Beta-thalassemia: from genotype to phenotype.
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ABSTRACT:
SUBMITTER: Danjou F
PROVIDER: S-EPMC3208672 | biostudies-literature | 2011 Nov
REPOSITORIES: biostudies-literature
Publications
Beta-thalassemia: from genotype to phenotype.
Danjou Fabrice F Anni Franco F Galanello Renzo R
Haematologica 20111101 11
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Project description:To look over the distribution of the mutations in a large series from Adana province, Southern Turkey, and determine the genotype-phenotype correlation of the frequent mutations. Among the 2500 individuals with mild or moderate anemia, microcytosis, and normal iron levels that were referred to our Genetic Diagnosis Center, a population consisting of 539 individuals were included in the study and tested for alpha-thalassemia mutations by using reverse dot blot hybridization technique. Twelve different mutations were detected in 539 patients. Among the 12 different mutations found, the most frequent mutations were the -α(3.7) (63.3 %), --(MED) (11.7 %), --(20.5) (10.7 %), α2(IVS1(-5nt)) (3.9 %), and α2(polyA-2) (3.5 %). The most frequent genotypes were -α(3.7)/αα (35.8 %), -α(3.7)/-α(3.7)(18.9 %), -(20.5)/αα (11.5 %), and --(MED)/αα (10.4 %), respectively. There were statistically significant differences in hematological findings between -α(3.7)/-α(3.7) and --(MED)/αα, even though both have two mutated genes in the genotype. Our results show that alpha-thalassemia mutations are highly heterogeneous as well as deletional and -α(3.7) single gene deletion is particularly prevalent at Adana province in agreement to other studies from Turkey.
| S-EPMC4375160 | biostudies-literature
Project description:Messenger RNA (mRNA) stability is a critical determinant that affects gene expression. Many pathways have evolved to modulate mRNA stability in response to developmental, physiological and/or environmental stimuli. Eukaryotic mRNAs have a considerable range of half-lives, from as short as a few minutes to as long as several days. Human globin mRNAs constitute an example of highly stable mRNAs. However, a wide variety of naturally occurring mutations that result in the clinical syndrome of thalassemia can trigger accelerated mRNA decay thus controlling mRNA quality prior to translation. Distinct surveillance mechanisms have been described as being targeted for specific defective globin mRNAs. Here, we review mRNA stability mechanisms implicated in the control of ?-globin gene expression and the surveillance pathways that prevent translation of aberrant ?-globin mRNAs. In addition, we emphasize the importance of these pathways in modulating the severity of the ?-thalassemia phenotype.
| S-EPMC3105653 | biostudies-literature
Project description:β-thalassemia is a prevalent genetic disorder causing severe anemia due to defective erythropoiesis, with few treatment options. Studying the underlying molecular defects is impeded by paucity of suitable patient material. In this study we create human disease cellular model systems for β-thalassemia by gene editing the erythroid line BEL-A, which accurately recapitulate the phenotype of patient erythroid cells. We also develop a high throughput compatible fluorometric-based assay for evaluating severity of disease phenotype and utilize the assay to demonstrate that the lines respond appropriately to verified reagents. We next use the lines to perform extensive analysis of the altered molecular mechanisms in β-thalassemia erythroid cells, revealing upregulation of a wide range of biological pathways and processes along with potential novel targets for therapeutic investigation. Overall, the lines provide a sustainable supply of disease cells as research tools for identifying therapeutic targets and as screening platforms for new drugs and reagents.
