The differences in quantities of α2‐and α1‐globin gene variants in heterozygotes

Molchanova, T. P.; Pobedimskaya, D. D.; Huisman, T. H. J.

doi:10.1111/j.1365-2141.1994.tb05022.x

Cited by 74 publications

(44 citation statements)

References 54 publications

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“…In the present study, we showed that HbO is stable in vitro, consistent with the previous study of Molchanova et al (1994). An α1-globin gene carrying a HbO mutation is transcribed normally, and its mRNA represents around 21% of the total Hb mRNA (Molchanova et al 1994).…”

Section: Discussionsupporting

confidence: 78%

“…The replacement of negatively charged glutamic acid by positively charged lysine at residue 116 is structurally significant and thus could potentially lead to a functional or assembly defect. The HbO level in all but two of our cases was in fact found to be significantly lower (10.1% to 13.8%) than that expected from a stable α 1 -globin variant; stable α 1 -variants have been reported to be present in the range of 16.9% to 22.5% (Molchanova et al 1994). The level of HbO has been determined previously in two studies only.…”

Section: Discussionmentioning

confidence: 78%

“…An α1-globin gene carrying a HbO mutation is transcribed normally, and its mRNA represents around 21% of the total Hb mRNA (Molchanova et al 1994). Our hemoglobin analysis data, therefore, suggest that the HbO mutation is associated with instability of either the α OIna -globin chain or with less efficient assembly of the hemoglobin in vivo, which has been shown to be one of the consequences of the -globin Glu26Lys amino acid changes associated with the HbE mutation (Huisman 1997).…”

Section: Discussionmentioning

confidence: 79%

“…In all of these cases, the mutation could be shown by tryptic digestion experiments to be associated with an amino acid change at residue 116 (Glu116Lys) of the α-globin chain. The underlying mutation, however, has been defined only in one case of undefined ethnic origin, a GAG to AAG base substitution at codon 116 of the α 1 -globin gene (Molchanova et al 1994).…”

Section: Introductionmentioning

confidence: 99%

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The Hemoglobin O mutation in Indonesia: distribution and phenotypic expression

et al. 2001

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We have investigated hemoglobin O Indonesia (HbO Ina ) in related ethnic populations of the Indonesian archipelago: 1725 individuals of the five ethnic populations of South Sulawesi (Bugis, Toraja, Makassar, Mandar, and Kajang) and 959 individuals of the neighboring islands, who were divided into five phylogenetic groups: (a) Batak; (b) Malay from Padang, Pakanbaru, and Palembang in the island of Sumatra; (c) Javanese-related populations (Java, Tengger, and Bali) from the islands of Java and Bali; (d) populations of the Lesser Sunda Islands of Lombok, Sumba, and Sumbawa; and (e) the Papuan-languagespeaking population of Alor Island. Nineteen individuals heterozygous for HbO Ina were identified from the Bugis, Toraja, Makassar, and Kajang ethnic populations, but none from the other populations. In all cases, the underlying mutation was found to be in codon 116 (GAG to AAG) of the α 1 -globin gene, resulting in the Glu116Lys amino acid change. The level of HbO in the 17 individuals plus 12 additional family members carrying the mutation was found to be 11.6 Ϯ 1.0%, significantly lower than the expected 17%-22%, indicating the instability of HbO.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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The Hemoglobin O mutation in Indonesia: distribution and phenotypic expression

et al. 2001

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“…Total globin chain content and the rate of protein synthesis was determined by labeling immature red cells with 3 H-leucine and separation of the globins by HPLC (6); as plasma erythropoietin and red cell DPG concentrations were determined by RIA (7) and an enzymatic method, respectively (8). Finally, DNA and mRNA analysis was carried out on the samples as described below.…”

Section: Methodsmentioning

confidence: 99%

The Biologic Implications of a Rare Hemoglobin Mutant That Decreases Oxygen Affinity

