Alpha-, beta-, and gamma-mRNA levels in beta-thalassemia; transcriptional and translational differences in heterozygotes, homozygotes, and compound heterozygotes.

We have determined the relative levels of alpha-, beta-, and gamma- (G gamma- and A gamma-) mRNAs in the reticulocytes of patients with mild beta-thalassemia intermedia due to combinations of promoter mutations and a classical type of beta-thalassemia, as well as in their relatives. The expected differences in the alpha/beta-mRNA ratio confirmed the mild suppression of beta-mRNA synthesis, particularly in heterozygotes for the -101 (C-->T) promoter mutation and the large increase in the relative gamma-mRNA level in compound heterozygotes. A significant discrepancy between Hb F and gamma-mRNA levels, observed in previously published studies, was confirmed indicating a less efficient gamma-mRNA translation. When the two different gamma-mRNA (G gamma- and A gamma-) levels were determined it was observed that in beta-thalassemia heterozygotes the extra gamma-mRNA was primarily of the G gamma type suggesting a more efficient translation of the A gamma-mRNA. This difference disappeared in homozygotes and compound heterozygotes: both mRNAs (G gamma- and A gamma-) translate with an equal efficiency.

The gamma-globin gene rearrangements in newborns from the Republic of Macedonia.

Cord blood samples of 3,232 newborns of different ethnic origins living in the Republic of Macedonia were analyzed by starch gel electrophoresis, polyacrylamide gel electrophoresis and reversed phase high performance liquid chromatography. Hb Bart's was detected in 26 newborns (0.8%) indicating the low incidence of alpha-thalassemia in the Republic of Macedonia. Five different hemoglobin variants (Hb O-Arab, Hb Hamilton, Hb Strumica, Hb F-Macedonia-I, and Hb F-Macedonia-II) were also detected. The levels of the G gamma chains fell into three categories; normal range with G gamma between 50 and 80% (3,143 newborns or 97.2%), low range with G gamma levels of < 50% (35 newborns or 1.1%), and high range with G gamma levels of > 80% (54 newborns or 1.7%). The overall incidence of the A gamma T variant was 20.8%, similar to that found in several Mediterranean populations. DNA analyses showed that the molecular basis of high and low G gamma determinants are heterogeneous in our population. gamma-Gene triplications and the G gamma G gamma arrangements were detected in newborns with high G gamma levels, while gamma gene deletions and A gamma A gamma arrangements were found in newborns with low G gamma levels. All but one of the 135 samples with G gamma between 50 and 80% had the normal G gamma A gamma arrangement on both chromosomes; the only exception was an Albanian newborn (G gamma = 63%) with an-A gamma/G gamma G gamma A gamma arrangement.