Chloride conductance and genetic background modulate the cystic fibrosis phenotype of ΔF508 homozygous twins and siblings

Bronsveld, Inez; Mekus, Frauke; Bijman, J.; Ballmann, Manfred; Jonge, Hugo R. de; Laabs, Ulrike; Halley, Dicky; Ellemunter, Helmut; Mastella, G; Thomas, Stephen R.; Veeze, Henk J.; Tümmler, Burkhard

doi:10.1172/jci12108

Cited by 135 publications

(129 citation statements)

References 47 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…An immunohistochemical study detected CFTR in the apical PM at similar intensities in airway and intestinal epithelia from ⌬F508 homozygous and normal subjects, suggesting that the maturation defect of ⌬F508 CFTR is tissuespecific (Kalin et al, 1999). Similarly, recent functional studies concluded that residual CFTR-mediated Cl Ϫ secretion was present in rectal and nasal epithelia from a large subgroup of ⌬F508 homozygous CF subjects (Bronsveld et al, 2000(Bronsveld et al, , 2001.…”

Section: Introductionmentioning

confidence: 91%

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

Kreda

Mall

Mengos

et al. 2005

MBoC

234

210

View full text Add to dashboard Cite

Previous studies in native tissues have produced conflicting data on the localization and metabolic fate of WT and ⌬F508 cystic fibrosis transmembrane regulator (CFTR) in the lung. Combining immunocytochemical and biochemical studies utilizing new high-affinity CFTR mAbs with ion transport assays, we examined both 1) the cell type and region specific expression of CFTR in normal airways and 2) the metabolic fate of ⌬F508 CFTR and associated ERM proteins in the cystic fibrosis lung. Studies of lungs from a large number of normal subjects revealed that WT CFTR protein localized to the apical membrane of ciliated cells within the superficial epithelium and gland ducts. In contrast, other cell types in the superficial, gland acinar, and alveolar epithelia expressed little WT CFTR protein. No ⌬F508 CFTR mature protein or function could be detected in airway specimens freshly excised from a large number of ⌬F508 homozygous subjects, despite an intact ERM complex. In sum, our data demonstrate that WT CFTR is predominantly expressed in ciliated cells, and ⌬F508 CFTR pathogenesis in native tissues, like heterologous cells, reflects loss of normal protein processing.

show abstract

Section: Introductionmentioning

confidence: 91%

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

Kreda

Mall

Mengos

et al. 2005

MBoC

234

210

View full text Add to dashboard Cite

show abstract

“…However, in more recent immunocytochemical studies of intestinal, respiratory and hepatobiliary epithelia of F508 homozygous CF patients, a proportion of CFTR protein was shown to be targeted to the apical membranes (Kalin et al 1999). Further, measurements of Cl − conductance of intestine and respiratory tissues of F508 homozygote CF patients suggested that, in vivo, at least some F508 CFTR can reach the plasma membrane (Bronsveld et al 2001).…”

Section: Class I Mutations Affecting Biosynthesismentioning

confidence: 99%

The Phenotypic Consequences of CFTR Mutations

Rowntree¹,

Harris²

2003

Annals of Human Genetics

299

215

View full text Add to dashboard Cite

SummaryCystic fibrosis is a common autosomal recessive disorder that primarily affects the epithelial cells in the intestine, respiratory system, pancreas, gall bladder and sweat glands. Over one thousand mutations have currently been identified in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that are associated with CF disease. There have been many studies on the correlation of the CFTR genotype and CF disease phenotype; however, this relationship is still not well understood. A connection between CFTR genotype and disease manifested in the pancreas has been well described, but pulmonary disease appears to be highly variable even between individuals with the same genotype. This review describes the current classification of CFTR mutation classes and resulting CF disease phenotypes. Complex disease alleles and modifier genes are discussed along with alternative disorders, such as disseminated bronchiectasis and pancreatitis, which are also thought to result from CFTR mutations.

show abstract

“…The CF basic defect can be assessed in vivo by sweat chloride measurement and nasal potential difference measurement or ex vivo by intestinal current measurement on excised intestinal biopsies. 1,9 Among F508del-CFTR homozygotes, the observation of small to subnormal chloride conductance assessed in nasal or intestinal tissue, described as CFTR-mediated residual chloride secretion, correlates with a milder course of CF disease. 9 Although the mode of inheritance defines CF as a single-gene disorder, its variable course indicates that non-inherited and inherited factors shape the manifestation of the monogenic disease, which has been acknowledged by several research groups with an investigation of CF-modifying genes.…”

Section: Introductionmentioning

confidence: 99%

“…1,9 Among F508del-CFTR homozygotes, the observation of small to subnormal chloride conductance assessed in nasal or intestinal tissue, described as CFTR-mediated residual chloride secretion, correlates with a milder course of CF disease. 9 Although the mode of inheritance defines CF as a single-gene disorder, its variable course indicates that non-inherited and inherited factors shape the manifestation of the monogenic disease, which has been acknowledged by several research groups with an investigation of CF-modifying genes. The disease is characterized by a proinflammatory state, 10 which has been described in-vitro in cell systems, [11][12][13][14][15][16] using a murine model 17 and was confirmed mostly, [18][19][20][21] albeit not exclusively, 22,23 in ex-vivo material studied from CF patients.…”

Section: Introductionmentioning

confidence: 99%

Initial interrogation, confirmation and fine mapping of modifying genes: STAT3, IL1B and IFNGR1 determine cystic fibrosis disease manifestation

et al. 2011

Self Cite

View full text Add to dashboard Cite

We have used a stepwise approach consisting of initial interrogation, confirmation and fine mapping to analyze STAT3, IL1B and IFNGR1 as modifiers of cystic fibrosis disease building upon the data and sample collection of the European Cystic Fibrosis Twin and Sibling Study. We have observed direct correlation between the length of the intronic microsatellite STAT3Sat to STAT3 expression levels among F508del-CFTR homozygous patients (P¼0.0075), and an association of longer STAT3Sat-alleles with the presence of CFTR-mediated residual chloride secretion (P¼0.0031), measured as the manifestation of the CF basic defect in intestinal tissue. Both, family-based analysis by TDT and case-reference comparison identified consistently the same intragenic IL1B haplotype as a risk variant (P raw ¼0.055 for TDT, P raw o0.3 for case-reference comparison). Using haplotypeguided hierarchical fine mapping, we have identified two single nucleotide exchanges for which concordant and discordant sibling pairs differ at a 7 kb -spanning core haplotype in IFNGR1 (P raw ¼0.0113). Taken together, our findings imply that immunorelevant pathways and ion secretion, dominated by CFTR in intestinal and respiratory epithelium, merge at the level of the epithelial cell to integrate the signaling of cytokines due to innate and acquired immune defense.

show abstract

Chloride conductance and genetic background modulate the cystic fibrosis phenotype of ΔF508 homozygous twins and siblings

Cited by 135 publications

References 47 publications

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

The Phenotypic Consequences of CFTR Mutations

Initial interrogation, confirmation and fine mapping of modifying genes: STAT3, IL1B and IFNGR1 determine cystic fibrosis disease manifestation

Contact Info

Product

Resources

About