Cystic fibrosis gene mutation in two sisters with mild disease and normal sweat electrolyte levels

Article Abstract:

Cystic fibrosis (CF) is the most common fatal genetic disorder among white populations. The advent of molecular biology has permitted the identification of the gene that is abnormal in patients with CF; the CF gene is called the cystic fibrosis transmembrane regulator or CFTR. Prior to the identification of this gene, the diagnosis of CF could only be based on effects of the genetic mutation, rather than on the mutant gene itself. The traditional diagnostic indicator of CF in patients with suspicious symptoms was the presence of excess chloride in the sweat after stimulation with pilocarpine; the sweat test has been in use since 1959. However, it had become clear that not all patients with CF had abnormal ions in the sweat. Indeed, the symptoms of CF, including viscous mucus, which contributes to respiratory problems, and inadequate secretion of digestive enzymes by the pancreas, have proved to be markedly varied among CF patients. Now that gene cloning techniques have become available, it is possible to determine if at least some of these differences in the observed trait, called the phenotype, may be a direct result of different mutations in the CF gene, the genotype. A genetic study was performed on two sisters with mild cystic fibrosis and normal results on the sweat test. One subject was 50 years old; her sister died at 48 years. Genetic analysis revealed a mutation in the CF gene that is different from previously described mutations. Curiously, this mutation occurred in a spot that would change a particular amino acid in a fold of the resulting protein; this same protein fold has been found to be affected by different mutations in other CF patients. The present patients were found to be homozygous, which means that the CFTR genes on both chromosomes were the same. This occurrence considerably aided the genetic analysis, and reflected the way these cases came to light. The symptoms of cystic fibrosis in the sisters were so mild that cystic fibrosis would not likely have been considered as a possible diagnosis. However, the fact that the parents of these women were second cousins hinted that a genetic disorder might be present. (Consumer Summary produced by Reliance Medical Information, Inc.)

Analysis, Case studies, Perspiration

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Mutation analysis for heterozygote detection and the prenatal diagnosis of cystic fibrosis

Article Abstract:

Cystic fibrosis is a genetic disease that causes the secretions of the body to be thick and consequently difficult to eliminate, and as a result the lungs are usually severely affected. The condition occurs when an infant receives a defective gene from both parents; cystic fibrosis is classified as a Mendelian dominant genetic disorder. The exact gene that causes cystic fibrosis was recently located on the long-arm of chromosome 7. Even more recently the gene was duplicated in the laboratory (cloned); this has made it possible to develop test agents for detecting cystic fibrosis. The specific biochemical change (a three-base deletion) was also identified as representing the greatest number of defects to the gene (75.8 percent of all cases observed). This study uses advanced DNA probes to identify the number of individuals within a population of cystic fibrosis patients who show this form of the cystic fibrosis gene abnormality. The frequency of cystic fibrosis reported in white populations in North America is approximately one in 2,500 individuals, which implies a rate of occurrence for the cystic fibrosis gene in approximately one in 50 individuals. The methods developed in this study should allow better medical screening for carriers of the cystic fibrosis gene. Although a test for the presence of the dominant mutation could only identify 30.3 percent of Ashkenazic carriers (European Jewish community, group with a high level of cystic fibrosis), more extensive tests for the common cystic fibrosis chromosome type (haplotype) was able to identify 97 percent of these cases. The new test provides effective screening of parents for the presence of the cystic fibrosis gene (homozygous), and allows a better calculation of the risk for conceiving a cystic fibrosis child. The ease and relatively inexpensive nature of this test suggest that population screening for the cystic fibrosis trait can now be carried out for the dominant mutation, and that such screening would identify approximately 57 percent of non-Ashkenazic couples who are at risk for producing a child with cystic fibrosis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Research, Evaluation, Testing, Lung diseases, Genetic disorders

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The relation between genotype and phenotype in cystic fibrosis - analysis of the most common mutation (delta F-508)

Article Abstract:

Cystic fibrosis is an inherited disorder that causes the exocrine glands to produce abnormally thick secretions of mucus, an increased loss of electrolytes (essential elements in the blood) through sweating, changes in the components of saliva, and hyperactivity of the autonomic nervous system (which regulates vital functions such as heart rate). It is incurable, and treatment consists of measures to prevent respiratory infection, the most frequent cause of death. As a means of relating the symptoms and severity of the disease (phenotype) with the genetic markers linked to the cystic fibrosis gene (genotype), 293 patients were examined. Because of the similarity of the amount of pancreatic secretions within a family, it has been suggested that genetic factors may influence the severity of cystic fibrosis and the rate of disease progression. In fact, a difference has been detected between cystic fibrosis patients who have sufficient pancreatic secretions and those who do not, leading to the hypothesis that mutations associated with the cystic fibrosis gene might determine the severity of the disease. The principal mutation that causes the disease is delta F-508 on chromosome 7, but variability in the severity of the disease is related to three different expressions of the genotype. The 293 patients were divided into three genotypic groups. Results revealed that those with pancreatic insufficiency had more severe disease, and patients with two copies of the mutation were more severely affected than those with one or none. Pancreatic insufficiency may eventually develop in those with satisfactory pancreatic function. So far, 21 patients have died, not enough to draw any conclusions about differences in survival among the groups, but the differences are expected to be significant. Additional factors may also affect severity and survival, and genetic information should be used with caution when counseling families regarding prenatal diagnosis of cystic fibrosis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Services, Development and progression, Prognosis

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