The triplicated α‐globin gene locus in β‐thalassaemia heterozygotes: clinical, haematological, biosynthetic and molecular studies

Abstract

Excess alpha-globin chains play a major role in the pathophysiology of homozygous beta-thalassaemia. In beta-thalassaemia carriers a minor effect of alpha-globin chain excess is reflected in a minimal or mild anaemia without clinical symptoms. Factors that increase alpha-chain excess in heterozygotes are expected to accentuate the severity of the clinical and haematological phenotype. We report the clinical, haematological, biosynthetic and molecular data in three beta-thalassaemia heterozygotes with the rare interaction of homozygosity for alpha-globin gene triplication, and in 17 heterozygotes with a single additional alpha-globin gene. The three patients homozygous for the alpha-globin gene locus (anti 3.7 kb arrangement) had beta(0)-thalassaemia mutations and a diagnosis of thalassaemia intermedia, preserving haemoglobin levels around 7-8 g/dl. Of the 17 beta-thalassaemia heterozygotes (six children and 11 adults), 16 had severe beta-thalassaemia mutations interacting with an additional alpha-globin gene (13 with alpha alpha alpha anti-3.7 and four with alpha alpha alpha anti-4.2). Compared to simple beta-thalassaemia heterozygotes, they had lower haemoglobin levels and red cell indices, but higher alpha/beta biosynthesis, HbF levels and reticulocytes. Our results suggest that homozygous alpha-gene triplication interacts with a severe beta-thalassaemia mutation to cause an alpha-chain excess equivalent to that observed in homozygous beta-thalassaemia intermedia. In heterozygotes for severe beta-thalassaemia mutations with one additional alpha-globin gene, the alpha-chain excess causes a more pronounced degree of anaemia than is usually seen in simple beta-thalassaemia heterozygotes.

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

“…Although genotypically identical, six subjects showed a ß-thalassemia intermedia phenotype, while two were clinically indistinguishable from ß-thalassemia minor, implying the presence of genetic modifying factors that remained undefined. Similar data have been reported by others (1,(11)(12)(13)(14)(15).…”

“…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).…”

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.…”

Controlling -globin: a review of -globin expression and its impact on -thalassemia

“…79 Conversely, the inheritance of extra copies of α-globin can also convert the normally clinically silent phenotype of heterozygous β-thalassemia to a clinically significant anemia. 55,[80][81][82][83][84][85] In extreme cases where homozygous triplicated or quadruplicated α-globin are present, a relatively severe transfusion-dependent phenotype can emerge. 80 Hence, alterations in α-globin synthesis have considerable effect on β-thalassemic phenotypes; increased α-globin expression in heterozygous β-thalassemia leads to greater imbalance and converts a silent carrier state to a clinically significant anemia while reduced α-globin synthesis in homozygous β-thalassemia reduces the severity of anemia by restoring globin balance.…”