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Mutations in the paralogous human alpha-globin genes yielding identical hemoglobin variants.

Moradkhani K, Préhu C, Old J, Henderson S, Balamitsa V, Luo HY, Poon MC, Chui DH, Wajcman H, Patrinos GP - Ann. Hematol. (2008)

Bottom Line: There have been very few previous examples of hemoglobin variants that can be found at both HBA1 and HBA2 genes.We identified 14 different Hb variants resulting from identical mutations on either one of the two human alpha-globin paralogue genes.Based on these data, we propose a nomenclature for hemoglobin variants that fall into this category.

View Article: PubMed Central - PubMed

Affiliation: Biochimie Génétique, AP-HP, Hôpital Henri Mondor, Créteil, France.

ABSTRACT
The human alpha-globin genes are paralogues, sharing a high degree of DNA sequence similarity and producing an identical alpha-globin chain. Over half of the alpha-globin structural variants reported to date are only characterized at the amino acid level. It is likely that a fraction of these variants, with phenotypes differing from one observation to another, may be due to the same mutation but on a different alpha-globin gene. There have been very few previous examples of hemoglobin variants that can be found at both HBA1 and HBA2 genes. Here, we report the results of a systematic multicenter study in a large multiethnic population to identify such variants and to analyze their differences from a functional and evolutionary perspective. We identified 14 different Hb variants resulting from identical mutations on either one of the two human alpha-globin paralogue genes. We also showed that the average percentage of hemoglobin variants due to a HBA2 gene mutation (alpha2) is higher than the percentage of hemoglobin variants due to the same HBA1 gene mutation (alpha1) and that the alpha2/alpha1 ratio varied between variants. These alpha-globin chain variants have most likely occurred via recurrent mutations, gene conversion events, or both. Based on these data, we propose a nomenclature for hemoglobin variants that fall into this category.

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Related in: MedlinePlus

Box plots (p < 0.001) indicating the range and mean values (thick black lines) of the Hb Winnipeg variant percentage between carriers bearing the HBA1 or HBA2 mutation. In our evaluation, the Hb Winnipeg/α-thalassemia compound heterozygous case, as well as the cases described in Ref. [32], is excluded
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Fig1: Box plots (p < 0.001) indicating the range and mean values (thick black lines) of the Hb Winnipeg variant percentage between carriers bearing the HBA1 or HBA2 mutation. In our evaluation, the Hb Winnipeg/α-thalassemia compound heterozygous case, as well as the cases described in Ref. [32], is excluded

Mentions: Subsequently, we exploited the large number of unrelated Hb Winnipeg carriers bearing the c.226G>T mutation in either the HBA2 or HBA1 gene to address whether the percentage of the Hb variant can be correlated to the α-globin gene mutation. Statistical analysis, using SPSS 10 software, showed that Hb Winnipeg carriers cluster in two distinct groups, determined by the percentage of the Hb Winnipeg variant. In 38 Hb Winnipeg carriers bearing the HBA1 gene mutation, Hb Winnipeg percentage varied from 10.3 to 14.2 (13.0 ± 0.7), while in 12 Hb Winnipeg carriers bearing the HBA2 gene mutation, the percentage of the variant hemoglobin was between 15.6 and 18.4 (16.9 ± 0.9, Fig. 1). The ration of the average percentage of the abnormal Hb in heterozygotes with HBA2 (α2) and HBA1 mutations (α1) varied from 1.1 to 1.8, with a mean value of 1.3. These results showed that (1) Hb Winnipeg is produced at a higher rate (approx. 23%) when the underlying mutation is in the HBA2 gene, and (2) the percentage of Hb variant could provide initial information regarding the α-globin gene molecular defect.Fig. 1


Mutations in the paralogous human alpha-globin genes yielding identical hemoglobin variants.

Moradkhani K, Préhu C, Old J, Henderson S, Balamitsa V, Luo HY, Poon MC, Chui DH, Wajcman H, Patrinos GP - Ann. Hematol. (2008)

Box plots (p < 0.001) indicating the range and mean values (thick black lines) of the Hb Winnipeg variant percentage between carriers bearing the HBA1 or HBA2 mutation. In our evaluation, the Hb Winnipeg/α-thalassemia compound heterozygous case, as well as the cases described in Ref. [32], is excluded
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2690850&req=5

Fig1: Box plots (p < 0.001) indicating the range and mean values (thick black lines) of the Hb Winnipeg variant percentage between carriers bearing the HBA1 or HBA2 mutation. In our evaluation, the Hb Winnipeg/α-thalassemia compound heterozygous case, as well as the cases described in Ref. [32], is excluded
Mentions: Subsequently, we exploited the large number of unrelated Hb Winnipeg carriers bearing the c.226G>T mutation in either the HBA2 or HBA1 gene to address whether the percentage of the Hb variant can be correlated to the α-globin gene mutation. Statistical analysis, using SPSS 10 software, showed that Hb Winnipeg carriers cluster in two distinct groups, determined by the percentage of the Hb Winnipeg variant. In 38 Hb Winnipeg carriers bearing the HBA1 gene mutation, Hb Winnipeg percentage varied from 10.3 to 14.2 (13.0 ± 0.7), while in 12 Hb Winnipeg carriers bearing the HBA2 gene mutation, the percentage of the variant hemoglobin was between 15.6 and 18.4 (16.9 ± 0.9, Fig. 1). The ration of the average percentage of the abnormal Hb in heterozygotes with HBA2 (α2) and HBA1 mutations (α1) varied from 1.1 to 1.8, with a mean value of 1.3. These results showed that (1) Hb Winnipeg is produced at a higher rate (approx. 23%) when the underlying mutation is in the HBA2 gene, and (2) the percentage of Hb variant could provide initial information regarding the α-globin gene molecular defect.Fig. 1

Bottom Line: There have been very few previous examples of hemoglobin variants that can be found at both HBA1 and HBA2 genes.We identified 14 different Hb variants resulting from identical mutations on either one of the two human alpha-globin paralogue genes.Based on these data, we propose a nomenclature for hemoglobin variants that fall into this category.

View Article: PubMed Central - PubMed

Affiliation: Biochimie Génétique, AP-HP, Hôpital Henri Mondor, Créteil, France.

ABSTRACT
The human alpha-globin genes are paralogues, sharing a high degree of DNA sequence similarity and producing an identical alpha-globin chain. Over half of the alpha-globin structural variants reported to date are only characterized at the amino acid level. It is likely that a fraction of these variants, with phenotypes differing from one observation to another, may be due to the same mutation but on a different alpha-globin gene. There have been very few previous examples of hemoglobin variants that can be found at both HBA1 and HBA2 genes. Here, we report the results of a systematic multicenter study in a large multiethnic population to identify such variants and to analyze their differences from a functional and evolutionary perspective. We identified 14 different Hb variants resulting from identical mutations on either one of the two human alpha-globin paralogue genes. We also showed that the average percentage of hemoglobin variants due to a HBA2 gene mutation (alpha2) is higher than the percentage of hemoglobin variants due to the same HBA1 gene mutation (alpha1) and that the alpha2/alpha1 ratio varied between variants. These alpha-globin chain variants have most likely occurred via recurrent mutations, gene conversion events, or both. Based on these data, we propose a nomenclature for hemoglobin variants that fall into this category.

Show MeSH
Related in: MedlinePlus