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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 ...

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