A C → T Substitution at nt – 101 in a Conserved DNA Sequence of the Promotor Region of the β-GIobin Gene Is Associated With “Silent” β-Thalassemia

Sequence analyses and dot-blot analyses with synthetic oligonucleotide probes have identified eight individuals in three Turkish families and one Bulgarian family with one chromosome having a C → T mutation at nucleotide position -101 relative to the Cap site of the β-globin gene. This nucleotide is part of one of the conserved blocks of nucleotides within the promoter region; in vitro expression analyses with the chloramphenicol acetyltransferase system showed that this substitution will decrease the effectiveness of transcription. Five subjects had a thalassemia intermedia due to the additional presence of a known classical high hemoglobin (Hb) A2β-thalassemia mutation on the second chromosome; their hematologic condition was relatively mild. The three persons with a heterozygosity for the -101 C -→ T mutation had normal hematologic data without microcytosis but with high-normal levels of Hb A2and a mild imbalance in chain synthesis. The newly discovered mutation is considered one of the silent types of β-thalassemia. It is relatively rare because it was absent among several hundred normal and β-thalassemia chromosomes.