place of birth was recorded, as were the birthplaces and family names of their parents and grandparents, as far as could be ascertained. Login to comment 43 ABCC7 p.Ala455Glu For A455E compound heterozygotes, the place of birth was recorded, as were the birthplaces and family names of their parents and grandparents, as far as could be ascertained. Login to comment 50 ABCC7 p.Ala455Glu Statistical Analysis Each of the patients with the A455E mutation was matched with the F508 homozygote closest in age, within two years, and of the same sex. Login to comment 51 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu Statistical Analysis Each of the patients with the A455E mutation was matched with the ⌬F508 homozygote closest in age, within two years, and of the same sex. Login to comment 52 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu The patient who died at the age of 71 and four other A455E compound heterozygotes (40, 43, 53, and 47 years old, with the first three having a genotype of A455E/1717-1G→A and the fourth a genotype of A455E/⌬F508) could not be matched within two years of age with a ⌬F508 homozygote and were excluded. Login to comment 60 ABCC7 p.Ala455Glu As far as could be determined, the families of the A455E compound heterozygotes were not related, nor did they come from geographically isolated regions. Login to comment 61 ABCC7 p.Ala455Glu As far as could be determined, the families of the A455E compound heterozygotes were not related, nor did they come from geographically isolated regions. Login to comment 62 ABCC7 p.Ala455Glu At least four A455E heterozygotes were former cigarette smokers, whereas none of the F508 homozygotes had ever smoked. Login to comment 63 ABCC7 p.Ala455Glu At least four A455E heterozygotes were former cigarette smokers, whereas none of the ⌬F508 homozygotes had ever smoked. Login to comment 65 ABCC7 p.Ala455Glu The patients with the A455E mutation had significantly better lung function than did the F508 homozygotes (mean FEV1, 73.9 percent of the predicted value vs. 54.3 percent of the predicted value; P0.002). Login to comment 66 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu The patients with the A455E mutation had significantly better lung function than did the ⌬F508 homozygotes (mean FEV1, 73.9 percent of the predicted value vs. 54.3 percent of the predicted value; Pϭ0.002). Login to comment 67 ABCC7 p.Ala455Glu The mean FVC was 88.7 percent for A455E compound heterozygotes and 76.3 percent for ⌬F508 homozygotes (Pϭ0.04). Login to comment 69 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Glu60* †The following genotypes were identified: A455E/⌬F508 (25 patients), A455E/E60X (4), A455E/G542X (2), A455E/R553X (1), and A455E/1717-1G→A (1). Login to comment 70 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Glu60* ߤThe following genotypes were identified: A455E/F508 (25 patients), A455E/E60X (4), A455E/G542X (2), A455E/R553X (1), and A455E/1717-1G࢐A (1). Login to comment 75 ABCC7 p.Ala455Glu Characteristics of Pairs of ⌬F508 Homozygotes and A455E Compound Heterozygotes Matched According to Sex and Age. Login to comment 76 ABCC7 p.Ala455Glu Characteristics of Pairs of F508 Homozygotes and A455E Compound Heterozygotes Matched According to Sex and Age. Login to comment 77 ABCC7 p.Ala455Glu OF PAIRS ⌬F508 HOMOZYGOTES A455E COMPOUND HETEROZYGOTES† P VALUE Sex - no. Login to comment 78 ABCC7 p.Ala455Glu OF PAIRS F508 HOMOZYGOTES A455E COMPOUND HETEROZYGOTESߤ P VALUE Sex - no. Login to comment 81 ABCC7 p.Ala455Glu (%) 33 9 (27.3) 0 0.004¶ Weight - (percentile)ʈ 33 61.0Ϯ29.4 53.4Ϯ30.3 NS Height - (percentile) Men 16 21.4Ϯ25.0 42.0Ϯ27.6 0.03‡ Women 17 38.1Ϯ28.2 38.7Ϯ29.4 NS less prevalent in patients with the A455E mutation, and diabetes mellitus was absent in this group (Pϭ0.004). Login to comment 82 ABCC7 p.Ala455Glu (%) 33 9 (27.3) 0 0.004&#b6; Weight - (percentile) 33 61.029.4 53.430.3 NS Height - (percentile) Men 16 21.425.0 42.027.6 0.03ߥ Women 17 38.128.2 38.729.4 NS less prevalent in patients with the A455E mutation, and diabetes mellitus was absent in this group (P0.004). Login to comment 83 ABCC7 p.Ala455Glu The men with the A455E mutation, but not the women, were significantly taller than matched ⌬F508 