TY - JOUR
T1 - Nonsense mutations accelerate lung disease and decrease survival of cystic fibrosis children
AU - ECFSPR Steering group
AU - Orenti, Annalisa
AU - Pranke, Iwona
AU - Faucon, Caroline
AU - Varilh, Jessica
AU - Hatton, Aurelie
AU - Golec, Anita
AU - Dehillotte, Clemence
AU - Durieu, Isabelle
AU - Reix, Philippe
AU - Burgel, Pierre Régis
AU - Grenet, Dominique
AU - Tasset, Céline
AU - Gachelin, Elsa
AU - Perisson, Caroline
AU - Lepissier, Agathe
AU - Dreano, Elise
AU - Tondelier, Danielle
AU - Chevalier, Benoit
AU - Weiss, Laurence
AU - Kiefer, Sébastien
AU - Laurans, Muriel
AU - Chiron, Raphael
AU - Lemonnier, Lydie
AU - Marguet, Christophe
AU - Jung, Andreas
AU - Edelman, Aleksander
AU - Kerem, Bat Sheva
AU - Girodon, Emmanuelle
AU - Taulan-Cadars, Magali
AU - Hinzpeter, Alexandre
AU - Kerem, Eitan
AU - Naehrlich, Lutz
AU - Sermet-Gaudelus, Isabelle
N1 - Publisher Copyright:
© 2023
PY - 2023/11
Y1 - 2023/11
N2 - RATIONALE: 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+/+).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 (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.
CONCLUSIONS: Nonsense mutations decrease the survival and accelerate the course of respiratory disease in children and adolescents with Cystic Fibrosis.
AB - RATIONALE: 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+/+).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 (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.
CONCLUSIONS: Nonsense mutations decrease the survival and accelerate the course of respiratory disease in children and adolescents with Cystic Fibrosis.
KW - Cystic fibrosis (MeSH: DO008550)
KW - Cystic fibrosis transmembrane conductance regulator (MeSH: DO19005)
KW - Premature termination codon (MeSH: DO:18389)
UR - http://www.scopus.com/inward/record.url?scp=85164610892&partnerID=8YFLogxK
U2 - 10.1016/j.jcf.2023.06.005
DO - 10.1016/j.jcf.2023.06.005
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C2 - 37422433
AN - SCOPUS:85164610892
SN - 1569-1993
VL - 22
SP - 1070
EP - 1079
JO - Journal of Cystic Fibrosis
JF - Journal of Cystic Fibrosis
IS - 6
ER -
