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

Abstract

The human α-globin genes are paralogues, sharing a high degree of DNA sequence similarity and producing an identical α-globin chain. Over half of the α-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 α-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 α-globin paralogue genes. We also showed that the average percentage of hemoglobin variants due to a HBA2 gene mutation (α2) is higher than the percentage of hemoglobin variants due to the same HBA1 gene mutation (α1) and that the α2/α1 ratio varied between variants. These α-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.

Alpha chain hemoglobins with electrophoretic mobility similar to that of hemoglobin S in a newborn screening program

“…According to the literature, Hb Hasharon would not cause clinical or hematological abnormalities unless co-inherited with alpha thalassemia (19, 20) as reported by other Brazilian studies (18, 19, 21, 22) . Patients with Hb Ottawa and Hb St. Luke's were considered normal upon clinical and hematological evaluation (8, 23, 24) .…”

A New Stable α Chain Variant: Hb Basel [α14(A12)Trp→Leu (α1)]

“…The identification of an HBA1 mutation causing the Hb variant is in good agreement with the amount of the variant in total Hb. Because the ratio of the transcription levels of HBA1 and HBA2 is known to be about 1:3, a stable Hb variant encoded by one HBA1 contributes approximately 12.5% of total α-globin (4,8). The amount of the Hb variant therefore is in good agreement with an HBA1 mutation, and also provides evidence for the stability of the variant.…”

Hb Nile[A1] and Hb Nile[A2]: Novel Identical [α77(EF6)Pro→Ser] Variants Found in Either the α1- or α2-Globin Genes

“…the same time, seems quite a coincidence. Hb Nile can be the result of independent base substitutions in HBA1 and HBA2 in two unrelated individuals or, more likely, because of the shared ethnic background of the two families, be the result of a mutation on one of the a genes, and subsequent interallelic gene conversion in a common ancestor (8). Thorough haplotype analysis of the a-globin cluster of the two Hb Nile families is required to elucidate which of these two mechanisms has led to the Hb Nile mutation on both a genes.…”