homozygotes. Login to comment 84 ABCC7 p.Ala455Glu The men with the A455E mutation, but not the women, were significantly taller than matched F508 homozygotes. Login to comment 85 ABCC7 p.Ala455Glu The regression line had a slope of -0.0089 for A455E compound heterozygotes and a significantly steeper slope of -0.0178 for ⌬F508 homozygotes (Pϭ0.02). Login to comment 86 ABCC7 p.Ala455Glu The regression line had a slope of 0.0089 for A455E compound heterozygotes and a significantly steeper slope of 0.0178 for F508 homozygotes (P0.02). Login to comment 87 ABCC7 p.Ala455Glu DISCUSSION The results of this study show that there is a relation between the presence of the A455E mutation and milder lung disease in patients with cystic fibrosis. Login to comment 88 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu Although the A455E mutation is known to be associated with pancreatic sufficiency,9 the association between A455E or any other cystic fibrosis mutation and milder lung disease has apparently not been found before. Login to comment 89 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu Although the A455E mutation is known to be associated with pancreatic sufficiency,9 the association between A455E or any other cystic fibrosis mutation and milder lung disease has apparently not been found before. Login to comment 90 ABCC7 p.Ala455Glu To overcome this problem, the Cystic Fibrosis Genotype-Phenotype Consortium initiated a large multicenter study that included 798 patients with cystic fibrosis.8 Of the eight mutations studied, none were associated with mild lung disease (A455E was not included). Login to comment 91 ABCC7 p.Arg117His ABCC7 p.Ala455Glu R117H, a mutation associated with residual transmembrane chloride transport,10 was also associated with an older age at diagnosis and with pancreatic sufficiency, but not with better lung function. Login to comment 92 ABCC7 p.Arg117His ABCC7 p.Ala455Glu The severity of disease in cystic fibrosis is determined by the mutation resulting in the least severe disease.9 All the A455E compound heterozygotes included in our study had a mutation on their other allele that was associated with severe disease. Login to comment 93 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu Mild symptoms in these patients are therefore most likely associated with the presence of the A455E mutation. Login to comment 94 ABCC7 p.Ala455Glu Mild symptoms in these patients are therefore most likely associated with the presence of the A455E mutation. Login to comment 97 ABCC7 p.Ala455Glu FEV1 in 34 A455E Compound Heterozygotes and 130 ⌬F508 Homozygotes, According to Age. Login to comment 98 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu Solid squares represent patients included in the matched-pairs analysis; 4 A455E compound heterozygotes and 21 ⌬F508 homozygotes were not included because they were too young for pulmonary-function testing. Login to comment 99 ABCC7 p.Ala455Glu Solid squares represent patients included in the matched-pairs analysis; 4 A455E compound heterozygotes and 21 F508 homozygotes were not included because they were too young for pulmonary-function testing. Login to comment 100 ABCC7 p.Ala455Glu The regression line had a slope of -0.0089 for A455E compound heterozygotes and -0.0178 for ⌬F508 homozygotes (Pϭ0.02). Login to comment 101 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu *Includes 31 A455E compound heterozygotes from the present study. Login to comment 102 ABCC7 p.Ala455Glu *Includes 31 A455E compound heterozygotes from the present study. Login to comment 105 ABCC7 p.Ala455Glu Frequency of ⌬F508 and A455E Mutations in Various Countries. Login to comment 106 ABCC7 p.Ala455Glu Frequency of F508 and A455E Mutations in Various Countries. Login to comment 107 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu OF CHROMOSOMES SCREENED ⌬F508 A455E % Present study The Netherlands 556 73 7.0 Cystic Fibrosis Genetic Analysis Consortium33 The Netherlands* 1043 77.1 3.0 Lindner et al.34 Southwestern Germany 220 67 0 Cuppens et al.35 Belgium 200 72.5 1.0 Super and Schwarz36 Northwestern England 1008 82 0 Shrimpton et al.37 Scotland 506 72.3 0.5 Claustres et al.38 Southern France 262 63 0 Cutting et al.39 Baltimore 163 76.1 0.6 Cutting