2001

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Blood from seven newborns, a 13-y-old, and seven adult family members with a suspected hemoglobinopathy because of unexplained cyanosis was obtained for analysis to determine Hb oxygen affinity and to characterize and quantify the Hb variants. Their oxygen saturation was 76 to 84%. The P 50 was 30.3 Ϯ 2.9 for the newborns and 32.5 Ϯ 2.6 mm Hg for their related adults. In the same order, the plasma erythropoietin was 7.4 Ϯ 2.9 and 15.9 Ϯ 3.7 mU/mL, whereas 2,3-diphosphoglycerate was 16.1. Ϯ 2.9 and 15.9 Ϯ 3.7 mol/g Hb. In four of the newborns with increased P 50 , the mother had a normal P 50 (27 mm Hg), which indicated a greater maternal oxygen affinity than the fetus with no adverse effects on the fetus. Genetic analysis of ␣-globin genes demonstrated a heterozygous mutation on the ␣2 gene [␣94(G1)Asp3 His] for each of the newborns and their related adults. The same mutation was found on the ␣1 gene in an adolescent and her father. The mRNA measurements showed that the ␣2-to ␣1-globin mRNA mean ratio was 2.5, ␣2 mutant globin mRNA/total ␣2-globin mRNA was 45.0%, whereas the ␣1 mutant globin mRNA/total ␣1-globin mRNA was 37.8%. The level of ␣2 mutant globin/total ␣-globin was 27.3 Ϯ 1%, and ␣1 mutant globin/total ␣-globin was 23.8 Ϯ 1%. The percentage of synthesized ␣2 and ␣1 mutant globins was 27.5 Ϯ 2 and 26.1 Ϯ 1, respectively. The ratio of the ␣2/␣1 mutant globins was 1.1, which corresponded to a ratio at the mRNA level of ␣2/␣1 of 2.5 Ϯ 0.5, which suggested that there is a less efficient translation of the ␣2 mRNA than ␣1 mRNA. The reversal of the physiologic fetomaternal oxygen affinity had no effects on fetal development. Abbreviations ODC, Hb-oxygen dissociation curve DPG, 2,3-diphosphoglycerate P 50 , PO 2 required to achieve a saturation of 50% at pH 7.4 and 37°CA rare mutant Hb with a low oxygen affinity designated as Sunshine Seth [␣94(G 1 ) Asp3 His] (1) was detected in a series of newborn infants as well as in a 13-y-old and her father. The infants, because of persistent cyanosis, were transferred soon after birth to a neonatal intensive care unit to investigate the cause of their Hb desaturation. The cyanotic infants and their parents provided an opportunity to evaluate the physiologic implications of low oxygen Hb affinity during the perinatal period as well as carry out genetic analysis to further the knowledge of the of human ␣-globin gene expression.The two human ␣-globin genes ␣1 and ␣2 are coexpressed in normal erythroid cells and encode identical ␣-globin protein products. The ␣2 gene encodes a 2-3-fold higher level of mRNA than the ␣1 gene (2). Because of the identical ␣-globin produced, the relative levels of expression are difficult to determine. Despite some data that suggest posttranscriptional/ translational modifications balancing the amount of protein expressed from these mRNA (3), it is still controversial how the difference in ␣2 and ␣1 mRNA levels are reflected at the protein level (4). Because of a rare occasion in which an identical mutation in both the ␣1 and ␣2 genes existed ...

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mRNA analysis in reticulocytes of subjects with Hb D, Hb Porto Alegre, Hb E, and different types of unstable hemoglobin variants

Smetanina

Huisman

1996

Am. J. Hematol.

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Using a reverse transcription-polymerase chain reaction (RT-PCR) technique we determined the alpha 2/alpha 1, alpha/beta, and gamma/beta mRNA ratios in reticulocytes of 11 patients with seven different unstable beta chain variants, of 4 patients with two unstable alpha chain variants, in hemoglobin (Hb) D, Hb Porto Alegre, and Hb E heterozygotes, and in 8 patients with Hb X-beta 0-thalassemia (thal) (three D-beta 0-thal, one Porto Alegre = beta 0-thal, one Lulu Island-beta 0-thal, and three E-beta 0-thal). In addition, we determined the beta X/beta A mRNA ratios (X = unstable) in some Hb D heterozygotes and in 6 subjects with an unstable beta chain variant. Normal alpha/beta and beta X/beta A mRNA ratios were found in all heterozygotes tested, indicating that the respective mutations did not alter the stability of the mRNAs. The alpha/beta mRNA ratio in four Hb E heterozygotes averaged 4.21 (normal, 4.47), and that in 2 patients with Hb E-beta 0-thal and four alpha-globin genes (alpha alpha/alpha alpha) averaged a high 22.4. The gamma mRNA level in the Hb E heterozygotes was < 1% but varied greatly in patients with Hb E-beta 0-thal; the alpha/(gamma + beta) mRNA ratios in the 2 patients were 15.5 and 16.7, respectively. The large differences in alpha/beta and alpha/(gamma + beta) mRNA ratios in reticulocytes of subjects with AE and with E-beta 0-thal may be due to differences in the levels of normally-spliced beta E and abnormally-spliced beta E mRNAs. Only the latter is unstable and is preferentially produced in bone marrow and reticulocytes of Hb E-beta 0-thal patients, where it is rapidly degraded.

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The differences in quantities of α2‐and α1‐globin gene variants in heterozygotes

Cited by 74 publications

References 54 publications

The Hemoglobin O mutation in Indonesia: distribution and phenotypic expression

The Hemoglobin O mutation in Indonesia: distribution and phenotypic expression

The Biologic Implications of a Rare Hemoglobin Mutant That Decreases Oxygen Affinity

mRNA analysis in reticulocytes of subjects with Hb D, Hb Porto Alegre, Hb E, and different types of unstable hemoglobin variants

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