Mechanical stability of hemoglobin subunits: an abnormality in betaS-subunits of sickle hemoglobin.
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Anemia, Sickle Cell↗
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Hb-M "Hyde Park": a de novo mutation, identified by mass spectrometry and DNA analysis.
BACKGROUND: Structural hemoglobinopathies usually are inherited as autosomic dominant traits; de novo mutations are uncommon. Analytical and preparative procedures for the characterization of an abnormal hemoglobin are complex and time-consuming. Mass spectrometer analysis allows a rapid identification of the amino acid substitution. METHODS AND RESULTS: A cyanotic 7-year-old girl was found to have 16% methemoglobin. Laboratory data showed the presence of an abnormal hemoglobin, which was isolated by collecting the abnormal peak from DEAE and globin chains from CM52. The amino acid substitution was rapidly identified by FAB mass spectroscopic analysis, leading to the recognition of HbM Hyde Park. These data were confirmed by molecular analysis (Southern blot and DNA sequencing). Neither the parents nor a sister showed any abnormality; non-paternity was excluded by blood group serology and HLA typing. CONCLUSIONS: This is a case of HbM Hyde-Park arising as a de novo mutation. FAB mass spectroscopic analysis is a rapid and useful analytical method for identifying aminoacid substitution.
Blotting, Southern↗
Hemoglobin E-Saskatoon and pregnancy: report of two cases.
Hemoglobin E-Saskatoon (beta22-Glu-Lys) is found worldwide but is extremely rarely. Two cases of pregnant women who carried the abnormal hemoglobin and the various problems that arise from it are reported. A discussion of the combinations with other abnormal hemoglobin is also presented.
Adult↗
A diabetic case with hemoglobin J-Meerut and low HbA1C levels.
A diabetic patient with hemoglobin (Hb) J-Meerut and low HbA1C levels is reported. An automatic glycohemoglobin analyzer used for the determination of HbA1C revealed an abnormal peak of the peripheral blood obtained from a Japanese female with diabetes. She showed a lower HbA1C level (3.7%) than expected from her fasting plasma glucose (172 mg/dl). High performance liquid chromatography and isoelectric focusing indicated that her abnormal hemoglobin was Hb J-Meerut [alpha 120(H3)Ala-->Glu] and it accounted for 28.3% of the total hemoglobin. Abnormal hemoglobinemia should be considered when a major discrepancy between the levels of HbA1C and fasting plasma glucose is observed.
Blood Glucose↗
[Multicenter evaluation of thr Abbott glycosylated hemoglobin assay on IMx].
The Abbott IMx glycated hemoglobin assay was evaluated in a multicentre study. This method utilizes boronate affinity chromatography, and ion-capture technology. This assay determines both total glycohemoglobin (% GHb) and percentage of hemoglobin Alc (% HbAlc). The precision of the assay was evaluated: the intra-assay and interassay coefficients of variation were judged to be satisfactory (< 6.5%). We determined the accuracy of the assay by comparison with a reference HPLC assay for 603 specimens; coefficients of correlation were between 0.88 and 0.96. We studied the interference of bilirubin and glucose and found no interference at usual concentrations. The presence of abnormal hemoglobins (HbF and some Hb structural variants HbS, HbC) was not detected with the Abbott IMx assay; however, this assay showed no significant interference from the hemoglobin variants tested for heterozygous hemoglobinopathies (percentage of abnormal hemoglobin < 60%). We also determined normal values for HbAlc with this technology (164 specimens): 4.1 to 6.1%.
Chromatography, Affinity↗
[Hemoglobin A1C determination and hemoglobinopathies: problems and strategies].
The semiological value of hemoglobin A1c (HbA1c) as a retrospective and cumulative marker of glycemic balance in diabetic patients is greatly weakened in case of hemoglobinopathy. The presence of an abnormal hemoglobin raises methodological problems due to the interferences generated in most assay methods, but also alters the normal process of HbA glycation to HbA1c, and often induces a certain level of hemolysis, very variable and impossible to quantify. This paper reviews methodological and semiological problems related to the presence of abnormal hemoglobin species, and proposes a standardized strategy in case of hemoglobinopathies.
Artifacts↗
Identification of Hb C [beta 6(A3)Glu-->Lys] in a Thai male.
The propositus was a 29-year-old Thai male, whose electrophoretic pattern showed Hb A (58%) plus an abnormal hemoglobin (42%) with mobility identical to Hb A2 and Hb E. Protein sequencer analysis and tryptic peptide mapping of the beta chain indicated that the abnormal hemoglobin was Hb C [beta 6(A3)Glu-->Lys], rather than Hb E which is more commonly found in South East Asia. This conclusion was confirmed by direct sequence analysis of the propositus' DNA, which showed AAG as well as GAG at codon 6 of the beta gene, in agreement with heterozygosity for Hb C and Hb A. Furthermore, the beta gene framework (Ava II-, Bam HI+) of the propositus suggested that the beta C gene may have arisen from an independent mutation. Since Hb C and Hb E have the same mutation (Glu-->Lys) in the beta chain, although at different positions, and behave similarly in electrophoresis, cases of Hb C and Hb E may sometimes have been mistakenly identified for each other, based on whichever variant is most prevalent in the particular population.
