Unstable hemoglobin Rush [beta 101(G3) Glu>Gln, HBB:c.304G>C] in a Brazilian family with moderate hemolytic anemia

Abstract

Hemoglobin Rush is an unstable variant generated by a mutation of the β-globin gene which causes amino acid replacement Glu>Gln in the central cavity of hemoglobin (G3). Many members of a Brazilian family of Italian descent have hemoglobin Rush. This is the second report in world literature. Clinical and laboratory features were retrieved and gene mutation was characterized. Hemoglobin electrophoresis, gene sequencing, and restriction fragment length polymorphism with Hpy188I were used to characterize it. In 13 affected members, hemoglobin ranged from 9.3 to 13.0 g/dL and reticulocyte count up to 12.8%. The intensity of hemolysis appeared to be linked to increased stress. The mutation was proved to be HBB:c.304G>C, beta 101(G3) Glu>Gln. Heterozygous hemoglobin Rush should be suspected when alkaline electrophoresis shows three bands, whereas isoelectric focusing and acid electrophoresis show only two. Adequate genetic counseling to avoid intermarriage should be provided because homozygous hemoglobin Rush is predicted to be clinically severe.

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

“…However, the migration of the Hb Rush faction is very similar to that of Hb F on these electrophoreses. As shown in our results, Hb Rush is distinguishable from Hb F on gel electrophoresis (Figure 2A), thus potentially confounding diagnosis [4,5]. Our findings revealed the capillary electrophoresis pattern of Hb Rush, which showed clearly separation of Hb Rush from the Hb F fraction (Figure 2B).…”

“…Therefore, our findings do not exclude the possibility that the unstable Hb Rush variant might have arisen more than once in Chinese populations. The Chinese families in this study and the two previously reported families of African and European origins exhibited wide geographical isolation and significant race differences [4,5]. Therefore, we propose that the Hb Rush variant has experienced multiple independent origins worldwide.…”

“…Moreover, our findings suggest that molecular genetics methods are necessary for accurate screening and diagnosis of Hb Rush, as other abnormal hemoglobin variants could occur at β101 codon as well [13,21]. An Hpy188I restriction enzyme site is involved in the nucleotide substitution of Hb Rush, and a PCR-RFLP protocol may be used to detect the variant [5]. The one-tube tetra-primer ARMS protocol we developed here have been proven as a rapid, cost-effective and accurate approach for screening of the Hb Rush variant.…”

“…Unstable Hb Rush variant is a rare hemoglobin disorder previously described in only two unrelated families [4,5], and knowledge of its genotype-to-phenotype relationship is limited and unrecognized. The present study found that the most of Hb Rush simple heterozygote were asymptomatic, yet moderate anemia (HGB 85 g/L) was observed in one patient (subject P3 in Table 1), suggesting that the clinical presentation of a simple heterozygous Hb Rush maybe heterogeneous.…”

“…Unstable hemoglobin (Hb) Rush [Beta 101(G3) Glu > Gln, HBB:c.304G > C] is one of the early identified hemoglobin variants has been described to be responsible for mild hemolytic anemia in an African-American family and a Brazilian family of Italian descent [4,5]. As only a few Hb Rush simple heterozygotes have been reported in the two isolated families, many characteristics about its clinical features still remain unclear.…”