Molecular Genetics

p-Thalassemias are very heterogeneous at the molecular level. More than 200 different disease-causing mutations have been identified so far (Table 1).[2,3,8] The large majority of mutations are simple single nucleotide substitutions or deletion/insertions of one nucleotide or oligonucleotides leading to frameshift. The p°-thalasse-mias are rarely a result of a mechanism of gross gene deletion involving the p-globin gene or the LCR. The p°-thalassemias result from nonsense mutation, frame-shift, or splicing mutations involving the invariant dinucleotides. The p+-thalassemia mutations are produced by mutations of the promoter area (CACCC or TATA box), the polyadenylation signal, conserved sequences in the 5' or 3' untranslated regions, or by splicing abnormalities resulting from mutation of the consensus sequences around the GT/AG invariant dinucleotides. An interesting category of p+-thalassemias is that associated with a consistent residual output of p-globin chains or constantly associated with a high g-chain production rate, thereby determining a mild phenotype (Table 2). The most common mild mutations are p + IVS1 nt 6 (T! C), which is found in the Mediterranean area, and p codon 26 (G! A), which gives rise to HbE that prevails in Southeast Asia. Finally, silent alleles result from mutations of the distal CACCC box and from conserved sequences in the 5' untranslated region, in the polyade-nylation signal, or within consensus sequences affecting the splicing process (Table 3). The complex p-thalasse-mias (8p or g8p-thalassemias) result from deletion of a variable extent of the p-globin gene cluster.

Several nucleotide substitutions (polymorphisms) in the p-globin cluster have been found not randomly associated, but grouped in subsets (in linkage), called haplotypes. In each population, different specific p-Thal-assemia mutations are associated with different haplo-types. However, the same mutation can be contained in different haplotypes.

For example, in Mediterranean countries, most of the patients with haplotype I have the mutation IVS1-110 G! A. More rarely, the frameshift mutation at codon 6 (-A) and the p° 39 C ! T mutation are also associated with haplotype I.

Table 1 Most common ß-thalassemia mutations in populations at risk


Percentage of patients (%)


- 87 C ! G IVS1-1 G ! A IVS1-6 T ! C IVS1-110 G ! A cd 39 C ! T IVS2-745 C ! G

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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