Molecular Genetics of the α‐Thalassaemias


With the exception of rare non‐α‐globin gene‐related forms and of acquired forms in patients with myelodysplasia, α‐thalassaemias are very widespread worldwide. However, the most severe forms are found among populations of Asian and Mediterranean ancestry. Clinical manifestations of α‐thalassaemia are highly variable, ranging from asymptomatic subjects to a more or less severe haemolytic anaemia. The most severe form, haemoglobin (Hb) Bart's hydrops fetalis (absence of functional α‐globin genes), leads to death in utero or at birth. Antenatal screening is available for couples at risk for this severe form, that is, carriers of an α zero thalassaemia allele (absence of any functional α gene on one chromosome 16). Carrier detection is first based on red blood cell indices and confirmed by molecular analysis. Selective advantage against severe Plasmodium falciparum infection has been demonstrated for individuals with α‐thalassaemia. α‐Thalassaemia is also a genetic modifier in sickle cell syndromes.

Key Concepts:

  • α‐Thalassaemia has become a widespread genetic disorder worldwide due to the relative protection it confers against life‐threatening malarial anaemia.

  • There are four main forms of α‐thalassaemia depending on the number of remaining functional α‐globin gene(s) in the individual.

  • α‐Thalassaemia can be a severe condition: absence of three α genes results in chronic haemolytic anaemia of variable severity (Hb H disease), whereas the total absence of functional α‐globin gene leads to haemoglobin Bart's hydrops fetalis, a usually lethal condition.

  • In utero transfusion therapy and stem cell transplantation may improve the outcome of fetuses and infants with Hb Bart's hydrops fetalis in very rare cases.

  • α‐Thalassaemia carriers are usually clinically asymptomatic; however, detection of carriers of α zero thalassaemia is of utmost importance to prevent hydrops fetalis.

  • α‐Thalassaemia carriers may benefit from the diagnosis of their condition, as this may avoid unnecessary iron therapy due to the presence of microcytosis.

  • α‐Thalassaemia is a genetic modifier of sickle cell disease severity through the reduction in the haemolytic rate and a higher haemoglobin level.

Keywords: α‐thalassaemia; molecular genetics; prevention; malaria; sickle cell disease

Figure 1.

α‐Globin genes. The 30‐kb α‐globin gene cluster is located on chromosome 16 (16 p13‐2pter). The locus name is HBA. It comprises three functional genes, ζ, α2, α1; three expressed genes with unknown function, μ and θ1; and three pseudogenes, ψζ, ψα1 and ψρ. The ζ gene is expressed during the embryonic period, rapidly followed by the expression of adult α genes, α1 (gene symbol HBA1) and α2 (gene symbol HBA2). Four conserved DNase I hypersentitive sites (HS‐10, HS‐40, HS‐33 and HS40) are located upstream the α genes and are known to bind erythroid transcription factors.

Figure 2.

Molecular mechanisms leading to either inherited or acquired forms of α‐thalassaemia have been found to be similar with mutations or deletions lying in the same genes. Abbreviations: AHSP, alpha haemoglobin stabilising protein; AT, α‐thalassaemia and ATMDS, α‐thalassaemia myelodysplasic syndrome.

Figure 3.

Schematic relationship between α‐thalassaemia phenotype according to the number of active α‐globin genes. Normal individuals have four functional α‐globin genes; this number decreases while the phenotype worsens in α‐thalassaemia. Abbreviation: MCV, mean corpuscular volume.



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Further Reading

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Steinberg MH, Forget BG, Higgs DR and Nagel RL (eds) (2001) Disorders of Hemoglobin. Genetics, Pathophysiology, and Clinical Management, 1st edn, 1268pp. Cambridge, UK: Cambridge University Press.

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Aguilar‐Martinez, Patricia, and Gulbis, Béatrice(Sep 2010) Molecular Genetics of the α‐Thalassaemias. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022439]