et al.,39 Zielenski et al.40 Toronto 1030 68.4 0.2 Rozen et al.31 Quebec 84 71 1 Rozen et al.31 Saguenay-Lac St. Jean, Quebec 182 58 8 Cutting et al.39 United States† 43 37 0 Cutting et al.39 Israel‡ 94 30 0 FEV1(%ofpredictedvalue) 140 120 100 80 60 40 20 0 706050403020100 A455E Compound Heterozygotes Age (years) FEV1(%ofpredictedvalue) 140 120 100 80 60 40 20 0 706050403020100 DF508 Homozygotes Age (years) Our results show that the type of mutation has a significant impact on pulmonary function in cystic fibrosis. Login to comment 108 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu Because of the relatively high frequency of the A455E mutation among our patients, we were able to include 33 patients, as compared with the 23 patients with the R117H mutation included in the consortium`s report.8 When sufficient numbers of patients are studied, it should be possible to show that other mutations associated with the preservation of pancreatic function and residual transmembrane chloride transport are also associated with milder pulmonary disease. Login to comment 109 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu A455E is a missense mutation that leads to a change from alanine to glutamic acid in amino acid residue 455 of the CFTR protein.27 CFTR is a chloride transporter driven by cAMP, and the A455E mutation is situated in the first nucleotide-binding fold, two residues removed from the so-called Walker-A motif, the proposed site of interaction with the phosphoryl moiety of the bound cAMP.28 The A455E mutation may interfere with the binding of cAMP to the CFTR protein. Login to comment 110 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu The CFTR protein coded for by the ⌬F508 mutation is subject to defective intracellular processing and does not reach the cell membrane, but is degraded intracellularly.29 The CFTR protein containing the A455E mutation may also be subject to this mechanism, but to a lesser degree.30 Unlike ⌬F508 homozygotes, patients with cystic fibrosis who have the A455E mutation have residual transmembrane chloride transport,11 a point that increases the likelihood that at least some functioning CFTR protein reaches the cell membrane. Login to comment 111 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu The A455E mutation was first found in patients from the Saguenay-Lac St. Jean region in northern Quebec.27,31 In this formerly isolated community, the incidence of cystic fibrosis and other inherited diseases is higher than normal.32 The A455E mutation is seldom found elsewhere in the world (Table 2),31,33-40 but it is relatively common in the Netherlands, where it is the second most common cystic fibrosis mutation (3.0 percent of all cystic fibrosis alleles).33 The two mutations that we studied, ⌬F508 and A455E, account for 80.1 percent of the mutations found in Dutch patients with cystic fibrosis. Login to comment 112 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu In our study the frequency of A455E was 7.0 percent, which may be related to the age distribution of our patients. Login to comment 113 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu In our patients, the presence of the A455E mutation was associated with the preservation of both endocrine and exocrine pancreatic function, less frequent colonization with P. aeruginosa, and mild lung disease. Login to comment 114 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu The regression line for FEV1 according to age was less steep in A455E compound heterozygotes than in ⌬F508 homozygotes, an indication that the progression of pulmonary disease is slower in patients with the A455E mutation. Login to comment 115 ABCC7 p.Ala455Glu A455E is the first CFTR mutation for which an association with mild lung disease could be found. Login to comment 116 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu The regression line for FEV1 according to age was less steep in A455E compound heterozygotes than in F508 homozygotes, an indication that the progression of pulmonary disease is slower in patients with the A455E mutation. Login to comment 117 ABCC7 p.Ala455Glu A455E is the first CFTR mutation for which an association with mild lung disease could be found. Login to comment