Regulation of human alpha-globin gene expression and alpha-thalassemia

Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.
Genetics and molecular research: GMR (Impact Factor: 0.78). 02/2008; 7(4):1045-53. DOI: 10.4238/vol7-4gmr472
Source: PubMed


Hemoglobin and globin genes are important models for studying protein and gene structure, function and regulation. We reviewed the main aspects of regulation of human alpha-globin synthesis, encoded by two adjacent genes (alpha(2) and alpha(1)) clustered on chromosome 16. Their expression is controlled mainly by a regulatory element located 40 kb upstream on the same chromosome, the alpha-major regulatory element, whose activity is restricted to a core fragment of 350 bp, within which several regulatory protein binding sites have been found. Natural deletions involving alpha-major regulatory element constitute a particular category of alpha-thalassemia determinants in which the alpha-globin genes are physically intact but functionally inactive.

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    • "Zhou et al.[15] described another qPCR approach based on nested tailed-primer PCR combined with real-time qPCR. Neither of the mentioned methods investigate the erythroid-specific DNase I hypersensitive site HS-40, in which there are known mutations causing α-thalassemia [9]. By using only four target CNV assays, our method covers deletions affecting the important regulatory HS-40 region in addition to both of the α-globin genes and the common –α3.7 deletion. "
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    ABSTRACT: Alpha-thalassemia is the most common human genetic disease worldwide. Copy number variations in the form of deletions of alpha-globin genes lead to alpha-thalassemia while duplications of alpha-globin genes can cause a severe phenotype in beta-thalassemia carriers due to accentuation of globin chain imbalance. It is important to have simple and reliable methods to identify unknown or rare deletions and duplications in cases in which thalassemia is suspected but cannot be confirmed by multiplex gap-PCR. Here we describe a copy number variation assay to detect deletions and duplications in the alpha-globin gene cluster (HBA-CNV). Quantitative real-time PCR was performed using four TaqMan(R) assays which specifically amplify target sequences representing both the alpha-globin genes, the -alpha3.7 deletion and the HS-40 region. The copy number for each target was determined by the 2-DeltaDeltaCq method. To validate our method, we compared the HBA-CNV method with traditional gap-PCR in 108 samples from patients referred to our laboratory for hemoglobinopathy evaluation. To determine the robustness of the four assays, we analyzed samples with and without deletions diluted to obtain different DNA concentrations. The HBA-CNV method identified the correct copy numbers in all 108 samples. All four assays showed the correct copy number within a wide range of DNA concentrations (3.2-100 ng/muL), showing that it is a robust and reliable method. By using the method in routine diagnostics of hemoglobinopathies we have also identified several deletions and duplications that are not detected with conventional gap-PCR. HBA-CNV is able to detect all known large deletions and duplications affecting the alpha-globin genes, providing a flexible and simple workflow with rapid and reliable results.
    Full-text · Article · Jan 2014
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    • "Alpha thalassemia (α-thal) is one of the hemoglobinopathy that is characterized by a quantitative reduction of the α globin chains (1-2). α-thal is most common in Southeast Asia but is also prevalent in the Mediterranean, Middle East, India, and sub-Saharan Africa, with carrier frequencies ranging from 15% to 30% (3). "
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    ABSTRACT: Alpha thalassemia (α-thal) is relatively common worldwide. Most carriers are defective in either one or two alpha globin genes out of four functional ones, with deletions being more common than point mutations. The hematologic features are very important for the selection of the appropriate molecular tests while determining the genotype. The aim of this study was to compare hematologic features of patients with various types of α globin mutations. Hematological indices including red blood cells (RBC), hemoglobin concentration (Hb), mean cell volume (MCV), mean cell hemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC) and percentage of Hemoglobin (HBA1, HBA2 and HBF) of seven-hundred and twenty two patients presenting ten different α-thal genotypes were considered. All patients showed reduced MCV and/or MCH values.Moreover, MCV and MCH were lower in patients with two functional alpha globin genes in comparison to patients with one mutated alpha globin gene (P value<0.001). In conclusion, MCV and MCH valuescan be helpful for the selection of the appropriate molecular tests to determine the genotype of alphathalassemia carriers.
    Full-text · Article · Mar 2012
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    • "Silent carrier is characterized by the loss of only one gene whereas the second carrier state is characterized by the loss of two genes producing a condition with small red blood cells and, at most, a mild anemia. Besides there are two clinically significant forms of alpha thalassemia syndrome [2] [3]. These are Hemoglobin H (HbH) disease and Hb Bart hydrops fetalis. "
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    ABSTRACT: Thalassemia is an inherited blood disorder which is divided into two groups: alpha and beta. HBA1 and HBA2 are the two genes associated with alpha thalassemia. The aim of this study is to investigate abnormal hemoglobin variants of alpha globin gene in healthy abnormal hemoglobin carrying individuals with intact beta globin gene. DNA was extracted from peripheral blood sam-ples of seven healthy carrier individuals who have abnormal hemoglobin variants and 16 control individuals from Turkey. Complete coding and intronic sequences of HBA1 and HBA2 genes were amplified by polymerase chain reaction (PCR) and PCR products of HBA1 and HBA2 were sequenced. We were unable to find any base change in our carrier group in the HBA1 gene. We have observed an A/G polymorphism in the downstream untranslated region (+861 G>A) of the HBA2 gene. Our study showed that 14.29% (1/7 carriers) of the carrier group and 37.50% (6/16 controls) of the control group were heterozygous for the +861 G>A polymorphism. The distribution of allele frequencies and genotypes of HBA2 between carrier and control samples were analyzed and it is seen that the distribution of allele frequencies and that of genotypes were not statistically significant between carrier and control samples (P-value = 0.4131, P-value = 0.366, respectively). HBA2 +861 G>A nucleotide substitution is a neutral polymorphism previously reported in other populations. This is the first report in Turkish population.
    Full-text · Article · May 2011 · Egyptian Journal of Medical Human Genetics
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