Thalassemia intermedia: moderate reduction of beta globin gene transcriptional activity by a novel mutation of the proximal CACCC promoter element

A patient with homozygous p thalassemia of Germadtalian descent was found to be doubly heterozygous for the common IVSI-110 G -+ A mutation of the p globin gene and for a novel C -+ T mutation of the proximal CACCC-box of the p globin gene promoter at position -87 relativeto the transcription start site (cap). Transcription analysis in an HeLa cell transfection assay indicated a 45% to 51% residual activity of the gene with the -87 C -+ T mutation relative to normal, further underlining the physiologic role of the affected promoter element. The finding of an only moderately reduced HE CLINICAL picture of homozygous p thalassemia is T characterized by a severe anemia that usually becomes transfusion dependent in early childhood.' Atypically mild courses of the illness can result from the coinheritance of 01 thalassemia' or from mutations causing the hereditary persistence of fetal hemoglobin ~ynthesis.~ A mild clinical phenotype can also result from mutations that allow a high residual activity of the p globin gene. Some such changes can be found in the less stringently conserved nucleotides of the splice consensus sequences:' Others are located at transcription factor binding sites within the promoter region, resulting in a reduced efficiency of transcription initiati~n.'~ " We describe here a patient of GermadItalian descent with thalassemia intermedia who is doubly heterozygous for the common IVSl position 110 G -+ A mutation and for a novel C + T mutation at position -87 relative to the transcription start site (cap). This -87 mutation affects the proximal CACCC element of the p globin gene promoter and reduces th; amount of RNA accumulated in an HeLa cell transfection assay to about half the normal level.