Adult↗
[Determination of a primary structure of abnormal D-like hemoglobin isolated from a blood donor].
Abnormal hemoglobin with contents 40% was isolated from the blood of a donor. It was purified, its chains were separated, and the defect was found to locate at beta-chain. Abnormal betaT13 peptide was found under the separation of tryptic hydrolysate. Data on its amino acid composition, electrophoretic mobility as well as attempts to determine its N-terminal amino acid and N-terminal sequence made possible to identify the location and the character of the amino acid substitution in the abnormal hemoglobin. The first case of the presence of hemoglobin D Penjab alpha2beta2(121Glu leads to Gln) among the Russian population is described.
Amino Acid Sequence↗
Sickle cell hemoglobinopathies: a protocol for management.
Two cases have been presented: one shows complications when a latent form of sickle cell disease was manifested after orthognathic surgery; the other illustrates a protocol for management of patients with abnormal hemoglobins who are candidates for orthognathic surgery. The protocol includes an initial screening test for all black patients who are hospitalized for elective orthognathic surgery. When the screening test is positive, afollow-up hemoglobin electrophoresis is obtained to identify the specific hemoglobinopathy. Transfusions, when indicated, are given to alter the percentages so that the patient has no greater than 40% abnormal hemoglobin. Precautions are taken during anesthesia and after surgery to ensure that the patient is well oxygenated and is not in a hypothermic state. Serial electrophoreses are performed and transfusions, if indicated, are given during the postoperative and healing phases according to the postoperative status.
Adolescent↗
Hemoglobin Kariya [alpha 40 (C5) Lys leads to Glu]: a new hemoglobin variant with an increased oxygen affinity.
A new abnormal hemoglobin, Hb Kariya [alpha 40 (C5) Lys leads to Glu], with an amino acid substitution at the alpha 1 beta 2 contact was discovered in a young Japanese man. This variant migrated to the anode faster than Hb A, being nearly the same as Hb I in electrophoretic mobility. It amounted to about 6% of the total hemoglobin of the hemolysate. This hemoglobin showed an increased oxygen affinity, decreased heme-heme interaction and a lowered 2,3-DPG effect.
Adult↗
Hemoglobin Gavello - alpha 2 beta 2 47 (CD6) Asp replaced by Gly. A new hemoglobin variant from Polesine (Italy).
During a survey for abnormal hemoglobins in Polesine (a region north of the Po river, where beta-thalassemia is very frequent) a slow moving variant was noted in a 79-yr-old woman living in Gavello, a small town in the province of Rovigo. Structural studies demonstrated a previously undescribed amino acid substitution, beta47 Asp replaced by Gly. This new variant has been named Hb Gavello.
Aged↗
[The unstable hemoglobin disease].
The unstable hemoglobin disease result from the presence of a structurally abnormal hemoglobin variant with substitution or deletion of amino acid in the red cell. Characteristic of the unstable hemoglobin disease is the presence of inclusions of precipitated denatured hemoglobin called Heinz bodies in the red cells. Almost 200 unstable hemoglobins have now been identified. Hundred of these hemoglobins arise hemolysis or abnormal oxygen affinity, and another 100 hemoglobins have no hematological abnormalities but with instability on in vitro test. The inheritance pattern of the unstable hemoglobin is autosomal dominant. The most common causes of instability re amino acid substitutions that disrupt the alpha-helix of globin or alter the steric configuration of the hem pocket by the insertion of polar amino acid in the interior of the hemoglobin molecule, or deletion of amino acid in the helix. The unstable hemoglobins have a greater tendency to be spontaneously oxidized to methemoglobin with subsequent formation of hemichromes and precipitations.
Hemoglobinopathies↗
Hemolytic anemia in children.
This article provides an overview of hemolytic anemia in children. Main focus areas include acquired immune-mediated hemolysis, hemolytic anemia due to hereditary RBC disorders, hereditary hemolytic disorders caused by enzyme abnormalities, and hereditary hemolytic anemia due to hemoglobin abnormalities.
Adolescent↗
Laboratory diagnosis for thalassemia.
Thalassemia is one of the common genetic disorders worldwide. alpha-thalassemia, beta-thalassemia, Hb E and Hb Constant Spring are common mutations found in S E Asia. The diagnoses of thalassemia and some abnormal hemoglobin carriers are very crucial for the identification of a high risk couple who will need further investigation of prenatal diagnosis. Determination of any thalassemic disease such as Hb H disease, homozygous beta-thalassemia, beta-thalassemia/Hb E can be carried out easily from the clinical findings, changes in hematologic data and hemoglobin electrophoresis. But the diagnoses of thalassemia carriers are cumbersome and sometimes need very sophisticated techniques of in vitro protein synthesis and DNA analysis. In this paper we review the laboratory methods and strategies for the diagnosis of thalassemia and abnormal hemoglobin commonly found in S E Asia.
Clinical Laboratory Techniques↗
HbS-oman heterozygote: a new dominant sickle syndrome.
