Thalassemia: genotypes and phenotypes

Abstract

The large degree of phenotypic heterogeneity of thalassemia can now be related to the underlying genomic defects. This information has accumulated rapidly over the last years through the recent advances in molecular technology. The list of main types of thalassemia (α or β) that can be differentiated includes several gene deletions (complete or partial) and point mutations (or very short deletions). These occur within the genes or across the flanking DNA sequences and apparently interfere with the expression of these genes. From a quantitative point of view, the severity of the condition is directly related to the amount of functional globin chain mRNA which is made available to the ribosomes; this may vary from zero (gene deletions, frameshift, non-sense mutations or mutations at the splice-junction nucleotides) to very little (mostly hnRNA processing mutants) or to slightly subnormal (transcriptional mutants, mutations resulting in cryptic site activation or in defective cleavage of the poly-A tail). A few hyper-unstable globin chains also produce a thalassemic phenotype. This pattern is straightforward in the α-thalassemias. In the β-thalassemias, the decreased β-chain synthesis reflects the available mRNA, but the phenotypic expression depends also on the ability of the patient to reactivate γ-chain synthesis and complement the red cell content with hemoglobin F.