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

A patient with homozygous beta thalassemia of German/Italian descent was found to be doubly heterozygous for the common IVS1–110 G----A mutation of the beta globin gene and for a novel C----T mutation of the proximal CACCC-box of the beta globin gene promoter at position -87 relative to 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 transcriptional activity of the beta globin gene with the -87 C----T mutation corresponds well with the clinical phenotype of the reported patient, which is characterized by a late onset of symptoms, moderate anemia, and normal physical development. The ethnically German mother of the propositus has minimal anemia with only slightly changed red blood cell indices, which can also be explained by the relatively high residual activity of the gene with the -87 C----T mutation.