| S-EPMC10558456 | biostudies-literature
Project description:BackgroundThe frequency of the beta-thalassemia (β-thalassemia) gene in Indonesia ranges from 3 to 10%. However, in the East Java province, there is still limited information on the prevalence of β-thalassemia mutations in clinically diagnosed beta-thalassemia patients of East Java. Therefore, this study aimed to characterize β-thalassemia mutations in selected patients in the East Java province of Indonesia.MethodsThis is an analytical observational study. Diagnosis of β-thalassemia was based on clinical presentation, complete blood count (CBC), and hemoglobin (Hb) electrophoresis. Blood specimens taken from each patient in three ethylenediaminetetraacetic acid (EDTA) tubes were analyzed for CBC and Hb electrophoresis and processed for DNA extraction and subsequent polymerase chain reaction (PCR). Detection of mutations in Hemoglobin Subunit Beta (HBB) gene exons 1-3 of the β-thalassemia gene as the common mutation in Indonesia was done using PCR followed by Sanger sequencing.ResultsIn total, 33 (n = 33) participants were involved in this study with ages ranging from 5 to 17 years comprising 19 women and 14 men. Their ethnic origins were Javanese (n = 30) and Chinese (n = 3). CBC results showed that mean ± standard deviation (SD) for Hb, red blood cell (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW)-CV were 81.2 ± 7.0 g/L; 3.40 ± 0.39 × 109/L; 71.05 ± 5.72 fL; 24.12 ± 2.45 pg; 33.91 ± 1.47 g/dl; 24.38 ± 6.02%, respectively. Hb electrophoresis revealed that 5 out of 33 participants had beta-thalassemia and 28 out of 33 participants had hemoglobinopathy (Hb) E/beta-thalassemia. Results of Sanger sequencing showed the following genotype variations in the samples: 12 (36.4%) with β CD26 /β IVS-I-5; 6 (18.2%) with β CD26 /β CD35; 3 (9.1%) with β CD26 /β IVS-I-2; 2 (6.1%) with β CD27/28 /β CD40; 2 (6.1%) with β IVS-I-1 /β CAP+1; and β CD26 /β IVS-I-1; β IVS-I-5 /β CAP+1; β IVS-I-5 /β CD35; β CD26 /β CD37; β CD26 /β CD15; β CD26 /β CD40; and β IVS-I-5 /β CD19 in 1 (3%) sample, respectively, and 1 (3%) had no abnormality detected in sequencing even though electrophoresis showed abnormality in the migration pattern. The β CD26 /β IVS-I-5 mutation was found in samples that were noted to have Hb E/beta-thalassemia on Hb electrophoresis.ConclusionThe underlying genetic variations are heterogeneous in thalassemia patients in East Java, where 12 variants were found. The most common variant was β CD26 /β IVS-I-5, which all accounted for Hb E/beta-thalassemia on Hb electrophoresis. Furthermore, 28 out of 33 participants had hemoglobinopathy (Hb) E/beta-thalassemia.
| S-EPMC9335155 | biostudies-literature
Project description:Correlation of resistance associated mutations and minimum inhibitory concentrations of 900 Mycobacterium tuberculosis complex isolates
| PRJEB48275 | ENA
Project description:BackgroundHemoglobin E beta-thalassemia (beta-thalassemia/Hb E) has a variable severity, and the cost of treatment has not been well studied. The aim of this study was to analyze the societal cost of caring for children with beta-thalassemias in Thailand. The study was designed as a prevalence-based cost-of-illness analysis in a societal perspective. Medical records from three public hospitals of children aged 2-18 years with beta-thalassemia/Hb E and homozygous beta-thalassemia were reviewed for direct medical cost determination. For direct non-medical cost and indirect cost, a family member was interviewed.FindingsIt was found that 201 patients with beta-thalassemia/Hb E (91%) and homozygous beta-thalassemia (9%) were recruited for this study. Ninety-two (46%) were severe thalassemia and 109 (54%) were mild to moderate severity. The annual average cost of treatment was US$950; 59% was direct medical cost, 17% direct non-medical cost, and 24% indirect cost. The costs were differentiated by some potential predictors. Significant predictor variables were: hospital, health insurance scheme, blood transfusion pattern, and iron chelation drug use.ConclusionsThe average annual cost per patient was calculated, and the cost model was estimated. These would be applied for national planning, economic evaluation of treatment and prevention interventions, and budget impact analysis.
| S-EPMC2835719 | biostudies-literature
Project description:BackgroundFor the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by variants in the cystathionine beta-synthase (CBS) gene, most of which are rare. With early detection, existing therapies are highly effective.MethodsDamaging CBS variants can be detected based on their failure to restore growth in yeast cells lacking the yeast ortholog CYS4. This assay has only been applied reactively, after first observing a variant in patients. Using saturation codon-mutagenesis, en masse growth selection, and sequencing, we generated a comprehensive, proactive map of CBS missense variant function.ResultsOur CBS variant effect map far exceeds the performance of computational predictors of disease variants. Map scores correlated strongly with both disease severity (Spearman's ϱ = 0.9) and human clinical response to vitamin B6 (ϱ = 0.93).ConclusionsWe demonstrate that highly multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic.
| S-EPMC6993387 | biostudies-literature
Project description:a comparison of a control and a mutant condition (Th3) of the Hemoglobin Beta major and minor chain, used as Beta Thalassemia mouse model. 4 controls and 4 mutants
2012-03-07 | E-GEOD-36312 | biostudies-arrayexpress
Project description:a comparison of a control and a mutant condition (Th3) of the Hemoglobin Beta major and minor chain, used as Beta Thalassemia mouse model.
2012-03-07 | GSE36312 | GEO
Project description:This study analyzes gene expression in beta-thalassemic fetal liver erythroblasts in the Th3 murine model. FACS-purified wild-type, heterozygous, and homozygous stage-matched erythroblasts from E14.5 fetal livers are compared. We used FACS to purify CD71+Ter119+FSChigh matched populations from E14.5 fetal livers of wild-type, Th3/+, and Th3/Th3 embryos
2012-03-31 | E-GEOD-34125 | biostudies-arrayexpress