Molecular defects in beta-thalassemia

Our studies have shown that globin-gene structure, as revealed by Southern blot analysis, is normal in most patients who are homozygous for beta-thalassemia. In many, but not all patients, evidence for mutations which alter the metabolism of beta-globin RNA molecules was obtained by several methods of analysis. The most specific and sensitive of these involves the use of single-stranded, highly radioactive probes generated using the M13 cloning system. Such probes allow detection of aberrantly processed RNA molecules by S1 nuclease analysis, thereby providing clues as to the position and nature of mutations within individual thalassemic globin genes. Of greatest potential interest are those genes which provide no evidence, in bone marrow RNA, of aberrantly processed intermediates. Analysis of these genes by molecular cloning and DNA sequencing may lead to identification of sequences which are important for initiation or termination of RNA transcription. Mutations which cause beta-thalassemia continue to provide a rich source of information about the nature of DNA sequences which are essential for efficient gene expression. By study of thalassemic patients, new insights are obtained into normal mRNA metabolism.