Hemoglobinopathies in Southeast Asia: Molecular Biology and Clinical Medicine

Fucharoen, Suthat; Winichagoon, Pranee

doi:10.3109/03630269709000664

Cited by 149 publications

(97 citation statements)

References 54 publications

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“…Additional cases would be required to obtain more insight into the genotype-phenotype correlation of these genetic compound disorders. Nonetheless, our study confirms that for areas where both thalassemias and hemoglobinopathies are prevalent as in Southeast Asia [26], complex syndromes may result from the interaction of several defects with a spectrum of clinical and hematological manifestations. It is therefore important to understand these gene-gene interactions to be able to provide appropriate genetic counseling as well as facilitating a prevention and control program for thalassemia and hemoglobinopathies in the region.…”

Section: Resultssupporting

confidence: 63%

Compound heterozygote state for ^Gγ^Aγ(δβ)°‐thalassemia and hereditary persistence of fetal hemoglobin

et al. 2005

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We report a hitherto undescribed interaction of a deletional (db) -thalassemia and a deletional hereditary persistence of fetal hemoglobin (HPFH) in an adult Thai individual. He was a 40-year-old Thai male who had the following hematologic data: Hb 13.9 g/dL, Hct 43.8%, MCV 78.0 fL, MCH 24.7 pg, MCHC 31.6 g/dL, and RDW 17.1%. Hemoglobin analysis revealed 97% Hb F with G g -globin chain predominant. Globin gene analyses demonstrated that he carried the-thalassemia deletion in trans to the HPFH-6. Hematologic data of the patient were compared to those of the heterozygotes for these high-Hb F determinants found in his parents and an unrelated Thai patient with a compound HPFH-6/deletion-inversion G g ( A gdb) -thalassemia previously described. Am.

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Section: Resultssupporting

confidence: 63%

Compound heterozygote state for ^Gγ^Aγ(δβ)°‐thalassemia and hereditary persistence of fetal hemoglobin

et al. 2005

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“…The retained fragment prevents proper translation of ␤-globin, leading to hemoglobin deficiency and ␤-thalassemia. The IVS2-654 mutation is a common cause of thalassemia in Thailand and other countries of Southeast Asia (5). Work in this laboratory showed that splice-switching oligonucleotides (SSOs), which block aberrant splice sites in IVS2-654 and other pre-mRNAs (IVS1-5, IVS1-6, IVS1-110, IVS2-705, and IVS2-745) as well as in the coding sequence (HbE) of the ␤-globin gene, force the splicing machinery to reselect the existing correct splice sites, repairing the splicing pattern of ␤-globin pre-mRNA.…”

mentioning

confidence: 99%

RNA repair restores hemoglobin expression in IVS2–654 thalassemic mice

Svasti

Suwanmanee

Fucharoen

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Repair of ␤-globin pre-mRNA rendered defective by a thalassemiacausing splicing mutation, IVS2-654, in intron 2 of the human ␤-globin gene was accomplished in vivo in a mouse model of IVS2-654 thalassemia. This was effected by a systemically delivered splice-switching oligonucleotide (SSO), a morpholino oligomer conjugated to an arginine-rich peptide. The SSO blocked the aberrant splice site in the targeted pre-mRNA and forced the splicing machinery to reselect existing correct splice sites. Repaired ␤-globin mRNA restored significant amounts of hemoglobin in the peripheral blood of the IVS2-654 mouse, improving the number and quality of erythroid cells.oligonucleotides ͉ RNA splicing ͉ thalassemia ͉ therapy ͉ morpholino oligomers O ne of the most common inherited diseases, ␤-thalassemia, is caused by defects in the ␤-globin gene that affect production of ␤-globin, a subunit of hemoglobin (1). Current therapy consists of frequent blood transfusions combined with iron chelation (2). The only cure, bone marrow transplantation, is limited by the scarcity of suitable histocompatible donors (3). Although more than 200 mutations cause the disease, some of the most common ones induce aberrant splicing of ␤-globin pre-mRNA, interfering with proper translation of ␤-globin protein. The IVS2-654 (C Ͼ T) mutation creates an aberrant 5Ј splice site and activates a cryptic 3Ј splice site within intron 2 of the ␤-globin pre-mRNA, leading to retention of the intron fragment in the spliced mRNA even though the correct splice sites remain undamaged and potentially functional ( Fig. 1A) (4). The retained fragment prevents proper translation of ␤-globin, leading to hemoglobin deficiency and ␤-thalassemia. The IVS2-654 mutation is a common cause of thalassemia in Thailand and other countries of Southeast Asia (5). Work in this laboratory showed that splice-switching oligonucleotides (SSOs), which block aberrant splice sites in IVS2-654 and other pre-mRNAs (IVS1-5, IVS1-6, IVS1-110, IVS2-705, and IVS2-745) as well as in the coding sequence (HbE) of the ␤-globin gene, force the splicing machinery to reselect the existing correct splice sites, repairing the splicing pattern of ␤-globin pre-mRNA. This repair, which restores production of correctly spliced ␤-globin mRNA and protein, was accomplished in several in vitro systems and ex vivo in erythroid progenitor cells from thalassemic patients (6)(7)(8)(9)(10)(11)(12). In this study, we investigated the effectiveness in thalassemic splicing correction of a modified morpholino oligomer, SSO 654-P005, in a mouse model of IVS2-654 ␤-thalassemia. Results and DiscussionTo be effective in splicing repair, SSOs must hybridize tightly to the targeted splicing elements, such as aberrant splice sites, and prevent their recognition by the splicing factors. Furthermore, the resulting double-stranded structures must not be recognized by RNase H, which degrades RNA in RNA-DNA duplexes (13). These conditions are satisfied in cell culture and in vivo by modified oligomers with various backbones, includi...

