An Initiation Codon Mutation as a Cause of β-Thalassemia in a Belgian Family

Abstract

Nine asymptomatic members of a family of Belgian origin, spanning three generations, present typical features of heterozygous β-thalassemia. Since no mutation was detected with a large panel of oligonucleotide probes, the thalassemia gene was investigated by direct sequencing of DNA segments amplified by the polymerase chain reaction. A T → C transition was detected in the translation initiation codon (ATG). The mutation, which abolishes an Nco I restriction site, was further confirmed by enzymatic digestion as well as by dot-blot hybridization of the amplified products with allele-specific oligonucleotide probes. It produced a β⁰-thalassemia phenotype characterized by marked microcytosis and hypochromia, as well as by an in vitro β/α chain synthesis ratio close to 0.5. Search for haplotype linkage showed the mutation to be associated with haplotype IX [− + − + +].