Interactions of unstable hemoglobin Rush with thalassemia and hemoglobin E result in thalassemia intermedia

Abstract

Background: The clinical consequences and significance of many unstable hemoglobins interacting with other hemoglobinopathies remain unrecognized. Here we first explore molecular and hematological characterizations of previously undescribed compound heterozygosity states for unstable hemoglobin Rush (Hb Rush, Beta 101 Glu > Gln, HBB: c.304G > C) with Hb E and different forms of thalassemia. Methods: Hematological assays, globin gene mutation assays and β-globin gene cluster haplotype were conducted in 11 patients from 8 unrelated Chinese ethnic families with unexplained hemoglobin separation fraction in hemoglobin gel electrophoresis. Results: Hb Rush in various combinations with Hb E, β 0 -thalassemias and α + -thalassemia were identified. Hb Rush simple heterozygote was generally associated with mild hemolytic anemia, and the compound heterozygotes of Hb Rush and the other β-globin variants led to thalassemia intermedia phenotypes with moderate anemia. Hemoglobin electrophoreses showed that the co-presence of Hb Rush with either Hb E or β 0 -thalassemias increased proportion of Hb Rush due to relative decrease of other globin chain synthesis. Beta-globin gene cluster haplotype analysis suggested a common origin of the Hb Rush variant in the Chinese families of different ethnic ancestry. Conclusions: Unstable Hb Rush interacting with β-thalassemia result in thalassemia intermedia phenotypes, which demonstrated the clinical significance of Hb Rush and new insights into complex mechanism of clinical heterogeneity of thalassemia.

Hemoglobin Ottawa (HBA2:c.46G>C) and β+ Thalassemia (HBB:c.-138C>T) Detected in an Indian Male by Capillary Zone Electrophoresis

“…It has been suggested that the MCV may be affected by the presence of a mildly unstable Hb, with some unstable Hbs in association with β thalassemia resulting in red cell indices consistent with thalassemia intermedia, or even thalassemia major. 16 However, the MCV for our subject was consistent with previous reports of simple heterozygotes for HBB:c.-138C>T, so it seems unlikely co-inheritance of Hb Ottawa has influenced the mild thalassemia presentation. It should be noted that Hb instability was not demonstrated for our subject during this investigation but one previous report suggested Hb Ottawa was mildly unstable.…”

“…5 Regardless, many reports of unstable Hb variants indicate nor-mal MCV in the absence of complicating factors. 16 The β + thalassemia mutation (HBB:c.-138C>T) was identified as African in origin by Orkin et al, 11 but has also been observed in Asian Indians with the same nucleotide substitution but on a different chromosomal background as indicated by haplotype analysis, suggesting two independent mutation origins. 17 Even though the β + thalassemia allele is mild, carriers of the HBB promoter mutation tend to have relatively high values for HbA 2 [12][13] but with variable HbF levels that might be reflective of the ethnic background and haplotype of the individual.…”

The first Chinese with Hb Chile leading to chronic anemia and methemoglobinemia: a case report

“…For instance, previous studies have demonstrated that unstable Hb Rush [β101 (G3) Glu > Gln; HBB: c.304G > c] co-inherited with Hb E or β-thalassemia increases the proportion of Hb Rush and manifests as thalassemia intermedia. However, individuals who are heterozygous for Hb Rush alone typically exhibit mild hemolytic anemia [ 16 ]. It has also been shown that unstable Hb-Haná [β63 (E7) His > Asn; HBB: c.190 C > A] alone generally does not cause hemolytic anemia.…”

Evaluation of the level of 5'-nucleotidase and some biochemical parameters in the sera of beta-thalassemia patients

“…This genetic mutation disrupts normal hemoglobin production (Hemoglobin A). Therefore, the low levels of hemoglobin and the high rate of red blood cell damage lead to symptoms of anemia (thalassemia) (Huang et al, 2019).…”