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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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Comparison of the calculated α2/α1 ratio of the average percentage of the stable (S, shown in blue bars) and mildly unstable abnormal Hbs (MU, shown in red bars) reported in this paper
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Fig2: Comparison of the calculated α2/α1 ratio of the average percentage of the stable (S, shown in blue bars) and mildly unstable abnormal Hbs (MU, shown in red bars) reported in this paper

Mentions: Our data show that the α2/α1 ratio of the average percentage of the abnormal Hb in heterozygotes with HBA2 and HBA1 mutations, respectively, varies from 0.98 (Hb J-Paris-I) to 1.67 (Hb Gerland; Tables 2 and 3). Moreover, comparison of the α2/α1 ratio of the average percentage of the abnormal Hbs showed that stable and mildly unstable abnormal Hbs nicely cluster in two distinct groups with average α2/α1 ratios of 1.15 ± 0.10 and 1.60 ± 0.09, respectively (Fig. 2). Notably, in all cases summarized in Tables 2 and 3, the percentage of variant Hb has been calculated using cation-exchange HPLC. Therefore, although these values come from different centers and published reports, the use of similar analytical method, apparatus, and analysis software makes these values virtually comparable. Also, the large number of Hb Winnipeg cases studied in this context statistically strengthens the above claims (Table 2). These data are comparable with previous results from heterozygous cases for 24 different α-globin chain variants [14] but sharply contradicts with a previous study [13], which indicated that a mutated HBA2 gene yielding a variant α-globin chain is expressed at a two- to threefold higher level than a mutated HBA1 gene. The main supporting data for this claim were the Hb levels of Hb J-Oxford (40%) and Hb Hasharon (35%), which are comparable to levels expected for Hb variant/α-thalassemia compound heterozygotes (see also Table 3). However, these data were obtained from in vitro translation experiments, and hence, this discrepancy is most likely due to the experimental approach rather that directly measuring Hb variant levels in vivo.Fig. 2


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)

Comparison of the calculated α2/α1 ratio of the average percentage of the stable (S, shown in blue bars) and mildly unstable abnormal Hbs (MU, shown in red bars) reported in this paper
© Copyright Policy
Related In: Results  -  Collection

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

Fig2: Comparison of the calculated α2/α1 ratio of the average percentage of the stable (S, shown in blue bars) and mildly unstable abnormal Hbs (MU, shown in red bars) reported in this paper
Mentions: Our data show that the α2/α1 ratio of the average percentage of the abnormal Hb in heterozygotes with HBA2 and HBA1 mutations, respectively, varies from 0.98 (Hb J-Paris-I) to 1.67 (Hb Gerland; Tables 2 and 3). Moreover, comparison of the α2/α1 ratio of the average percentage of the abnormal Hbs showed that stable and mildly unstable abnormal Hbs nicely cluster in two distinct groups with average α2/α1 ratios of 1.15 ± 0.10 and 1.60 ± 0.09, respectively (Fig. 2). Notably, in all cases summarized in Tables 2 and 3, the percentage of variant Hb has been calculated using cation-exchange HPLC. Therefore, although these values come from different centers and published reports, the use of similar analytical method, apparatus, and analysis software makes these values virtually comparable. Also, the large number of Hb Winnipeg cases studied in this context statistically strengthens the above claims (Table 2). These data are comparable with previous results from heterozygous cases for 24 different α-globin chain variants [14] but sharply contradicts with a previous study [13], which indicated that a mutated HBA2 gene yielding a variant α-globin chain is expressed at a two- to threefold higher level than a mutated HBA1 gene. The main supporting data for this claim were the Hb levels of Hb J-Oxford (40%) and Hb Hasharon (35%), which are comparable to levels expected for Hb variant/α-thalassemia compound heterozygotes (see also Table 3). However, these data were obtained from in vitro translation experiments, and hence, this discrepancy is most likely due to the experimental approach rather that directly measuring Hb variant levels in vivo.Fig. 2

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