Genotype/Phenotype Association in Cystic Fibrosis: Analyses of the ΔF508, R553X, and 3905insT Mutations

Liechti‐Gallati, Sabina; Bonsall, Irene; Malik, Naseem; Schneider, Verena; Kraemer, Lilliane G; Ruedeberg, Anna; Moser, Hans; Kraemer, Richard

doi:10.1203/00006450-199208000-00010

Cited by 44 publications

(25 citation statements)

References 15 publications

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“…[9][10][11][12] The mutation is characterized by the introduction of a PTC in exon 20 of the CFTR gene. PTCs can be recognized by the so-called NMD, which degrades transcripts bearing such PTCs thereby preventing the formation of a truncated protein.…”

Section: Discussionmentioning

confidence: 99%

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The CFTR frameshift mutation 3905insT and its effect at transcript and protein level

et al. 2009

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Cystic fibrosis (CF) is one of the most common genetic diseases in the Caucasian population and is characterized by chronic obstructive pulmonary disease, exocrine pancreatic insufficiency, and elevation of sodium and chloride concentrations in the sweat and infertility in men. The disease is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a protein that functions as chloride channel at the apical membrane of different epithelia. Owing to the high genotypic and phenotypic disease heterogeneity, effects and consequences of the majority of the CFTR mutations have not yet been studied. Recently, the frameshift mutation 3905insT was identified as the second most frequent mutation in the Swiss population and found to be associated with a severe phenotype. The frameshift mutation produces a premature termination codon (PTC) in exon 20, and transcripts bearing this PTC are potential targets for degradation through nonsense-mediated mRNA decay (NMD) and/or for exon skipping through nonsense-associated alternative splicing (NAS). Using RT-PCR analysis in lymphocytes and different tissue types from patients carrying the mutation, we showed that the PTC introduced by the mutation does neither elicit a degradation of the mRNA through NMD nor an alternative splicing through NAS. Moreover, immunocytochemical analysis in nasal epithelial cells revealed a significantly reduced amount of CFTR at the apical membrane providing a possible molecular explanation for the more severe phenotype observed in F508del/3905insT compound heterozygotes compared with F508del homozygotes. However, further experiments are needed to elucidate the fate of the 3905insT CFTR in the cell after its biosynthesis.

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Section: Discussionmentioning

confidence: 99%

“…Earlier studies based on clinical parameters have shown that the 3905insT mutation is associated with a severe phenotype. [9][10][11][12] The insertion of an additional thymidine in exon 20 leads to a premature termination codon (PTC) in the same exon. It is well known that PTCs can activate the nonsense-mediated mRNA decay (NMD).…”

Section: Introductionmentioning

confidence: 99%

The CFTR frameshift mutation 3905insT and its effect at transcript and protein level

et al. 2009

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“…The study included a homogenous collective of patients ethnically originating from Switzerland. In a smaller group of CF patients, the genotype-phenotype association of the first 13 patients with the 3905insT [8] have been previously described. The present study was made to test these findings concerning morbidity and mortality after having studied the long-term clinical course.…”

Section: Limits Of the Methodsmentioning

confidence: 99%

“…Comparison of the long-term clinical course of CF in patients with different genotypes is difficult because therapy modalities have improved consistently over the last few years and therapy compliance varies from patient to patient. Recently a novel insertion mutation in exon 20 of the CFTR gene, 3905insT, was discovered [8]. This mutation accounts for the second most common (4.8%) CFTR gene mutations in Switzerland [15] and among the Amish population in USA, its frequency is reported as high as 16.9% [16].…”

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High morbidity and mortality in cystic fibrosis patients compound heterozygous for 3905insT and ΔF508

et al. 2001

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High morbidity and mortality in cystic fibrosis patients compound heterozygous for 3905insT and DF508. A. Schibler, I. Bolt, S. Gallati, M.H. Schöni, R. Kraemer. #ERS Journals Ltd 2001. ABSTRACT: Genotype-phenotype association in cystic fibrosis (CF) is difficult because of heterogeneous disease expression. The genotype-phenotype correlation for the 3905insT mutation in comparison to DF508 was studied here.Thirty CF patients compound heterozygous for 3905insT were compared to clinical presentation of matched patients homozygous for DF508 (1960 -1997). Sweat tests, age at diagnosis, at death and at onset of Pseudomonas aeruginosa colonization were analysed. Chrispin-Norman scores and pulmonary function forced expiratory volume in one second (FEV1) determined severity of lung disease. Twenty-five of the patients with 3905insT had DF508 as a second mutation and five had another rare mutation.At the age of 15 yrs, 60% of patients with 3905insT had an FEV1v60% predicted in comparison to 25% of patients with DF508 (pv0.05). Age at death and cumulative survival rate was significantly lower (pv0.05) in the 3905insT than in the DF508 group (20.3 and 24.0 yrs, respectively). Age at onset of P. aeruginosa colonization was not different in the study groups. Sweat chloride concentrations were lower in patients homozygous for DF508 (105.63¡15.3 mmol?L -1 ) than in patients with 3905insT (119.9¡22.1 mmol?L -1 ) (pv0.05). Patients compound heterozygous for 3905insT have similar high morbidity and mortality to patients homozygous for DF508.

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“…Previous studies analyzed the genotype-phenotype correlation in several mutations for which a large enough number of patients was available. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] These studies have shown that genetic factors influence the severity of the disease, and that there are two groups of mutations. One group is associated with pancreatic insufficiency (PI) (Ͼ95% of cases) and a young age at diagnosis (usually Ͻ1 year of age), high sweat chloride levels (Ͼ80 meq/L), and meconium ileus (20% to 30% of the cases).…”

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A Missense Cystic Fibrosis Transmembrane Conductance Regulator Mutation With Variable Phenotype

et al. 1997

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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

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Genotype/Phenotype Association in Cystic Fibrosis: Analyses of the ΔF508, R553X, and 3905insT Mutations

Cited by 44 publications

References 15 publications

The CFTR frameshift mutation 3905insT and its effect at transcript and protein level

The CFTR frameshift mutation 3905insT and its effect at transcript and protein level

High morbidity and mortality in cystic fibrosis patients compound heterozygous for 3905insT and ΔF508

A Missense Cystic Fibrosis Transmembrane Conductance Regulator Mutation With Variable Phenotype

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