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  • Each of the thalassemic disorders results from an inherited defect in the synthesis of one or another of globin chains.

  • Resultant imbalance of globin chain production can cause ineffective erythropoiesis, defective hemoglobin production, red cell hemoglobin precipitates, hemolysis, anemia of variable degree, and propensity to iron overload.


Genetic Control and Synthesis of Hemoglobin

  • Each hemoglobin (Hb) molecule consists of two pairs of identical globin chains.

  • All normal adult human Hb molecules have one pair of α-chains. The α-chains can combine with β-chains (α2β2) to form HbA, δ-chains (α2δ2) to form HbA2, and γ-chains (α2γ2) to form HbF.

  • In adults, Hb is ~97% HbA, <2% HbF, and <3.5% HbA2.

  • In embryonic life, Hb Gower 1 (ζ2ε2), Hb Gower 2 (α2ε2) and Hb Portland (ζ2γ2) are the first Hb molecules made.

  • In fetal life, HbF (α2γ2) predominates. Position 136 of some γ-chains is occupied by glycine and in others by alanine. These are designated Gγ and Aγ, respectively. At birth, HbF is a mixture of α2Gγ2 and α2Aγ2 in a ratio of 3:1.

  • During fetal life, globin gene expression switches occur from ζ- to α- and from ∈- to γ-chain production, followed by β- and δ-chain production during the perinatal period.

Globin Gene Clusters

  • α-Gene cluster on chromosome 16 consists of one functional ζ gene and two α genes (α2 and α1).

  • Exons of the two α-globin genes have identical coding sequences; however, they differ in their second intron.

  • Production of α2 mRNA exceeds that of α1 by a factor of 1.5- to 3-fold.

  • β-Gene cluster on chromosome 11 consists of one functional ∈ gene, a Gγ gene, an Aγ gene, a pseudo β gene, a δ gene, and a β gene.

  • Flanking regions contain conserved sequences essential for gene expression.

Regulation of Globin Gene Clusters

  • Primary transcript is a large mRNA precursor, with both intron and exon sequences, which is extensively processed in the nucleus to yield the final mRNA.

  • Expression of the globin genes is regulated by complex control mechanisms involving interaction of the respective upstream control sequences in each globin gene cluster with the immediate upstream local gene promoter.

Developmental Changes in Globin Gene Expression

  • β-Globin is produced at low levels beginning at 8 to 10 weeks of fetal life but increases considerably starting at about 30 weeks’ gestation.

  • γ-Globin produced at high levels early starts to decline at ~36 weeks.

  • At birth, β-globin and γ-globin production are approximately equal.

  • By ...

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