Unusually Severe Heterozygous β-Thalassemia: Evidence for an Interacting Gene Affecting Globin Translation
| Autor: | W G Wood, G W Hall, P. J. Ho, J W Wimperis, S Watt, N C West, S. L. Thein |
|---|---|
| Rok vydání: | 1998 |
| Předmět: | |
| Zdroj: | Blood. 92:3428-3435 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | A common β-thalassemia mutation in Asian populations is the C → T substitution at position 654 of intron 2, which leads to the activation of two cryptic splicing sites and the incorporation of 73 extra nucleotides into the mutant mRNA. Like most β-thalassemia mutations, it normally exhibits recessive inheritance. We investigated the unusually severe phenotype in two heterozygotes for this mutation, father and son, who had thalassemia intermedia and an apparent dominant mode of inheritance. An increased level of aberrantly spliced transcript in the reticulocytes of the probands compared with asymptomatic β654heterozygotes led us to investigate the production and processing of β654 RNA. We showed that large amounts of the aberrant β654 transcript were detectable in erythroblasts from one of the asymptomatic cases. The translation product of this mRNA was not detectable in vivo, and we were unable to demonstrate the translation of the mutant mRNA in a cell-free translation system. Although the reticulocyte :β mRNA ratios in the two probands were within the range observed in the asymptomatic heterozygotes, globin chain biosynthesis studies showed that the probands had considerably greater :β chain imbalance. These results imply that the more severe phenotype may be due to a second defect, possibly unlinked to the β-globin cluster, that acts at the translational or posttranslational level.© 1998 by The American Society of Hematology. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|