Molecular characteristics of three hemoglobin variants observed in a Chinese population: Hb Ube-1 [β98 (FG5) Val→Met], Hb�Ube‑2 [α68 (E17) Asn→Asp] and Hb�Ube‑4 [α116 (GH4) Glu→Ala]

Abstract

Abstract. In this study we report three cases of Hb Ube-1, one case of Hb Ube-2 and one case of Hb Ube-4 in mainland China. One case of Hb Ube-1 had the clinical manifestation of hemolytic anemia. Hb Ube-2 and Hb Ube-4 did not appear to be associated with clinical or hematological abnormalities. The variants were detected by Hb electrophoresis during a thalassemia screening. Genomic DNA was extracted from the peripheral blood leukocytes of Hb specimens. α1, α2 and β-globin genes were amplified by polymerase chain reaction (PCR). All variants were confirmed by DNA sequence analysis and the PCR-restriction fragment length polymorphism assay. IntroductionA recent query of the Human Hemoglobin Variant database (HbVar) (http://globin.cse.psu.edu) identified 652 variants of the α-globin chain and 775 variants of the β-globin chain. The majority of these hemoglobin variants do not have any hematological or clinical effects and are often found incidentally, for example during newborn screening or health examination, and are finally identified by DNA sequencing.Hb Ube-1 [β98 (FG5) Val→Met], also known as Hb Koln, was first observed in Cologne, Germany, by Pribilla in 1965. It is often found in Europe and America, and has occasionally been reported in Japan, South Korea and Taiwan (1-3). Hb Ube-1, in which the β98 (FG5) valine residue is replaced by methionine (G→A), is the most frequent unstable hemoglobin. However, it presents very few features that allow its distinction from other unstable hemoglobin variants. Mild anemia, jaundice and persistent excretion of dark urine characterize the clinical manifestations of Hb Ube-1. The relationship between the amino acid substitution (Val→Met) and the instability of this hemoglobin suggests that the valine residue is in contact with the heme in the normal β-chain. The substitution of valine for methionine changes the steric configuration of the β-globin, which either alters the enzymatic reduction of iron or results in an increased conversion of meta-hemoglobin into denatured hemoglobin. When Hb Ube-1 is in the oxygenated conformation, the molecule is saturated with heme groups and is stable. The transition to the deoxygenated state results in the loss of heme groups, the instability of Hb and the precipitation and formation of Heinz bodies, which are cytoplasmic degradation products attached to the cell membrane (4). Heinz bodies induce hemolysis and splenomegaly (5).Hb Ube-2 [α68 (E17) Asn→Asp] was originally observed in a Japanese individual in 1967 (6). To our knowledge, it has only ever been observed in the Japanese and Taiwanese population (7). This Hb variant resulted from an AAC→GAC mutation at codon 68 of the α-globin gene. Hb Ube-2 carriers do not have clinical symptoms or hematological changes, and their oxygen affinity is normal.Hb Ube-4 [α116 (GH4) Glu→Ala (α1)] is an abnormal hemoglobin, that was first observed in a Korean family residing in Japan (8). To the best of our knowledge, all Hb Ube-4 carriers have been found in Korea or Japan (9). This hemoglobin varian...

"A Rare Interactions Between Heterozygous --SEA Deletion and Hb Ube-2 [α68 (E17) Asn →Asp]; First Reported Case from Malaysia"

“…These findings were consistent in all previous liter-atures with Hb variant level ranges from 22-35.2% from either capillary electrophoresis, alkaline gel electrophoresis or HPLC. [2][3][4]6] Interestingly, our case reported as first case of Hb Ube-2 with interaction between -SEA deletion causing mild thalassaemia phenotype. No history of transfusion or any significant organomegaly or chronic haemolytic features.…”

“…As per date, very limited data available in the Volume 51-Issue 4 DOI: 10.26717/BJSTR.2023.51.008128 literature describing this abnormal haemoglobin. Previous literature described three types of Hb Ube namely Ube-1, Ube-2 and Hb Ube-4 in mainland of China [4]. Both Hb Ube-2 and Ube-4 does not have any significant haematological and clinical manifestation in heterozygous.…”

“…This variant has been classified as benign (B) or likely benign variant (LB) [5]. The percentage of the Hb Ube-2 variant reported by [4,3] was 26.16% and 25.1% with normal HbA2 level and the variant moved faster than Hb A in an alkaline gel electrophoresis but slower than Hb H band. These findings were consistent in all previous liter-atures with Hb variant level ranges from 22-35.2% from either capillary electrophoresis, alkaline gel electrophoresis or HPLC.…”

“…In our case, the variant showed higher percentage (45.2%) as expected than usual heterozygous case with the presence of deletional mutation (Figure 1). Three types of Hb Ube described in literature, and the one with significant clinical phenotype is Hb Ube-1[β98 (FG5) Val→ Met] or Hb Köln as described by [4,7]. Hb Köln is one of the commonest unstable haemoglobin variants that cause Heinz bodies formation with significant anaemia.…”