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

Annalisa Orenti1, Iwona Pranke2, Caroline Faucon3

  • 1Department of Clinical Sciences and Community Health, Laboratory of Medical Statistics, Biometry and Epidemiology "G. A. Maccacaro", University of Milan, Milan, Italy.

Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society
|July 8, 2023
PubMed

Insights

People with Cystic Fibrosis (pwCF) with two nonsense mutations (PTC/PTC) experience faster lung function decline and higher mortality. This study highlights the severe impact of PTC/PTC mutations on CF progression and survival.

Area of Science:

  • Pulmonology
  • Genetics
  • Medical Research

Background:

  • Limited data exists on the clinical status of individuals with Cystic Fibrosis (CF) who carry two nonsense mutations (PTC/PTC).
  • Understanding the disease severity associated with different CFTR mutation types is crucial for patient management and therapeutic development.

Purpose of the Study:

  • To compare disease severity in people with Cystic Fibrosis (pwCF) with two nonsense mutations (PTC/PTC) against those with compound heterozygous (F508del/PTC) and homozygous (F508del/F508del) F508del mutations.
  • To assess CFTR mRNA and protein activity in nasal epithelial cells of pwCF with PTC/PTC mutations.

Main Methods:

  • Retrospective analysis of clinical data from the European CF Society Patient Registry for pwCF in high and middle-income countries.
  • Comparison of disease progression metrics (e.g., FEV1 decline, mortality, Pseudomonas aeruginosa infection rates) across different CFTR mutation groups.
  • Assessment of CFTR mRNA and protein activity in primary human nasal epithelial (HNE) cells from 22 pwCF with PTC/PTC mutations.

Main Results:

  • pwCF with PTC/PTC and F508del/PTC mutations showed a significantly faster decline in Forced Expiratory Volume in 1 second (FEV1) from childhood into adulthood compared to F508del/F508del.
  • Mortality rates were significantly higher in pediatric pwCF with one or two PTC alleles versus F508del homozygous pairs.
  • Pseudomonas aeruginosa infection was more frequent in PTC/PTC individuals, and CFTR activity in their nasal cells was minimal (0-3% of wild-type).

Conclusions:

  • Nonsense mutations, particularly in the PTC/PTC genotype, significantly decrease survival and accelerate respiratory disease progression in children and adolescents with Cystic Fibrosis.
  • These findings underscore the severe clinical impact of PTC/PTC mutations in CF.
  • Targeted therapies for PTC/PTC mutations are warranted to improve outcomes.
Abstract

Keywords:
Cystic fibrosis (MeSH: DO008550)Cystic fibrosis transmembrane conductance regulator (MeSH: DO19005)Premature termination codon (MeSH: DO:18389)

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