Nonsense mutations accelerate lung disease and decrease survival of cystic fibrosis children.
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Orenti Annalisa, Pranke Iwona, Faucon Caroline, Varilh Jessica, Hatton Aurelie, Golec Anita, Dehillotte Clemence, Durieu Isabelle, Reix Philippe, Burgel Pierre-Régis, Grenet Dominique, Tasset Céline, Gachelin Elsa, Perisson Caroline, Lepissier Agathe, Dreano Elise, Tondelier Danielle, Chevalier Benoit, Weiss Laurence, Kiefer Sébastien, Laurans Muriel, Chiron Raphael, Lemonnier Lydie, Marguet Christophe, Jung Andreas, Edelman Aleksander, Kerem Bat-Sheva, Girodon Emmanuelle, Taulan-Cadars Magali, Hinzpeter Alexandre, Kerem Eitan, Naehrlich Lutz, Sermet-Gaudelus Isabelle, ECFSPR Steering group
Аннотация
METHODS: 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.
MAIN RESULTS: 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 (FEV1) 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 FEV1 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.
CONCLUSIONS: Nonsense mutations decrease the survival and accelerate the course of respiratory disease in children and adolescents with Cystic Fibrosis.