Showing papers by "Stylianos E. Antonarakis published in 1983"

Prenatal diagnosis using DNA polymorphisms. Report on 95 pregnancies at risk for sickle-cell disease or beta-thalassemia.

Abstract: DNA polymorphisms are normal inherited variations in DNA that can often be used to document the inheritance of genes that produce disease. In this report we summarize our experience with prenatal diagnosis in 95 pregnancies in which the fetus was at risk for a hemoglobinopathy; the diagnosis was performed with use of DNA polymorphisms located so near the beta-globin gene that they are inherited along with that gene. Of the 95 pregnancies, 57 involved fetuses at risk for sickle-cell anemia, 32 fetuses at risk for beta-thalassemia, and 6 fetuses at risk for other beta-chain hemoglobinopathies. Diagnosis was achieved solely by analysis of DNA polymorphisms in cells recovered by amniocentesis in 82 cases (86 per cent) and was completed by fetoscopy and fetal-blood study in an additional 6 cases (6 per cent). Prenatal diagnosis was proved correct in all 78 cases that have been available for confirmation to date. Our experience demonstrates that DNA polymorphisms can be useful for the prenatal diagnosis of genetic diseases in which the basic defect cannot be directly detected.

Molecular Heterogeneity of Inherited Antithrombin III Deficiency

Abstract: Inherited antithrombin III deficiency is associated with an increased risk of thromboembolism. Using recombinant-DNA techniques, we isolated a molecular probe for the antithrombin III structural gene and identified a common DNA polymorphism within the gene. We found that there is genetic heterogeneity in this disorder. In one family, the antithrombin III gene was deleted in affected members, whereas in another no deletion occurred. Use of the DNA polymorphism should allow identification and further characterization of abnormal antithrombin III genes. (N Engl J Med 1983; 308:1549–52.) Inherited deficiency of antithrombin III, an inhibitor of serine proteases in plasma, was first . . .

Beta-globin locus is linked to the parathyroid hormone (PTH) locus and lies between the insulin and PTH loci in man

Abstract: Using a parathyroid hormone (PTH) cDNA probe we found a common Pst I polymorphic restriction site 3' to the PTH gene in all ethnic groups examined. Because the PTH, insulin, and beta-globin loci have been localized to the short arm of chromosome 11 (11p) we used DNA polymorphisms adjacent to each of these three loci to determine whether they are genetically linked and to determine their order. We found that the PTH and beta-globin loci are closely linked (estimated recombination fraction, 0.07; 95% confidence limits, 0.05-0.10; lod score, 4.63; odds favoring linkage, 42,000:1). Furthermore, our findings strongly indicate that the beta-globin gene cluster lies between the PTH and insulin loci. Therefore, the gene order on 11p is centromere-PTH-beta-globin-insulin.

beta-Thalassemia due to a deletion of the nucleotide which is substituted in the beta S-globin gene

Abstract: Sickle-cell anemia results from an A leads to T transversion in the second nucleotide of codon 6 of the beta-globin gene. We now report an uncommon beta-thalassemia gene that contains a deletion of this nucleotide. Thus, one mutation (GAG leads to GTG) produces sickle-cell anemia, while the other (GAG leads to GG) eliminates beta-globin production. These data establish that different alterations affecting one specific nucleotide can produce either an abnormal hemoglobin or beta-thalassemia. Moreover, the nucleotide sequence comprising codons 6-8 of the beta-globin gene appears to be particularly susceptible to mutations affecting nucleotide number.

Use of haplotype analysis in the beta-globin gene cluster to discover beta-thalassemia mutations.

Abstract: DNA polymorphisms have been of great value in defining a small number of common sequences in the beta-globin gene cluster and a region within which recombination may be restricted. Moreover, they have led to a screening procedure that not only has been of great value for the molecular characterization of beta-thalassemia mutations but also has implications for the characterization of other single-gene disorders.