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Title: The application of genetic analysis in cystic fibrosis.
Author: Schwarz, Martin.
Awarding Body: Manchester Metropolitan University
Current Institution: Manchester Metropolitan University
Date of Award: 1993
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Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in Caucasians, with an incidence of approximately 1 in 2,500 newborns and a carrier frequency of 1 in 25. The major symptoms of the disease are due to malfunction of exocrine glands; sweat glands in the skin secrete excessive sodium and chloride, pancreatic ducts become blocked with thickened mucus, giving rise to pancreatic insufficiency, and the lungs also produce a thickened mucus which facilitates bacterial infection, notably with Pseudomonas species. The gene for CF has been isolated and its product, Cystic Fibrosis Transmembrane conductance Regulator (CFTR), has been determined. Over 240 different mutations of the CFTR gene have so far been described, and most of these have been shown to be disease-causing. CFTR protein is itself a chloride channel regulated by cyclic AMP-dependent protein kinase and it is expressed primarily in epithelial cells. The highest level of transcription is found in those tissues involved in the major symptoms of the disease, notably the pancreas, sweat and salivary glands, the intestine and the reproductive tract. Genetic analysis in cystic fibrosis has enabled accurate first-trimester prenatal diagnosis, initially using linked markers and latterly using direct mutation analysis. Since the isolation of the gene in 1989 it has become of considerable importance to identify CF mutations in a population (for the purpose of population screening) and in individuals with CF (to enable carrier detection and prenatal diagnosis within that family). To that end, the CF population of the North-West of England has been extensively studied. A total of 1108 CF chromosomes of the native North-West population have been investigated and 92% of mutations (comprising 20 different mutations of the CFTR gene) in that group have been identified. Two further groups were of interest, namely a small number of Pakistani CF patients in whom 50% of mutations were identified, and a phenotypically variant group with atypical sweat test results, which yielded no mutations. During the course of the investigation, five previously unrecorded mutations were identified: DeltaI507 in a patient from Bath, 300delA in one from Birmingham, 1161de1C in a Pakistani CF patient, and E60X and 1138insG in patients from the North-West of England. Since these comprise a three-base deletion, a stop codon mutation, and three frameshift mutations, they can all be accepted as diseasecausing mutations. While some headway has been made in identifying CF mutations in Pakistani patients, none has been possible in the phenotypically variant group. There remains some doubt, therefore, that individuals in the latter group do in fact have CF or whether a phenocopy disease is present.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Genetics Molecular biology Cytology Genetics Medicine