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DEFINITION

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

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

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ETIOLOGY AND PATHOGENESIS

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Genetic Control and Synthesis of Hemoglobin

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

  • All normal human Hb molecules 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% Hb A (α2β2), ~0.5% Hb F α2γ2, and ~2.5% Hb A22δ2).

  • In 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.

  • In embryonic life, Hb Gower 1 is composed of dimers of zeta (ζ) and epsilon (ε) globins (ζ2ε2). Hb Gower 2 (α2ε2) and Hb Portland (ζ2γ2) are only present before the 8th week of intrauterine life.

  • 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 at perinatal life.

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Globin Gene Clusters

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  • 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 coding 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 ∈ 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.

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Regulation of Globin Gene Clusters

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  • 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.

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Developmental Changes in Globin Gene Expression

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  • 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% of ...

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