UNUSUALLY SEVERE HETEROZYGOUS BETA-THALASSEMIA - EVIDENCE FOR AN INTERACTING GENE AFFECTING GLOBIN TRANSLATION

A common beta-thalassemia mutation in Asian populations is the C --> T substitution at position 654 of intron 2, which leads to the activati on of two cryptic splicing sites and the incorporation of 73 extra nuc leotides into the mutant mRNA, Like most beta-thalassemia mutations, i t normally exhibits recessive inheritance. We investigated the unusual ly 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 th e reticulocytes of the probands compared with asymptomatic beta(654) h eterozygotes led us to investigate the production and processing of be ta(654) RNA, We showed that large amounts of the aberrant beta(654) tr anscript were detectable in erythroblasts from one of the asymptomatic cases, The translation product of this mRNA was not detectable in viv o, and we were unable to demonstrate the translation of the mutant mRN A in a cell-free translation system. Although the reticulocyte alpha:b eta mRNA ratios in the two probands were within the range observed in the asymptomatic heterozygotes, globin chain biosynthesis studies show ed that the probands had considerably greater alpha:beta chain imbalan ce. These results imply that the more severe phenotype may be due to a second defect, possibly unlinked to the beta-globin cluster, that act s at the translational or posttranslational level. (C) 1998 by The Ame rican Society of Hematology.