Skip to Main Content

++

DEFINITION

++

  • A group of disorders, each resulting from an inherited defect in the rate of synthesis of one or more globin chains.

  • Resultant imbalance of globin chain production may cause ineffective erythropoiesis, defective hemoglobin production, red cell hemoglobin precipitates, hemolysis, and anemia of variable degree.

++

ETIOLOGY AND PATHOGENESIS

++

Genetic Control and Synthesis of Hemoglobin

++

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

  • All normal human hemoglobins found in an adult have one pair of α-chains. The α-chains can combine with β-chains (α2β2), δ-chains (α2δ2) and γ-chains (α2γ2).

  • Adult Hb is ~97 percent Hb A (α2β2), ~0.5 percent Hb F, and ~2.5 percent Hb A22δ2).

  • Fetal life: Hb F (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 Hb F is a mixture of α2Gγ2 and α2Aγ2 in a ratio of 3:1.

  • Embryonic Hb: Hb Gower 1 (ζ2ϵ2), Hb Gower 2 (α2ϵ2), and Hb Portland (ζ2γ2), before 8th week of intrauterine life.

  • During fetal life, globin gene expression switches occur from ζ- to α- and from ϵ- to γ-chain production, followed by β- and δ-chain production after birth.

++

Globin Gene Clusters

++

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

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

  • Production of α2 mRNA exceeds that of α1, by factor of 1.5 to 3.

  • β-Gene cluster (chromosome 11) consists of one functional ϵ 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.

++

Developmental Changes in Globin Gene Expression

++

  • β-Globin produced at low levels beginning at 8 to 10 weeks of fetal life, increases considerably at about 36 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 age 1 year, γ-globin production is less than 1 percent of total non–α-globin production.

  • Mechanism of switches is not clear, but probably involves a "time clock" in the hematopoietic stem cell.

  • Fetal ...

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.