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      Mislocalization of delta F508 CFTR in cystic fibrosis sweat gland.

      Nature genetics

      physiology, physiopathology, Base Sequence, Cystic Fibrosis, genetics, Cystic Fibrosis Transmembrane Conductance Regulator, Genetic Variation, Antibodies, Monoclonal, Humans, Intestines, Ion Channels, Membrane Proteins, analysis, Molecular Sequence Data, Organ Specificity, Pancreas, Recombinant Proteins, Reference Values, Respiratory Physiological Phenomena, Restriction Mapping, Rodentia, Salivary Glands, Skin, Skin Physiological Phenomena, Sweat Glands, Amino Acid Sequence, Animals

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          Abstract

          Misprocessing and mislocalization of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) has been described for the major CF-causing mutation (delta F508) in heterologous expression systems in vitro. We have generated monoclonal antibodies (mAbs) to CFTR with the aim of localizing the protein and its CF variants in vivo. Of the tissues where CFTR was observed, only the sweat gland is readily available and does not undergo secondary changes due to CF disease pathology. Sweat ducts from CF patients homozygous for delta F508 did not show the typical apical membrane staining seen in control biopsies. This demonstrates that the biosynthetic arrest and intracellular retention of delta F508 CFTR initially observed in vitro does occur in vivo and emphasizes the need to focus efforts on understanding the mislocalization.

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          Most cited references 25

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          Identification of the cystic fibrosis gene: genetic analysis.

          Approximately 70 percent of the mutations in cystic fibrosis patients correspond to a specific deletion of three base pairs, which results in the loss of a phenylalanine residue at amino acid position 508 of the putative product of the cystic fibrosis gene. Extended haplotype data based on DNA markers closely linked to the putative disease gene locus suggest that the remainder of the cystic fibrosis mutant gene pool consists of multiple, different mutations. A small set of these latter mutant alleles (about 8 percent) may confer residual pancreatic exocrine function in a subgroup of patients who are pancreatic sufficient. The ability to detect mutations in the cystic fibrosis gene at the DNA level has important implications for genetic diagnosis.
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            Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase

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              Identification of the cystic fibrosis gene: chromosome walking and jumping.

              An understanding of the basic defect in the inherited disorder cystic fibrosis requires cloning of the cystic fibrosis gene and definition of its protein product. In the absence of direct functional information, chromosomal map position is a guide for locating the gene. Chromosome walking and jumping and complementary DNA hybridization were used to isolate DNA sequences, encompassing more than 500,000 base pairs, from the cystic fibrosis region on the long arm of human chromosome 7. Several transcribed sequences and conserved segments were identified in this cloned region. One of these corresponds to the cystic fibrosis gene and spans approximately 250,000 base pairs of genomic DNA.
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                Author and article information

                Journal
                10.1038/ng0892-321
                1284548

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