ABCMdb

PMID: 9039981

Antinolo G, Borrego S, Gili M, Dapena J, Alfageme I, Reina F
Genotype-phenotype relationship in 12 patients carrying cystic fibrosis mutation R334W.
J Med Genet. 1997 Feb;34(2):89-91., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCC7 p.Arg334Trp Received 8 July 1996 Revised version accepted for publication 4 September 1996 Abstract We present a phenotype-genotype correlation analysis in 12 patients with cystic fibrosis (CF) carrying the mutation R334W in the CFTR gene. Login to comment 3 ABCC7 p.Arg334Trp Current age and age at diagnosis were significantly higher in the R334W mutation group (p=0.028 and p=0.0001). Login to comment 4 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp We found a lower rate of Pseudomonas aeruginosa colonisation in patients carrying the R334W mutation, although the difference was not found to be statistically significant. However, we found a statistically significant higher age of onset of Pseudomonas aeruginosa colonisation (p=0.0036) in the group of patients with the R334W mutation. Thirty three percent of R334W patients were pancreatic insufficient, significantly lower than the AF508/AF508 patients (p=0.004). Login to comment 5 ABCC7 p.Arg334Trp We also found that the weight expressed as a percentage ofideal weight for height was significantly higher in patients with the R334W mutation (p=0.0028). Login to comment 6 ABCC7 p.Arg334Trp (JMed Genet 1997;34:89-91) Keywords: cystic fibrosis; R334W mutation; genotype-phenotype correlation. Login to comment 11 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp We present an analysis of the phenotype-genotype correlation in 12 patients with the mutation R334W, an arginine to tryptophan change at codon 334 of the CFTR gene.7 Materials and methods PATIENTS A total of 102 unrelated families originating from the south of Spain, with at least one affected person with a confirmed diagnosis of CF, were included in this study. Login to comment 19 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* Patients were diagnosed as either pancreatic sufficient group.bmj.comon October 25, 2012 - Published byjmg.bmj.comDownloaded from Antinolo, Borrego, Gili, Dapena, Alfageme, Reina Table 1 Clinical characteristics of 12 patients with R334Wmutation Patients 1 2 3 4 5 6 7 8 9 10 11 12 Genotype Sex Current age Age at diagnosis Age at first clinical symptoms First clinical symptoms Sweat ClF mEq/l Weight* (%) Chrispin-Norman Schwachman-Kulcycki FEV1 % predicted FVC % predicted Lung colonisation (LC) Age of onset of LC Meconium ileus Dehydration Pancreatic insufficiency (PI) Age of onset ofPI Sterility R334W/ AF508 F 3 y 7 mth 5 mth 3 mth Pulmonary/ pancreatic 90 100 4 90 No R334W/ AF508 M 27 y R334W/ AF508 F 2 y 5 mth 15y 5mth I y 4 mth 5 mth R334W/ AF508 M R334W/ AF508 F R334W/ AF508 M R334W/ R334W/ G542X R1 162X F F 25y 17y 59y 1Oy9 23y mth 20y 2y 49y 5y6mth 15y 4y 3mth 35y 8y I y R334W/ del84 F 3 y 3 mth R334W/ R334W/ R334W/ G542X G542X G542X F F F 27 y 25y 23y 15mth 25y 24y 21y 4mth 5y 17y Pulmonary Dehydration Dehydration Pulmonary Pancreatic Pulmonary Dehydration Dehydration Pulmonary Pulmonary Asymptomatic 90 80 100 105 110 110 100 85 100 100 100 100 100 115 90 89 95 76 89 116 115 121 20 2 23 65 100 95 65 70 95 50 95 85 90 95 24 82 41 44 27 74 85 91 43 91 51 60 43 82 84 97 Yes No No Yes Yes No Yes No No No No - 15y No No Yes Yes Yes Yes 3 mth - - 17y 58y - 14y - - - - No No Yes No No No No No No No Yes Yes Yes No No Yes Yes No No No No No No Yes No No No No Yes No 26y - - - - Yes - Yes - Yes - - - 24y - - - No No No * Weight expressed as a percentage of ideal weight for height. Login to comment 23 ABCC7 p.Arg334Trp Results The 12 patients with R334W originated from Andalusia (south of Spain). Login to comment 24 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Gly542* ABCC7 p.Arg1162* Six patients were compound heterozygotes for R334W and AF508, four for R334W and G542X, one for R334W and 1949del84, and one for R334W and R1162X. Login to comment 25 ABCC7 p.Arg334Trp All the R334W chromosomes showed the intragenic microsatellite haplotype 17-46-13 (IVS8CA-IVS17BTA-IVS17BCA). Login to comment 30 ABCC7 p.Arg334Trp The current age and age at diagnosis were significantly higher in the R334W mutation group (p=0.028 and p=0.0001, respectively). Login to comment 31 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp A lower rate of PA colonisation was found in the group ofpatients with the R334W mutation, although the difference was not statistically significant. However, a statistically significant higher age of onset of PA colonisation (p=0.0036) was found in the group of patients with the R334W mutation. Thirty three percent of R334W patients were pancreatic insufficient, a figure significantly lower than the AF508/AF508 patients (p=0.004). Login to comment 32 ABCC7 p.Arg334Trp We also found that the weight expressed as a percentage of ideal weight for height was significantly higher in patients with the R334W