BETA-THALASSEMIA UNLINKED TO THE BETA-GLOBIN GENE INTERACTS WITH SICKLE-CELL TRAIT IN A PORTUGUESE FAMILY

An autosomally transmitted hypochromic microcytic mild anaemia with elevated haemoglobin (Hb) A(2) and globin chain imbalance has been observed in a three-generation family of Portuguese origin. Extensive DNA analysis of the beta-globin gene cluster, including the complete sequencing of the beta-globin gene and flanking regions, failed to reveal any genetic alteration, The co-segregation of sickle-cell trait in this family enabled us to postulate a defective erythroid trans-acting factor was playing a role in the downregulation of both beta(A)- and beta(S)-globin genes. Among the transcription factors that could possibly have caused the reported phenotype, NF-E2 is unlikely to be implicated, whereas Nrf1 and Nrf2 cannot be ruled out. Thus, this family carries a novel beta-thalassaemia autosomal determinant unlinked to the beta-globin gene. This observation reinforces the notion of the haemoglobinopathies as single gene disorders under polygenic regulation.