alpha-Thalassemia caused by an unstable alpha-globin mutant.

A Nucleolin-Binding 3′ Untranslated Region Element Stabilizes β-Globin mRNA In Vivo

“…Mutational analyses carried out with cultured cells (80,81) and with animal models (52,66) clearly demonstrate the importance of the 3Ј untranslated region (3ЈUTR) to the constitutively high stability of ␣-globin mRNA (45). Other studies have mapped this characteristic to a phylogenically conserved, 16-nucleotide (nt) C/U-rich element in this region (39,75,76).…”

“…As might be anticipated, mutations that impair the normal stabilities of globin mRNAs can severely impact the levels of their encoded proteins. For example, an mRNA-destabilizing mutation reduces the expression of ␣ Constant Spring to less than 2% of normal levels (45,51,80), resulting in a clinically important form of thalassemia characterized by a substantial imbalance in ␣-and ␤-globin chain accumulation (10, 64).The cis-acting determinants and trans-acting factors that participate in regulating ␣-globin mRNA stability have recently been identified, and the relevant molecular mechanisms have been described in detail. Mutational analyses carried out with cultured cells (80, 81) and with animal models (52, 66) clearly demonstrate the importance of the 3Ј untranslated region (3ЈUTR) to the constitutively high stability of ␣-globin mRNA (45).…”

“…As might be anticipated, mutations that impair the normal stabilities of globin mRNAs can severely impact the levels of their encoded proteins. For example, an mRNA-destabilizing mutation reduces the expression of ␣ Constant Spring to less than 2% of normal levels (45,51,80), resulting in a clinically important form of thalassemia characterized by a substantial imbalance in ␣-and ␤-globin chain accumulation (10, 64).…”

Molecular basis for nondeletion alpha-thalassemia in American blacks. Alpha 2(116GAG----UAG).

“…To date, a total of five nondeletion a-thalassemia defects have been defined in Mediterranean (8,9), Saudi Arabian (10), Algerian (11), and Chinese (12)(13)(14) populations. In addition, the a-globin structural variant Hb Constant Spring (15) is a frequent cause of a-thalassemia in Asia, and three related antitermination mutations have been identified in Greek (Hb Icara; 16), East Indian (Koya Dora; 17), and Black (Hb Seal Rock; 18) individuals.…”

Control of human -globin mRNA stability and its impact on beta-thalassemia phenotype

“…Since heterozygotes for the mutation express the C-terminally extended globin protein at only 3% of the wild-type α-globin level and the α CS mRNA is transcribed at normal rates while the α CS protein is stable, 14 the loss of expression reflects a defect in the cytoplasmic α CS mRNA accumulation. [15][16][17] Studies in the human α-globin mRNA showed that the loss of stability is related to the ribosome readthrough beyond the native stop codon that interferes with a determinant within the 3'UTR. This determinant comprises three non-contiguous C-rich sites (pyrimidine-rich element, PRE) and provides the binding site for the α-globin poly(C)-binding protein (αCP).…”