Molecular Basis of Thalassaemia

Summary.The thalassaemias are a heterogeneous group of conditions characterized by imbalanced globin chain production. In some forms there is a total absence of globin chain synthesis while in others globin chains are synthesized but at a reduced rate. There is increasing evidence that inefficiently synthesized structural haemoglobin variants can produce an identical clinical picture to thalassaemia.The molecular defect in the β thalassaemias is not yet worked out but in all forms studied, except the Ferrara type, there is an absolute reduction in the amount of β‐chain messenger RNA. In the Ferrara type there appears to be messenger RNA present but β‐chain synthesis does not occur unless induced by a soluble fraction from normal cells. The molecular pathology of the α thalassaemias is understood better. The severe type, α‐thalassaemia 1, results from a deletion of all or most of the α‐chain genes. There is good circumstantial evidence that the milder form, α‐thalassaemia 2, results from a loss of one of a pair of linked α‐chain genes. About half of the individuals with the haematological picture of α‐thalassaemia 2 are heterozygous for Hb Constant Spring, a chain‐termination mutant which is synthesized inefficiently. The chain‐termination mutants form a class of disorders which can produce the clinical picture of thalassaemia due to inefficient production of elongated α chains.