Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease

Article Abstract:

Recent studies have identified the gene responsible for cystic fibrosis, the most common lethal genetic disorder among whites. Epithelial cells from cystic fibrosis patients have been shown to have abnormal chloride conductance, and the sequence of the gene is consistent with the structure of a 1,480 amino acid protein with regulatory function. The protein has been termed the cystic fibrosis transmembrane regulator (CFTR). In the most common cystic fibrosis gene, a genetic mutation results in the deletion of a phenylalanine residue from a part of the molecule thought to be critical for the binding of ATP (adenosine triphosphate, a compound related the production of energy). As is usually the case for genetic disorders, it is possible to identify patients with less common mutations that affect the same gene. Such mutations generally vary in their severity; sometimes the change of an amino acid or a small deletion may have only a small affect on the overall function of the molecule, while a slightly different mutation may affect the resulting molecule a great deal. A mutation that results in the replacement of one amino acid with another is called a missense mutation. Occasionally, a mutation replaces an amino acid with the code signalling the termination of the protein at that point. Such a mutation is called a nonsense mutation. A nonsense mutation is usually severe, since the protein is not only likely to be too short function at all, but also because the short protein is likely to be unstable and quickly degraded. Two unusual cases are reported of unrelated black patients with cystic fibrosis with only mild pulmonary disease who carried genes with nonsense mutations. However, the pancreatic disease of these patients was severe. It has not yet been determined whether a truncated form of the CFTR protein is present in the cells of these patients. One possibility is that differences in the processing of the RNA (ribonucleic acid, genetic material) prior to protein synthesis may be responsible for the observed differences in the severity between the pancreatic and pulmonary disease. These cases raise the possibility that the absence of a protein may sometimes be more benign than the presence of an altered form. (Consumer Summary produced by Reliance Medical Information, Inc.)

Case studies, Physiological aspects, Suppression, Genetic, Lung diseases, Mutation (Biology), Mutation, Cystic fibrosis, Pancreatic diseases

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Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms

Article Abstract:

Trisomy 21 (Down syndrome), the most common chromosomal abnormality in children as well as the most common genetic cause of mental retardation, is a condition in which an extra chromosome 21 is present. Because of inherited patterns in parts of the abnormal chromosome (heteromorphisms), it is possible to tell whether the chromosome is of maternal or paternal origin; however, such analyses can only be performed for trisomies associated with certain heteromorphisms. Studies using these methods have found that the defective chromosome was of maternal origin in approximately 80 percent of the cases, and of paternal origin in the rest. However, these statistics did not include the large proportion (40 percent) of cases where the type of heteromorphism precluded identification of parental origin of the defect; furthermore, a subjective scoring bias is possible in analyzing heteromorphic data. Modern analytic methods that detect DNA polymorphisms (variants of specific DNA segments) were used to analyze the chromosomes from 200 children with trisomy 21, their parents, and, when possible, their siblings. Of interest was the site of nondisjunction, the point at which the chromosomes in the developing germ cell (destined to become either egg or sperm) fail to be divided equally among daughter cells, resulting in trisomy. This was determined for 193 of the families: in 184 (95.3 percent) the origin was maternal, and in nine (4.7 percent) it was paternal. These results are in contrast to the earlier reports that showed a much higher proportion (slightly less than 20 percent) of trisomies 21 to be of paternal origin. Possible explanations for this difference are discussed. The favored explanation is the superiority of the method of DNA polymorphism analysis used in the current report. One implication of the findings is that research concerning the cause of trisomy 21 should focus on the egg cell, rather than the sperm cell. (Consumer Summary produced by Reliance Medical Information, Inc.)

Analysis, Down syndrome, Chromosome abnormalities

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Diagnosis of genetic disorders at the DNA level

Article Abstract:

DNA, the genetic material of the cell, is inherited from both parents. Studies of gene structure and function can lead to the diagnosis of inherited diseases; defects of a single gene are responsible for most of the known disorders and have contributed to prenatal diagnosis and genetic counseling. These genes can be cloned in the laboratory. The arrangement of amino acids which make proteins can be mapped and mutations can be studied. Multiple abnormalities can be found when portions of the gene are deleted, inserted or rearranged. Mutations in one point or region result in single abnormalities. Several cases of genetically caused disorders are cited. The identification of unmapped hereditary disorders and how they can be detected and diagnosed in affected patients, persons at risk, and carriers is the future goal of research.

Research, Diagnosis, Birth defects, Forensic DNA testing

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