ΔF508 CFTR protein expression in tissues from patients with cystic fibrosis

Kälin, Nanette; Claass, Andreas; Sommer, Martin; Puchelle, Édith; Tümmler, Burkhard

doi:10.1172/jci5731

Cited by 250 publications

(210 citation statements)

References 72 publications

Supporting

Mentioning

179

Contrasting

Unclassified

Order By: Relevance

“…The explanation as why there is a difference in the pattern of CFTR expression in the submucosal glands among normal subjects remains obscure, and further investigation is required to understand the implication of this finding. However, it is noteworthy that a previous report also described that CFTR immunostaining signal within the submucosal gland acini was variable, i.e., only in 2 of 4 normal subjects (Kalin et al, 1999).…”

Section: Submucosal Glands Of Normal Airwaysmentioning

confidence: 79%

“…(Engelhardt et al, 1992(Engelhardt et al, , 1194Puchelle et al, 1992;Kalin et al, 1999;Penque et al, 2000). With the availability of very sensitive anti-CFTR mAbs (Mall et al, 2004) and LCM technologies, we initiated a comprehensive study to explore two major issues controversial in CF research: 1) the cell type specific localization of CFTR in the normal lung; and 2) the localization of ⌬F508 CFTR in native airway epithelium.…”

Section: Discussionmentioning

confidence: 99%

“…However, the concept that the pathophysiology of ⌬F508 CFTR in native epithelia reflects predominantly defective processing and protein mislocalization has been challenged. 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: 89%

“…This study clearly demonstrated that CFTR protein is expressed in all ciliated cells within the surface epithelium and is consistent with a significant role for CFTR in airway fluid balance. Other studies, however, have reported CFTR expression in mucous cells by immunohistochemistry (Jacquot et al, 1993;Kalin et al, 1999) and CFTR regulation of mucin sialylation and sulfation and granule exocytosis (Barasch et al, 1991;Glick et al, 2001). However, consistent with our data that CFTR is not expressed in goblet cells, mucin granule secretion rates have been reported not to differ in CF versus normal epithelium (Lethem et al, 1993), and there is little evidence for abnormal modifications of mucins in CF in the absence of infection/ inflammation (Roussel, 2001).…”

Section: Function Of Normal Superficial Epithelia In Mucus/fluidmentioning

confidence: 96%

“…Briefly, these mAbs recognize human WT and ⌬F508 CFTR heterologously expressed in epithelial MTE18 and BHK cells with high specificity and with 10 -100 times higher sensitivity than previously published antibodies (Cohn et al, 1991;Kalin et al, 1999) in biochemical and immunocytochemical assays (see Figure 2 in Mall et al, 2004). The mAbs used in this study react with different and nonoverlapping epitopes within the R-domain (570 and 217, biochemical studies) and NBD2 domain (596, 528, and 729, biochemical and immunocytochemical studies) of the CFTR molecule.…”

Section: Cftr Immunolocalizationmentioning

confidence: 99%

See 4 more Smart Citations

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: Submucosal Glands Of Normal Airwaysmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Section: Function Of Normal Superficial Epithelia In Mucus/fluidmentioning

confidence: 96%

Section: Cftr Immunolocalizationmentioning

confidence: 99%

See 3 more Smart Citations

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

Physiology of Electrolyte Transport in the Gut: Implications for Disease

Rao

2019

Comprehensive Physiology

View full text Add to dashboard Cite

We now have an increased understanding of the genetics, cell biology, and physiology of electrolyte transport processes in the mammalian intestine, due to the availability of sophisticated methodologies ranging from genome wide association studies to CRISPR‐CAS technology, stem cell‐derived organoids, 3D microscopy, electron cryomicroscopy, single cell RNA sequencing, transgenic methodologies, and tools to manipulate cellular processes at a molecular level. This knowledge has simultaneously underscored the complexity of biological systems and the interdependence of multiple regulatory systems. In addition to the plethora of mammalian neurohumoral factors and their cross talk, advances in pyrosequencing and metagenomic analyses have highlighted the relevance of the microbiome to intestinal regulation. This article provides an overview of our current understanding of electrolyte transport processes in the small and large intestine, their regulation in health and how dysregulation at multiple levels can result in disease. Intestinal electrolyte transport is a balance of ion secretory and ion absorptive processes, all exquisitely dependent on the basolateral Na + /K + ATPase; when this balance goes awry, it can result in diarrhea or in constipation. The key transporters involved in secretion are the apical membrane Cl − channels and the basolateral Na + ‐K + ‐2Cl − cotransporter, NKCC1 and K + channels. Absorption chiefly involves apical membrane Na + /H + exchangers and Cl − /HCO 3 − exchangers in the small intestine and proximal colon and Na + channels in the distal colon. Key examples of our current understanding of infectious, inflammatory, and genetic diarrheal diseases and of constipation are provided. © 2019 American Physiological Society. Compr Physiol 9:947‐1023, 2019.

show abstract

Misprocessing of theCFTRprotein leads to mild cystic fibrosis phenotype

et al. 2005

View full text Add to dashboard Cite

Cystic fibrosis (CF) is mainly caused by mutations that interfere with the biosynthetic folding of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The aim of this study was to determine the mechanism of dysfunction of a disease-causing mutation associated with variable phenotypes. In order to attain these objectives, we studied the effect of the p.L206W mutation on CFTR protein production and function, and we examined the genotype-phenotype correlation of [p.L206W]+[p.F508del] patients. We showed that p.L206W is a processing (class II) mutation since the CFTR biosynthetic pathway was severely impaired, whereas single-channel measurements indicated ion conductance similar to the wild-type protein. These data raise the larger question of the phenotypic variability of class II mutants, including p.F508del. Since multiple potential partners could modify the processing of the CFTR protein during its course to the cell surface, environmental and other genetic factors might contribute to this variability.

show abstract

ΔF508 CFTR protein expression in tissues from patients with cystic fibrosis

Cited by 250 publications

References 72 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

Physiology of Electrolyte Transport in the Gut: Implications for Disease

Misprocessing of theCFTRprotein leads to mild cystic fibrosis phenotype

Contact Info

Product

Resources

About