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“…2,3 In the case of sickle cell Hb, or in the thalassaemias where there is an imbalance in the ratio of globin chains, the mutations are maintained in populations through natural selection by indirectly protecting the carrier against malaria or other infections. 4,5 Haemoglobin-Howick is one of about 50 mutations found in the Australasian region. 6 Here, a glycine has been substituted for a tryptophan at a locus close to the ␣-␤ contact, destabilizing the deoxy-Hb structure with the result that the blood has a high affinity for oxygen, decreased cooperativity and reduced sensitivity to pH (Bohr effect) and DPG.…”

Section: Haemoglobin Function and The Haemoglobinopathiesmentioning

confidence: 99%

Evolution of Haemoglobin Function: Molecular Adaptations to Environment

Wells

1999

Clin Exp Pharma Physio

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SUMMARY1. Nearly 1000 mutations have been described for human haemoglobin (Hb), many of which result in subtle changes to the oxygen transport system. Similar changes have occurred over the course of animal evolution resulting in a diversity of functional attributes which appear to correlate the availability of oxygen in the environment with metabolic demand.2. At an early stage in evolution, worm-like animals had large, polymeric aggregations of Hb subunits circulating through primitive circulatory systems and some possessed monomeric Hb in blood cells functioning as an oxygen store.3. The circulating vertebrate red blood cell provides an environment allowing haem units to interact among themselves and with various organic phosphates to allow a responsive and highly regulated system of gas transport. During metazoan evolution the burden of physiological regulation has shifted from the cells to organ systems, as endothermy and aerial breathing permit a relatively constant environment.4. An understanding of the adaptive possibilities of Hb has helped us to understand the ontogeny of oxygen transport and to interpret recently described functional properties of human embryonic haemoglobins.

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Hemoglobinopathies in Southeast Asia: Molecular Biology and Clinical Medicine

Cited by 149 publications

References 54 publications

Compound heterozygote state for ^Gγ^Aγ(δβ)°‐thalassemia and hereditary persistence of fetal hemoglobin

Compound heterozygote state for ^Gγ^Aγ(δβ)°‐thalassemia and hereditary persistence of fetal hemoglobin

RNA repair restores hemoglobin expression in IVS2–654 thalassemic mice

Evolution of Haemoglobin Function: Molecular Adaptations to Environment

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Hemoglobinopathies in Southeast Asia: Molecular Biology and Clinical Medicine

Cited by 149 publications

References 54 publications

Compound heterozygote state for GγAγ(δβ)°‐thalassemia and hereditary persistence of fetal hemoglobin

Compound heterozygote state for GγAγ(δβ)°‐thalassemia and hereditary persistence of fetal hemoglobin

RNA repair restores hemoglobin expression in IVS2–654 thalassemic mice

Evolution of Haemoglobin Function: Molecular Adaptations to Environment

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Compound heterozygote state for ^Gγ^Aγ(δβ)°‐thalassemia and hereditary persistence of fetal hemoglobin

Compound heterozygote state for ^Gγ^Aγ(δβ)°‐thalassemia and hereditary persistence of fetal hemoglobin