Hemoglobin (Hb) S-Oman has two mutations in the beta-chains. In addition to the classic betaS mutation (beta6 Glu --> Val), it contains a second mutation in the same chain (beta121 Glu --> Lys) identical to that of HbOARAB. We have studied a pedigree of heterozygous carriers of HbS-Oman that segregates into two types of patients: those expressing about 20% HbS-Oman and concomitant -/ thalassemia and those with about 14% of HbS-Oman and concomitant -/- thalassemia. The higher expressors of S-Oman have a sickle cell anemia (SS) clinical syndrome of moderate intensity, while the lower expressors have no clinical syndrome, and are comparable to the solitary case first described in Oman. In addition, the higher expressors exhibit a unique form of irreversibly sickled cell reminiscent of a "yarn and knitting needle" shape, in addition to folded and target cells. The CSAT of S-Oman is identical to that of S-Antilles, another supersickling hemoglobin, whose carriers express the abnormal hemoglobin at 40% to 50%, with a very similar clinical picture to HbS-Oman. Because the level of expression is so different and the clinical picture so similar, and based on the hemolysates CSAT's, we conclude that HbS-Oman produces pathology beyond its sickling tendencies. A clue for this additional pathogenesis is found in the fact that homozygous HbOARAB, which has the same second substitution as S-Oman, has a moderately severe hemolytic anemia; when HbOARAB is combined with HbS, it makes the phenotype of this double heterozygote as severe as SS. Properties of HbS-Oman red blood cells (RBCs) include reticulocytes that are much denser than normal (similar to those of SC and CC disease), a decrease in the Km for Ca2+ needed to activate the Gardos' channel (making this transporter more sensitive to Ca2+), increased association of HbS-Oman with the RBC membrane, the presence of dense cells by isopycnic gradient, the presence of folded cells, and abundant nidus of polymerization under the membrane. Other properties include a clear increase in volume and N-ethylmaleimide-stimulated K:Cl cotransport in RBCs expressing more than 20% HbS-Oman. We conclude that the pathology of heterozygous S-Oman is the product of the sickling properties of the beta6 Val mutation which are enhanced by the second mutation at beta121. In addition, the syndrome is further enhanced by a hemolytic anemia induced by the mutation at beta121. We speculate that this pathology results from the abnormal association of the highly positively charged HbS-Oman (3 charges different from normal hemoglobin) with the RBC membrane.
Adolescent↗
Molecular genetics of human hemoglobin synthesis.
Molecular analysis of normal and abnormal human globin genes and their gene products has recently provided information on the precise genetic events that result in hemoglobinopathies. In the case of structurally abnormal hemoglobins, the following mechanisms can be invoked: single nucleotide base substitutions leading to amino acid replacement or chain termination variants; nucleotide deletions (or additions) leading to deletion and frameshift variants; and nonhomologous crossing over leading to the production of fused globin chains. The molecular basis of the thalassemia syndromes, disorders characterized by absent or decreased synthesis of alpha- or beta-globin chains, is quite heterogeneous. In some cases globin gene deletions have been demonstrated; whereas in others there is probably either a defect in globin gene transcription or a defect in nuclear globin messenger RNA (mRNA) processing, mRNA transport or globin mRNA stability. In one form of beta(0)-thalassemia a nonsense mutation has recently been demonstrated, and other cases are also associated with some as yet undetermined functional abnormality of beta-globin mRNA.
Amino Acid Sequence↗
Hemoglobin Providence. A human hemoglobin variant occurring in two forms in vivo.
Hemoglobin Providence Asn and Hemoglobin Providence Asp are two abnormal hemoglobins which apparently arise from a single genetic change that substitutes asparagine for lysine at position 82 (EF6) in the beta chain of human hemoglobin. The second form appears to be thr result of a partial in vivo deamidation of the asparagine situated at position beta 82. Cellulose acetate and citrate agar electrophoresis of hemolysates from patients with this abnormality shows three bands. Globin chain electrophoresis at acid and alkaline pH shows three beta chains. These three chains correspond to the normal beta A chain and two abnormal beta chains. Sequence analysis indicates that the two abnormal chains differ from beta A at only position beta 82. In the two abnormal chains, the residue which is normally lysine is substituted either by asparagine or by aspartic acid. These substitutions are notable because beta 82 lysine is one of the residues involved in 2,3-diphosphoglycerate binding. Additionally, beta 82 lysine is typically invariant in hemoglobin beta chain sequences. Sequence data on the two forms of Hemoglobin Providence are given in this paper. The functional properties of these two forms are described in the next paper.
Adult↗
Hb Okazaki [beta 93(F8) Cys----Arg], a new hemoglobin variant with increased oxygen affinity and instability.
A new abnormal hemoglobin, Hb Okazaki [beta 93(F9) Cys----Arg], with an amino acid substitution at the tyrosine pocket of the beta chain as well as at the alpha 2 beta 1 contact of the quaternary structure of molecule, was discovered in a Japanese man. This hemoglobin showed increased oxygen affinity and molecular instability.
Amino Acid Sequence↗