Abstract
ABSTRACTBackground: 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, β0-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 β0-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.
Highlights
Unstable hemoglobins include a large group of abnormal hemoglobins resulting from the synthesis of structurally abnormal globin chains with varying degrees of hemoglobin molecular instability
We found that Hb E, β0-thalassemia mutations CD17 (Beta 17, Lys > Stop, HBB:c.52A > T) and CD72 (Beta 72 + A, Phe Ser > Stop, HBB:c.216_217insA), and a deletional α+-thalassemia mutation −α3.7 in association with the Hb Rush variant in various combinations (Table 1)
The anemia of Hb Rush co-inherited with β0-thalassemia tended to be severer than that of Hb Rush coinherited with Hb E, but none of these patients required transfusion or splenectomization. These results showed that Hb Rush concurrent with Hb E or β0-thalassemia led to β-thalassemia intermedia (TI) syndromes with moderate anemia
Summary
Unstable hemoglobins include a large group of abnormal hemoglobins resulting from the synthesis of structurally abnormal globin chains with varying degrees of hemoglobin molecular instability. Some unstable hemoglobins in association with β-thalassemia can result in the presentation of thalassemia intermedia or even thalassemia major [1,2], demonstrating that unstable hemoglobins and thalassemia can modify each other’s clinical phenotypes and cause severe clinical manifestation. 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. 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
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