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

Abstract

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.

Progression of pulmonary hyperinflation and trapped gas associated with genetic and environmental factors in children with cystic fibrosis

“…Nevertheless, the variability of pulmonary function at time of diagnosis in infants [21] and children [84-86] has been found to be partially related to the genotype. In comparison to the inframe homozygotes ΔF508(2) and nonsense R553X/ΔF compound heterozygotes, patients carrying one frameshift mutation 3905insT have a poorer prognosis with respect to the onset of pulmonary disease, progression of lung function, and mortality [87]. Schaedel et al used FEV 1 % normal predicted to demonstrate a slower rate of decline in patients with missense mutations compared with ΔF508(2) homozygotes [86], and Cory et al used LMM analysis to show a slower rate of pulmonary function decline in some patients with non-ΔF508 mutations [51].…”

Growth failure in children with cystic fibrosis

“…Another study found that patients heterozygous for 3905insT have similar high morbidity and mortality to patients homozygous for Δ F508, including underweight and poor growth (51) .…”

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

“…[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.…”

“…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).…”