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Generation of Human Nasal Epithelial Cell Spheroids for Individualized Cystic Fibrosis Transmembrane Conductance Regulator Study
Published on: April 11, 2018
Multicenter Surveillance of Cystic Fibrosis in Korean Children
Hyung Young Kim1, Soo-Jong Hong2, Kangmo Ahn3
1Department of Pediatrics, Dongnam Institute of Radiological & Medical Sciences, Busan, Korea.
Insights
Cystic fibrosis (CF) is rare in Korean children, presenting unique CFTR mutations like L441P. Early diagnosis and CFTR modulators show promise for improving outcomes in this population.
Area of Science:
- Genetics and genomics
- Pediatric medicine
- Respiratory diseases
Background:
- Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
- CF is notably rare in non-Caucasian populations, with distinct genetic profiles.
- Understanding CF in diverse ethnic groups is crucial for effective diagnosis and treatment.
Purpose of the Study:
- To identify the clinical characteristics of CF in Korean children.
- To determine the spectrum of CFTR mutations prevalent in this pediatric population.
- To evaluate the potential efficacy of CFTR modulators for specific mutations found in Korean patients.
Main Methods:
- Retrospective analysis of 18 pediatric CF patients diagnosed over 30 years.
- Utilized sweat chloride tests and genetic analysis for diagnosis.
- Employed cell-based assays with HEK293 cells to assess CFTR corrector efficacy for identified mutations (e.g., L441P-CFTR).
Main Results:
- The median age at diagnosis was 9.2 years, with common issues including growth retardation and respiratory failure.
- The most frequent mutation was an exon 16-17b deletion; c.1322T>C (L441P) was identified in 4 patients.
- Functional assays demonstrated that CFTR correctors effectively restored L441P-CFTR function, unlike the ΔF508 mutation.
Conclusions:
- CF is exceptionally rare in Korean children, often associated with distinct CFTR mutations compared to Caucasian cohorts.
- Early detection and intervention are vital for improving patient prognosis.
- CFTR modulators, particularly for mutations like c.1322T>C (L441P), may offer therapeutic benefits for Asian patients.
Purpose:
Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is rare among non-Caucasians. We aimed to identify the clinical features and CFTR mutations in Korean children.
Methods:
We included 18 pediatric patients with CF diagnosed using sweat chloride test or genetic analysis for 30 years. HEK293 cells were transfected with wild-type CFTR, ΔF508-CFTR, and L441P-CFTR mutant plasmids for 24 hours and treated with CFTR correctors (VX809 and VX661).
Results:
The median age at diagnosis was 9.2 years. Eleven patients had growth retardation, and 6 had a respiratory failure at diagnosis. Genetic analysis was used for all patients, while sweat testing was for 8 patients. At diagnosis, the median z scores of forced expiratory volume in one second (FEV1), FEV1/forced vital capacity, and forced expiratory flow at 25%-75% of forced vital capacity were -3.61 (-5.78, 1.78), -3.38 (-4.40, -0.60), and -4.45 (-5.78, 0.54), respectively. Two patients were treated with dornase alfa and only one with CFTR modulator. Patients were followed up for 3.7 years as a median. Four patients died at 10.6 years, with 4.2 years of post-diagnosis survival. The most common mutation was exon 16-17b deletion (19.4%). Among 11 single nucleotide variants, c.1322T>C (p.Leu441Pro, L441P) was detected in 4 patients. In the functional assay, L441P-CFTR correction was well restored by CFTR correctors compared with ΔF508.
Conclusions:
CF is extremely rare in Korean children and is caused by different mutations from those commonly observed in Caucasians. Early diagnosis and treatment availability may improve outcomes. CFTR modulators may be effective for Asian patients with rare CFTR mutations, c.1322T>C (p.Leu441Pro).
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