Progression of pulmonary hyperinflation and trapped gas associated with genetic and environmental factors in children with cystic fibrosis

Kraemer, Richard; Baldwin, David N.; Ammann, Roland A.; Frey, Urs; Gallati, Sabina

doi:10.1186/1465-9921-7-138

Cited by 66 publications

(99 citation statements)

References 85 publications

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“…From the Bernese CF Patient Data Registry, 13 56 CF patients homozygous for CFTR p.Phe508del and with biometric and lung function data from age 6 to 20 years were analyzed (see Supplementary Data for detailed materials and methods). Lung function data included lung clearance index (LCI), forced expiratory volume in 1 s (FEV1), forced expiratory flow (FEF) at 50% (FEF50) and specific airway resistance (sReff), as well as the functional residual capacity and volume of trapped gas .…”

Section: Patientsmentioning

confidence: 99%

Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

et al. 2013

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Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR). Disease severity in CF varies greatly, and sibling studies strongly indicate that genes other than CFTR modify disease outcome. Syntaxin 1A (STX1A) has been reported as a negative regulator of CFTR and other ion channels. We hypothesized that STX1A variants act as a CF modifier by influencing the remaining function of mutated CFTR. We identified STX1A variants by genomic resequencing patients from the Bernese CF Patient Data Registry and applied linear mixed model analysis to establish genotype-phenotype correlations, revealing STX1A rs4363087 (c.467 À38A4G) to significantly influence lung function. The same STX1A risk allele was recognized in the European CF Twin and Sibling Study (P ¼ 0.0027), demonstrating that the genotype-phenotype association of STX1A to CF disease severity is robust enough to allow replication in two independent CF populations. rs4363087 is in linkage disequilibrium to the exonic variant rs2228607 (c.204C4T). Considering that neither rs4363087 nor rs2228607 changes the amino-acid sequence of STX1A, we investigated their effects on mRNA level. We show that rs2228607 reinforces aberrant splicing of STX1A mRNA, leading to nonsense-mediated mRNA decay. In conclusion, we demonstrate the clinical relevance of STX1A variants in CF, and evidence the functional relevance of STX1A variant rs2228607 at molecular level. Our findings show that genes interacting with CFTR can modify CF disease progression.

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Section: Patientsmentioning

confidence: 99%

Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

et al. 2013

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“…Measurement techniques have been described in detail previously. [8][9][10]37 All values were expressed by z-transformation in SD scores (SDS), based on gender-and age-specific regression equations. 38,39 Details regarding measurement techniques and clinical evidence of these target parameters are given in the online data supplement.…”

Section: Lung Function Testingmentioning

confidence: 99%

“…3 Clinically, CF is characterized by elevated sweat chloride concentration, exocrine pancreatic insufficiency, male infertility and progressive obstructive lung disease, the latter being the primary cause of mortality. 4,5 The respiratory disease progression in CF is expressed by various pulmonary dysfunctions, [6][7][8][9][10] such as ventilation inhomogeneities, 8,11 pulmonary hyperinflation, 9,12 bronchial obstruction, trapped gas and gas exchange disturbances, 10 most of them occurring early in life, 7,12,13 and progressing even in the absence of clinical signs and symptoms. 11,14,15 Owing to the great phenotypic variability in lung disease even observed among patients carrying the same CFTR genotype, several association studies have been conducted to find modifying genetic factors and to study their influence on CF disease outcome.…”

Section: Introductionmentioning

confidence: 99%

“…To achieve this, we used the clinically very carefully characterized patient cohort of the Children's University Hospital in Bern documented over a time period of 13 years. [8][9][10] Owing to the fact that these patients were treated at the same hospital, environmental influences in the context of medical treatment are reduced in this cohort, making it well suited to study-modifying effects.…”

Section: Introductionmentioning

confidence: 99%

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Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis

et al. 2012

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There is growing evidence that the great phenotypic variability in patients with cystic fibrosis (CF) not only depends on the genotype, but apart from a combination of environmental and stochastic factors predominantly also on modifier gene effects. It has been proposed that genes interacting with CF transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) are potential modifiers. Therefore, we assessed the impact of single-nucleotide polymorphisms (SNPs) of several of these interacters on CF disease outcome. SNPs that potentially alter gene function were genotyped in 95 well-characterized p.Phe508del homozygous CF patients. Linear mixed-effect model analysis was used to assess the relationship between sequence variants and the repeated measurements of lung function parameters. In total, we genotyped 72 SNPs in 10 genes. Twenty-five SNPs were used for statistical analysis, where we found strong associations for one SNP in PPP2R4 with the lung clearance index (Pr0.01), the specific effective airway resistance (Pr0.005) and the forced expiratory volume in 1 s (Pr0.005). In addition, we identified one SNP in SNAP23 to be significantly associated with three lung function parameters as well as one SNP in PPP2R1A and three in KRT19 to show a significant influence on one lung function parameter each. Our findings indicate that direct interacters with CFTR, such as SNAP23, PPP2R4 and PPP2R1A, may modify the residual function of p.Phe508del-CFTR while variants in KRT19 may modulate the amount of p.Phe508del-CFTR at the apical membrane and consequently modify CF disease.

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“…Earlier studies based on clinical parameters have shown that the 3905insT mutation is associated with a severe phenotype. [9][10][11][12] The insertion of an additional thymidine in exon 20 leads to a premature termination codon (PTC) in the same exon. It is well known that PTCs can activate the nonsense-mediated mRNA decay (NMD).…”

Section: Introductionmentioning

confidence: 99%

The CFTR frameshift mutation 3905insT and its effect at transcript and protein level

et al. 2009

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Cystic fibrosis (CF) is one of the most common genetic diseases in the Caucasian population and is characterized by chronic obstructive pulmonary disease, exocrine pancreatic insufficiency, and elevation of sodium and chloride concentrations in the sweat and infertility in men. The disease is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a protein that functions as chloride channel at the apical membrane of different epithelia. Owing to the high genotypic and phenotypic disease heterogeneity, effects and consequences of the majority of the CFTR mutations have not yet been studied. Recently, the frameshift mutation 3905insT was identified as the second most frequent mutation in the Swiss population and found to be associated with a severe phenotype. The frameshift mutation produces a premature termination codon (PTC) in exon 20, and transcripts bearing this PTC are potential targets for degradation through nonsense-mediated mRNA decay (NMD) and/or for exon skipping through nonsense-associated alternative splicing (NAS). Using RT-PCR analysis in lymphocytes and different tissue types from patients carrying the mutation, we showed that the PTC introduced by the mutation does neither elicit a degradation of the mRNA through NMD nor an alternative splicing through NAS. Moreover, immunocytochemical analysis in nasal epithelial cells revealed a significantly reduced amount of CFTR at the apical membrane providing a possible molecular explanation for the more severe phenotype observed in F508del/3905insT compound heterozygotes compared with F508del homozygotes. However, further experiments are needed to elucidate the fate of the 3905insT CFTR in the cell after its biosynthesis.

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Progression of pulmonary hyperinflation and trapped gas associated with genetic and environmental factors in children with cystic fibrosis

Cited by 66 publications

References 85 publications

Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis

The CFTR frameshift mutation 3905insT and its effect at transcript and protein level

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