Journal article
Genotypic analysis of respiratory mucous sulfation defects in cystic fibrosis
The Journal of clinical investigation, Vol.96(6), pp.2997-3004
12/01/1995
DOI: 10.1172/JCI118372
PMCID: PMC186012
PMID: 8675672
Abstract
Intracellular dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) has been proposed to alter endosomal acidification. The most widely studied consequence of this defect has been alterations in the biochemical properties of cystic fibrosis (CF) respiratory mucus glycoproteins. However, studies confirming the existence of mucous processing defects in CF have been hindered by the lack of in vivo animal models by which to test these hypotheses in the absence of secondary effects of chronic bacterial infection. The human bronchial xenograft model has been useful in evaluating the pathophysiologic differences between CF and non-CF airway epithelium, in the absence of secondary disease effects such as goblet cell hyperplasia. In this study we sought to compare the extent of sulfation within secreted mucus glycoproteins from CF and non-CF human bronchial xenografts. Cumulative results of xenografts generated from 13 independent CF tissue samples demonstrated a statistically significant higher level of sulfation (1.7 +/- 0.18, P < 0.026) as compared to non-CF paired controls. Such findings add to the growing body of knowledge that primary defects in sulfation exist in CF respiratory mucin. Correlation of genotype with the extent of mucus sulfation revealed two categories of CF tissues with statistically different mucus sulfation profiles. Results from these studies demonstrated a 2.0 +/- 0.15-fold higher level of mucus sulfation produced from xenografts of five defined CF genotypes as compared to non-CF controls (P < 0.004, n= 10). Interestingly, three CF samples for which one mutant allele remained undefined (deltaoff8/unknown or G551D/unknown) demonstrated no statistical difference in the level of sulfation as compared with matched non-CF controls (n= 3). This as yet unknown allele was not identified within a screen for the 26 most common CF mutations. These results provide preliminary evidence for allelic variation within the CF population which may begin to elucidate the structure-function of CFTR with regards to intracellular mucus processing defects.
Details
- Title: Subtitle
- Genotypic analysis of respiratory mucous sulfation defects in cystic fibrosis
- Creators
- Yulong Zhang - University of PennsylvaniaBenjamin Doranz - University of PennsylvaniaJames R Yankaskas - University of PennsylvaniaJohn F Engelhardt - University of Pennsylvania
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.96(6), pp.2997-3004
- DOI
- 10.1172/JCI118372
- PMID
- 8675672
- PMCID
- PMC186012
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Language
- English
- Date published
- 12/01/1995
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984284351902771
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