A Missense Cystic Fibrosis Transmembrane Conductance Regulator Mutation With Variable Phenotype

Abstract

ABSTRACT. Objective. Cystic fibrosis (CF) has variable clinical presentation. Disease severity is partially associated with the type of mutation. The aim of this study was to report genotype-phenotype analysis of the G85E mutation.Patients. The phenotype of 12 patients (8 were from the same extended family, and 5 of them were siblings from 2 families) carrying at least one copy of the G85E mutation was evaluated and compared with the phenotype of 40 patients carrying the two severe mutations, W1282X and/or ⌬F508 (group 1), and with 20 patients carrying the splicing mutation, 3849؉10kb C->T, which was found to be associated with milder disease (group 2).Results. A high phenotypic variability was found among the patients carrying the G85E mutation. This high variability was found among patients carrying the same genotype and among siblings. All the studied chromosomes carrying the G85E mutation had the 7T variant in the polythymidine tract at the branch/acceptor site in intron 8. Of the G85E patients, 25% had pancreatic sufficiency and none had meconium ileus, compared with 0% and 32%, respectively, of patients from group 1, and 80% and 0%, respectively, from group 2. Two patients carrying the G85E mutation had sweat chloride levels <60 mmol/L whereas all the others had typically elevated levels >80 mmol/L. Compared with group 2, patients carrying the G85E mutation were diagnosed at an earlier age and had higher sweat chloride levels, with mean values similar to group 1 but significantly more variable. Forced expiratory volume in 1 second (FEV 1 ) was similar in the three groups, with no differences in the slope or in age-adjusted mean values of FEV 1 . The levels of transcripts lacking exon 9 transcribed from the G85E allele measured in 3 patients were 55%, 49%, and 35% and their FEV 1 values were 82%, 83%, and 50% predicated, respectively.Conclusions. The G85E mutation shows variable clinical presentation in all clinical parameters. This variability could be seen among patients carrying on the other chromosome the same CFTR mutation, and also among siblings. This variability is not associated with the level of exon 9 skipping. Thus, the G85E mutation cannot be

Nasal potential difference measurements in patients with atypical cystic fibrosis

“…Genotype analysis for the known mutations in the Israeli population [21] revealed that none of the patients from the QCF-non-CF group carried two CFTR mutations or the 5T allele on both chromosomes, apart from one patient homozygous for 5T, compared to five patients (22%) in the QCF-CF group, pv0.001 (table 3). The frequency of the 5T allele in the QCF-CF group was 17.4%, significantly higher than the 6% frequency in the general population [19] (p~0.04), but not significantly higher than the 10.5% frequency in the QCF-non-CF.…”

Misprocessing of theCFTRprotein leads to mild cystic fibrosis phenotype

“…These three TM mutants should, therefore, be indexed as class II mutants. Interestingly, the phenotypes associated with them are characterized by variable and/or mild presentation of CF Kerem et al, 1997]. The fraction of mutant protein that reaches the plasma membrane ranges from almost none to 40%.…”

Genotype/phenotype correlation of the G85E mutation in a large cohort of cystic fibrosis patients

“…Earlier reports about G85E concern a small number of patients. It is not clear whether the mutation correlates with a mild, a severe or a variable phenotype [8][9][10][11].…”