Different hematological phenotypes caused by the interaction of triplicated α-globin genes and heterozygous β-thalassemia

Abstract

The pathophysiology and clinical severity of ␤-thalassemia are related to the degree of ␣/non-␣-chain imbalance. A triplicated ␣-globin gene locus can exacerbate effects of excess ␣-chains caused by a defective ␤-globin gene, although this is not observed in all cases. Extensive studies on this condition are lacking. We report a group of 17 patients who are heterozygous for both the ␣␣␣ anti-3.7 allele and a mutation in the ␤-globin gene cluster. Their clinical phenotypes varied: six had mild anemia with microcytosis and hypochromia, while 11 had more severe anemia with splenomegaly requiring splenectomy (three cases) and blood transfusions (four cases). Different phenotypes were also evident in the presence of the same ␤-thalassemia mutation: in one family, two individuals had the same ␣-and ␤-globin genotypes but presented with different hematologic phenotypes. In addition, the complex interaction involving a triplicated ␣-globin gene, ␤ -and ␦ +27-thalassemia mutations is studied in a family with two siblings presenting with hemolytic anemia, normal Hb A 2 and increased Hb F. Analysis of this series of patients suggests that additional genetic determinants play a role in modulating phenotypic expression in individuals with identical ␣-and ␤-globin genotypes. Interaction with a triplicated ␣-gene can play a role in the clinical presentation of patients with defective ␤-globin gene expression and should be considered in the diagnosis of atypical cases.

Thalassemia intermedia as a result of heterozygosis for ß0-thalassemia and <FONT FACE=Symbol>aaa</FONT>anti-3.7/<FONT FACE=Symbol>aa</FONT> genotype in a Brazilian patient

“…A triplicated α-globin gene locus can exacerbate the effects of α-chain excess caused by a defective ß-globin gene, although this is not observed in all cases (1,2). We report here a patient in whom the interaction of heterozygosis for both the ß 0 -IVS-II-1 (G→A) mutation and the ααα anti-3.7 allele in the globin genes was the probable cause of the clinical picture of thalassemia intermedia.…”

“…The pathophysiology and clinical severity of ß-thalassemia are associated with the degree of α/non-α-chain imbalance (1,2). A triplicated α-globin gene locus can exacerbate the effects of α-chain excess caused by a defective ß-globin gene, although this is not observed in all cases (1,2).…”

Thalassemic erythrocytes release microparticles loaded with hemichromes by redox activation of p72Syk kinase

“…TI may result from defective production of b-globin chains due to b-globin gene defects, or from the increased production of α-globin chains, resulting from a triplicate or quadruplicate α-genotype associated with b-thalassemia heterozygosity, the latter situation leading to a milder form of TI. [2][3][4][5] The excess free α-chains have been demonstrated to precipitate within the erythroid precursors as hemichromes (HMC), forming large inclusion bodies. 6 In turn HMC alter the membrane clustering band 3 and enhance the deposition of opsonin autologous immunogobulins and C3 fragments.…”

Association of globin gene quadruplication and heterozygous thalassemia in patients with thalassemia intermedia

“…Among them 3 groups have been defined: (i) the dominantly inherited β thalassemia mutations (also reported as inclusion body thalassemias); 4,5 (ii) the co-existence of somatic deletions of a region of chromosome 11 p15; 6,7 (iii) co-inheritance of triplicated α globin genes with excessive α globin production. [8][9][10] Recently cases of simple β thalassemia heterozygosity presenting with an intermediate to severe phenotype due to duplications of the complete α globin gene cluster, including the upstream regulatory element HS-40, have been reported; 11 (iv) interaction between severe and silent β thalassemia mutations.…”