Genotype Phenotype Correlations

Any inherited or acquired condition that reduces the a/non-a-globin chain imbalance results in a lesser degree of globin a-chain precipitation and leads to a mild ß-thalassemia phenotype. One of the most common and consistent mechanisms is homozygosity or compound heterozygosity for mild and silent ß+-thalassemia mutations. In contrast, compound heterozygosity for mild/ silent ß+ and severe mutations produces a variable phenotype, ranging from thalassemia intermedia to thalassemia major. Compound heterozygosity for ß-thal-assemia and hemoglobin E (HbE) results in a wide range of clinical phenotypes, often severe, although sometimes mild and even clinically asymptomatic. HbE is a thal-assemic structural variant, characterized by the presence of an abnormal structure as well as a biosynthetic defect. The nucleotide substitution at codon 26, producing the HbE variant (a2p226 Glu! Lys), activates a potential cryptic RNA splice site resulting in alternative splicing at this position. The homozygous state for HbE results in a mild hemolytic microcytic anemia. The clinical picture resulting from homozygosity for p°- or severe p+-thalassemia may be ameliorated by coinheritance of mutations in the gene encoding the a-globin chain (deletion of two a-globin genes or point mutations in the major a2 gene in ^"-thalassemia and even a single a-globin gene deletion in p+-thalassemia) associated with a-thalassemia, which reduces the output of the genes encoding the globin a-chains and therefore decreases the a/non-a-globin chain imbalance. However, the presence of coinherited a-thal-assemia does not always produce a consistent effect, thus precluding its use to predict phenotype. The coinheritance of some genetic determinants capable of sustaining a continuous production of globin g-chains (HbF) in adult life may also reduce the extent of a/non-a-globin chain imbalance.[2,3,9] This effect may be related to the p-thal-assemia mutation per se which increases the globin

Table 2 Mild ß-globin gene mutations causing ß-thalassemia

Mutation type

Mild ß+

Transcriptional mutants in the proximal CACC box

- 86 C ! G

- 29 A ! G

+33 C!G

Alternative splicing

cd19 A ! C (Hb Malay) cd24 T ! A

Consensus splicing

IVS1-6 T!C

Poly A site

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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