Two French Caucasian Families with Dominant Thalassemia-Like Phenotypes Due to Hyper Unstable Hemoglobin Variants: Hb Sainte Seve [Codon 118 (− T)] and Codon 127 [<i>C</i>AG→<i>T</i>AG (Gln→Stop])

Préhu, Claude; Pissard, Serge; Al-Sheikh, Maha; Niger, Catherine Le; Bachir, Dora; Galactéros, F; Wajcman, Henri

doi:10.1081/hem-200066335

Cited by 20 publications

(9 citation statements)

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“…Nonsense mutations, giving rise to UAA, UGA and UAG stop codons within the coding region of mRNAs, promote premature translational termination [1–4] and are the leading cause of up to 30 % of inherited diseases [2,4], including cystic fibrosis [5], Duchenne muscular dystrophy [6] and thalassaemia [7–12]. For instance, in β 0 39-thalassaemia the CAG (glutamine) codon of the β -globin mRNA is mutated to the UAG stop codon [7,8], leading to premature translation termination and to mRNA destabilization through the well-described NMD (nonsense-mediated mRNA decay) [3,4].…”

Section: Introductionmentioning

confidence: 99%

Development of K562 cell clones expressing β‐globin mRNA carrying the β⁰39 thalassaemia mutation for the screening of correctors of stop‐codon mutations

Salvatori

Cantale

Breveglieri

et al. 2009

Biotech and App Biochem

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Nonsense mutations, giving rise to UAA, UGA and UAG stop codons within the coding region of mRNAs, promote premature translational termination and are the leading cause of approx. 30 % of inherited diseases, including cystic fibrosis, Duchenne muscular dystrophy and thalassaemia. For instance, in β039-thalassaemia the CAG (glutamine) codon is mutated to the UAG stop codon, leading to premature translation termination and to mRNA destabilization through the well-described NMD (nonsense-mediated mRNA decay). In order to develop an approach facilitating translation and, therefore, protection from NMD, aminoglycoside antibiotics have been tested on mRNAs carrying premature stop codons. These drugs decrease the accuracy in the codon–anticodon base-pairing, inducing a ribosomal read-through of the premature termination codons. Interestingly, recent papers have described drugs designed and produced for suppressing premature translational termination, inducing a ribosomal read-through of premature but not normal termination codons. These findings have introduced new hopes for the development of a pharmacological approach to the therapy of β039-thalassaemia. In this context, we started the development of a cellular model of the β039-thalassaemia mutation that could be used for the screening of a high number of aminoglycosides and analogous molecules. To this aim, we produced a lentiviral construct containing the β039-thalassaemia globin gene under a minimal LCR (locus control region) control and used this construct for the transduction of K562 cells, subsequently subcloned, with the purpose to obtain several K562 clones with different integration copies of the construct. These clones were then treated with Geneticin (also known as G418) and other aminoglycosides and the production of β-globin was analysed by FACS analysis. The results obtained suggest that this experimental system is suitable for the characterization of correction of the β039-globin mutation causing β-thalassaemia.

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Section: Introductionmentioning

confidence: 99%

Development of K562 cell clones expressing β‐globin mRNA carrying the β⁰39 thalassaemia mutation for the screening of correctors of stop‐codon mutations

Salvatori

Cantale

Breveglieri

et al. 2009

Biotech and App Biochem

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“…Heterozygosity for a premature stop codon in b127 (CAG TO TAG) has also been to cause thalassemia intermedia in an English woman (Hall et al 1991), and a 29-year-old French Caucasian woman (Prehu et al 2005).…”

Section: Deletion or Insertion Of Intact Codonsmentioning

confidence: 99%

The Molecular Basis of -Thalassemia

Thein

2013

Cold Spring Harbor Perspectives in Medicine

291

189

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The b-thalassemias are characterized by a quantitative deficiency of b-globin chains underlaid by a striking heterogeneity of molecular defects. Although most of the molecular lesions involve the structural b gene directly, some down-regulate the gene through distal cis effects, and rare trans-acting mutations have also been identified. Most b-thalassemias are inherited in a Mendelian recessive fashion but there is a subgroup of b-thalassemia alleles that behave as dominant negatives. Unraveling the molecular basis of b-thalassemia has provided a paradigm for understanding of much of human genetics.

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“…The elongated b-chains are mostly caused by frameshift mutations in the third exon of the respective gene, as can be seen in Table I [ [8][9][10][11][12][13][14][15][16][17][18][19][20][21]. In the case we present here, the deletion of one nucleotide (-C) between codons 140 and 141 abolishes the stop codon at codon 147, transferring the termination of translation to the new codon 157.…”

Section: Discussionmentioning

confidence: 99%

Hb Florida: A novel elongated C‐terminal β‐globin variant causing dominant β‐thalassemia phenotype

et al. 2006

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We report here a new frameshift mutation in exon 3 of the b-globin gene, a single nucleotide deletion (-C) in between codons 140/141 (GCC/CTG?GCC/TG), found in an 8-year-old Argentinean girl with clinical picture of thalassemia intermedia. It leads to a b-chain that is elongated to 156 amino acids [(141)Trp-Pro-Thr-Ser-Ile-Thr-Lys-Leu-Ala-Phe-Leu-Leu-Ser-Asn-Phe-(156) Tyr-COOH]. The resulting hemoglobin, which we named Hb Florida, was not detected in peripheral blood; however, erythroid hyperplasia and dyserythropoiesis with large inclusion bodies on methyl violet staining were observed in bone marrow, suggesting that this is a hyperunstable variant producing a dominant b-thalassemia phenotype, since the other b-allele was completely normal. Am. J. Hematol. 81:358-360, 2006. V V C 2006 Wiley-Liss, Inc.

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Two French Caucasian Families with Dominant Thalassemia-Like Phenotypes Due to Hyper Unstable Hemoglobin Variants: Hb Sainte Seve [Codon 118 (− T)] and Codon 127 [CAG→TAG (Gln→Stop])

Cited by 20 publications

References 10 publications

Development of K562 cell clones expressing β‐globin mRNA carrying the β⁰39 thalassaemia mutation for the screening of correctors of stop‐codon mutations

Development of K562 cell clones expressing β‐globin mRNA carrying the β⁰39 thalassaemia mutation for the screening of correctors of stop‐codon mutations

The Molecular Basis of -Thalassemia

Hb Florida: A novel elongated C‐terminal β‐globin variant causing dominant β‐thalassemia phenotype

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Two French Caucasian Families with Dominant Thalassemia-Like Phenotypes Due to Hyper Unstable Hemoglobin Variants: Hb Sainte Seve [Codon 118 (− T)] and Codon 127 [CAG→TAG (Gln→Stop])

Cited by 20 publications

References 10 publications

Development of K562 cell clones expressing β‐globin mRNA carrying the β039 thalassaemia mutation for the screening of correctors of stop‐codon mutations

Development of K562 cell clones expressing β‐globin mRNA carrying the β039 thalassaemia mutation for the screening of correctors of stop‐codon mutations

The Molecular Basis of -Thalassemia

Hb Florida: A novel elongated C‐terminal β‐globin variant causing dominant β‐thalassemia phenotype

Contact Info

Product

Resources

About

Development of K562 cell clones expressing β‐globin mRNA carrying the β⁰39 thalassaemia mutation for the screening of correctors of stop‐codon mutations

Development of K562 cell clones expressing β‐globin mRNA carrying the β⁰39 thalassaemia mutation for the screening of correctors of stop‐codon mutations