DOMINANTLY TRANSMITTED BETA-THALASSEMIA ARISING FROM THE PRODUCTION OF SEVERAL ABERRANT MESSENGER-RNA SPECIES AND ONE ABNORMAL PEPTIDE

We describe a dominantly inherited beta-thalassemia intermedia phenoty pe observed in a five-generation Portuguese family. Carriers are chara cterized by moderate anemia, hypochromia, microcytosis, elevated hemog lobin (Hb)A(2) and HbF levels, splenomegaly, hepatomegaly, and inclusi on bodies in pheripheral red blood cells after splenectomy. The molecu lar basis of this condition is a small deletion within the 5' consensu s splicing sequence of the second intron of the beta-globin gene, IVS- II-4,5 (-AG). Reticulocyte RNA studies performed by reverse transcript ion-polymerase chain reaction (RT-PCR) and primer extension analysis s howed three abnormally processed transcripts, which, upon sequencing, were shown to correspond to (1) skipping of exon 2, and (2) activation of two cryptic splice sites (between codons 59/60, and at IVS-II-47). In vitro translation studies of these patients' reticulocyte RNA have shown that at least one of these aberrant mRNA species is translated into an abnormally elongated peptide whose cytotoxic properties could, in part, be causing the atypical dominant mode of inheritance observe d in this family. We suggest that this elongated beta chain is unable to combine with an alpha-globin chain to form a functional Hb molecule . Its degradation would, then, exhaust the proteolytic defense mechani sm of the erythroid precursors, leading to inefficient proteolysis of the free alpha chains in excess. (C) 1998 by The American Society of H ematology.