Nonsense mutations accelerate lung disease and decrease survival of cystic fibrosis children.

• Nearly 5% of people with CF worldwide carry a nonsense mutation on both alleles resulting in a premature termination codon (PTC). For those patients, no efficient targeted therapy is available yet. Limited information is available on their clinical status. • Our study shows thatPwCF carrying at least one PTC exhibited a significantly faster rate of yearly respiratory decline until ∼ 30 years. • Mortality of children and adolescents with one or two PTC alleles was significantly higher than that of their F508del homozygous pairs. • Infection with Pseudomonas aeruginosa was more frequent in patients carrying 2 PTC when compared to PTC/F508del or F508del homozygous patients. • These data highlight the urgent need to develop targeted interventions for patients carrying nonsense mutations in the CFTR gene. Limited information is available on the clinical status of people with Cystic Fibrosis (pwCF) carrying 2 nonsense mutations (PTC/PTC). The main objective of this study was to compare disease severity between pwCF PTC/PTC, compound heterozygous for F508del and PTC (F508del/PTC) and homozygous for F508del (F508del+/+). Based on the European CF Society Patient Registry clinical data of pwCF living in high and middle income European and neighboring countries, PTC/PTC (n = 657) were compared with F508del+/+ (n = 21,317) and F508del/PTC(n = 4254).CFTR mRNA and protein activity levels were assessed in primary human nasal epithelial (HNE) cells sampled from 22 PTC/PTC pwCF. As compared to F508del+/+ pwCF; both PTC/PTC and F508del/PTC pwCF exhibited a significantly faster rate of decline in Forced Expiratory Volume in 1 s (FEV 1) from 7 years (-1.33 for F508del +/+, -1.59 for F508del/PTC; -1.65 for PTC/PTC, p < 0.001) until respectively 30 years (-1.05 for F508del +/+, -1.23 for PTC/PTC, p = 0.048) and 27 years (-1.12 for F508del +/+, -1.26 for F508del/PTC, p = 0.034). This resulted in lower FEV 1 values in adulthood. Mortality of pediatric pwCF with one or two PTC alleles was significantly higher than their F508del homozygous pairs. Infection with Pseudomonas aeruginosa was more frequent in PTC/PTC versus F508del+/+ and F508del/PTC pwCF. CFTR activity in PTC/PTC pwCF's HNE cells ranged between 0% to 3% of the wild-type level. Nonsense mutations decrease the survival and accelerate the course of respiratory disease in children and adolescents with Cystic Fibrosis. [ABSTRACT FROM AUTHOR]