The Molecular Basis of α-Thalassemia: A Model for Understanding Human Molecular Genetics

Higgs, Douglas R.; Gibbons, Richard J.

doi:10.1016/j.hoc.2010.08.005

Cited by 32 publications

(20 citation statements)

References 73 publications

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“…This verified that the cells were indeed homozygous for ␣-thalassemia and revealed the presence of the South-East-Asian (SEA) deletion on one chromosome and of the Filipino deletion on the other one. 11 We therefore concluded that the cells contain no ␣-globin gene and a single -globin gene because the Filipino deletion encompasses both the -and ␣-globin genes.…”

Section: Reprogramming Of Homozygote ␣-Thalassemia Fibroblasts and Ermentioning

confidence: 88%

“…This revealed that the corrective transgene or the corrected gene were expressed but levels of expression were very low because current iPSC differentiation protocols yield erythroid cells that express mostly embryonic ( 2 ⑀ 2 ) and fetal hemoglobins (␣ 2 ␥ 2 ) and only trace amounts of ␤-globin, the gene that is mutated in both sickle cell disease and ␤-thalassemia. 9,10 ␣-thalassemias, which are caused by mutations in the ␣-globin gene cluster, 11 are therefore good models to test globin gene correction methods in iPSCs because the ␣-globin gene is expressed at very high levels in the erythroid cells that can currently be produced from iPSCs. ␣-thalassemias are divided into 2 major clinical categories: Hb H disease (a relatively severe hemolytic anemia caused by loss or decreased expression of 3 of the 4 ␣-globin genes) and homozygous ␣-thalassemia hydrops fetalis (caused by deletion of the 4 genes).…”

Section: Introductionmentioning

confidence: 99%

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Zinc-finger nuclease-mediated correction of α-thalassemia in iPS cells

Chang

Bouhassira

2012

Blood

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Induced pluripotent stem (iPS) cell technology holds vast promises for a cure to the hemoglobinopathies. Constructs and methods to safely insert therapeutic genes to correct the genetic defect need to be developed. Site-specific insertion is a very attractive method for gene therapy because the risks of insertional mutagenesis are eliminated provided that a “safe harbor” is identified, and because a single set of validated constructs can be used to correct a large variety of mutations simplifying eventual clinical use. We report here the correction of α-thalassemia major hydrops fetalis in transgene-free iPS cells using zinc finger–mediated insertion of a globin transgene in the AAVS1 site on human chromosome 19. Homozygous insertion of the best of the 4 constructs tested led to complete correction of globin chain imbalance in erythroid cells differentiated from the corrected iPS cells.

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Section: Reprogramming Of Homozygote ␣-Thalassemia Fibroblasts and Ermentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Zinc-finger nuclease-mediated correction of α-thalassemia in iPS cells

Chang

Bouhassira

2012

Blood

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“…Introduction a-Thalassemia (a-thal) is an inherited hemoglobin (Hb) disorder due to impaired a-globin genes, leading to a relative excessive expression of g-globin genes in fetus and newborn, and b-globin genes in children and adults that results in imbalance of aand gor b-globin chains (1,2). In normal individuals, there are four copies of a-globin genes with two genes on each chromosome 16 (aa/aa).…”

mentioning

confidence: 99%

The Prevalence and Spectrum of α-Thalassemia in Guizhou Province of South China

et al. 2015

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α-Thalassemia (α-thal) is one of the most prevalent genetic diseases in the world and is especially frequent in tropical and subtropical regions, including South China. The aim of this study was to investigate the prevalence and spectrum of α-thal in Guizhou Province as this information was unknown. A total of 40 α-thal carriers were determined in 1219 newborn umbilical cord blood samples by hemoglobin (Hb) electrophoresis combined with DNA analysis, which revealed that the carrier rate of α-thal in Guizhou Province was 3.28%. One thousand and forty-five individuals referred to our hospital were tested for α-thal mutations. Two hundred and twenty-four cases were determined as α-thal carriers or patients. A total of 11 genotypes and five different α-thal mutations were identified in these 224 cases. Of these mutations, more than 96.0% were deletions, including - -(SEA) (65.89%), -α(3.7) (rightward) (22.87%) and -α(4.2) (leftward) (7.74%). The other two nondeletional mutations, Hb Constant Spring (Hb CS, α(CS)α, HBA2: c.427T > C) and Hb Quong Sze [Hb QS, α(QS)α, HBA2: c.377T > C (or HBA1)] account for 2.71% and 0.78%, respectively. The results of this study will be useful in genetic counseling and prenatal diagnosis (PND) of α-thal in Guizhou Province.

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“…As shown in Table 1, most cases (436/523, 83.4%) required a PD for β-thalassaemia. PD of α-thalassaemia was performed only in seven cases, as expected on the basis of the relative low frequencies of this defect in our population [14][15][16].…”

Section: Resultsmentioning

confidence: 79%