mutation (p=0.0028). Login to comment 33 ABCC7 p.Arg334Trp Table 2 Clinical characteristics of 12 patients with R334Wmutation, compared to AF508/AF508 patients Genotype AF5081AF508 (n=28) R334W (n=12) Mean (SD) Current age 9.6 (6.0) 20.4 (15.6) p = 0.028 Age at diagnosis 2.4 (3.3) 14.7 (14.6) p = 0.0001 Sweat test 99.4 (6.4) 95.8 (9.0) NS FEVI % predicted 54.1 (21.6) 58.5 (27.4) NS FVC % predicted 59.9 (17.3) 68.9 (22.1) NS Weight* 0.9 (0.06) 1.0 (0.1) p = 0.0028 Chrispin-Norman 7.9 (4.3) 9.2 (5.1) NS Age of onset of LC 7.1 (4.8) 26.0 (21.4) p = 0.0036 Age of onset of PI 0.3 (1.2) 24.8 (20.0) Schwachman-Kulcycki 71.2 (23.2) 82.9 (16.2) NS No positivelNo studied (%) Meconium ileus 3/28 (10.7) 1/12 (8.3) NS Dehydration 9/28 (32.1) 7/12 (58.3) NS Pancreatic insufficiency 28/28 (100.0) 4/12 (33.3) p = 0.004 Lung colonisation 17/28 (60.7) 4/12 (33.3) NS * Weight expressed as a percentage of ideal weight for height. Login to comment 34 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp Genotype-phenotype relationship in 12 patients carrying cysticfibrosis mutation R334W Discussion The R334W mutation of the CFTR gene is a missense mutation, first identified in 1,991,' that corresponds to the substitution of an arginine by a tryptophan at position 334 in exon 7 ofthe CFTR gene. Login to comment 35 ABCC7 p.Arg334Trp R334W is a class IV (defective conductance) mutation. Login to comment 36 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro '2 Class IV mutations (for example, RI 17H, R334W, and R347P) occur in the membrane spanning domains and are predicted to cause a mild CF phenotype. Login to comment 37 ABCC7 p.Arg334Trp '2 The R334W mutation has been described in a number of patients in different populations, although the worldwide prevalence is less than 0.1 %. Login to comment 38 ABCC7 p.Arg334Trp In our CF patients, R334W has a prevalence of4.9% (10/204 CF chromosomes). Login to comment 39 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp The association of intragenic microsatellite haplotypes 17-46-13 (IVS8CA-IVS17BTA- IVS17BCA) with the different R334W chromosomes points to a single origin in the Spanish families described previously." Login to comment 40 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp Our results provide new data to support that patients with the R334W mutation suffer less severe expression of the disease and that the disease can be diagnosed later, as reported by Estivill et al.'4 The proportion of pancreatic insufficient patients with the R334W mutation in our study is lower (33%) when compared to the proportion of pancreatic insufficient patients in the paper by Estivill et al'4 (60%). Login to comment 41 ABCC7 p.Arg334Trp In our study the number of pancreatic sufficient patients with R334W varied according to the age at which pancreatic status was assessed, the later the age the smaller the number ofpancreatic sufficient patients, with most patients being pancreatic sufficient at 20 years of age. Login to comment 46 ABCC7 p.Arg334Trp We did not find statistically significant differences with regard to lung colonisation by this pathogenic bacteria, although a lower rate of colonisation was found in R334W patients. Login to comment 47 ABCC7 p.Arg334Trp A slightly higher proportion of lung colonisation in R334W patients compared to AF508/AF508 patients has previously been reported,14 although the lung colonisation was referred to as bacterial pathogens in that report. Login to comment 48 ABCC7 p.Arg334Trp On the other hand, a significant higher age at colonisation was found in our group of patients suggesting that R334W may be a lower risk allele than AF508 for the acquisition of PA. Login to comment 79 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Independent origins of cystic fibrosis mutations R334W, R347P, Ri 162X, and 3849+1OkbCT provide evidence ofmutation recurrence in the CFTR gene. Login to comment 80 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro 13 Morral N, Llevadot R, Casals T, et al. Independent origins of cystic fibrosis mutations R334W, R347P, Ri 162X, and 3849+1OkbCT provide evidence ofmutation recurrence in the CFTR gene. Login to comment 81 ABCC7 p.Arg334Trp 14 Estivill X, Ortigosa L, Perez-Frias J, et al. Clinical characteristics of 16 cystic fibrosis patients with the missense mutation R334W, a pancreatic insufficiency mutation with variable age of onset and interfamilial clinical differences. Login to comment 82 ABCC7 p.Arg334Trp 14 Estivill X, Ortigosa L, Perez-Frias J, et al. Clinical characteristics of 16 cystic fibrosis patients with the missense mutation R334W, a pancreatic insufficiency mutation with variable age of onset and interfamilial clinical differences. Login to comment 85 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp Nat Genet 1996;12:280-7. group.bmj.comon October 25, 2012 - Published byjmg.bmj.comDownloaded from doi: 10.1136/jmg.34.2.89 1997 34: 89-91J Med Genet G Antiñolo, S Borrego, M Gili, et al. R334W. Login to comment