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PubMed1991

The linkage of Hb Valletta [alpha 2 beta 287(f3)Thr----Pro] and Hb F-Malta-I [alpha 2G gamma 2117(G19)His----Arg] in the Maltese population.

We have identified a new stable abnormal hemoglobin called Hb Valletta, which is characterized by a Thr----Pro substitution at position 87 of the beta chain. This mutation was found to be linked to that of the gamma chain variant Hb F-Malta-I with a His----Arg mutation at position 117 of the G gamma chain. Both variants were detected in the blood samples of 34 Maltese and two Italian newborn babies with isoelectrofocusing and reversed phase high performance liquid chromatography. Similar analyses of cord blood from 388 additional Maltese newborns failed to identify either one of these two variants. Additional analyses of 353 Maltese adults (including 39 beta-thalassemia heterozygotes) resulted in the detection of two adult Hb Valletta heterozygotes. Dot-blot hybridization analyses of amplified DNA with a probe specific for the G gamma-F-Malta-I variant showed that both also carried that mutation. These results show close linkage of the mutant forms of the G gamma- and beta-globin genes, 27-28 kb apart, and a failure to identify chromosomes with either the Hb F-Malta-I mutation alone or with the Hb Valletta mutation alone, indicating a low recombination frequency.

Adult↗

PubMed2001

Hemoglobinopathy York [beta146 (HC3) His==>Pro]: first report of a family history.

The rare hemoglobinopathies with abnormal oxygen binding are usually characterized by erythropoietin-mediated erythrocytosis. Bare et al. first described a hemoglobinopathy with mild erythrocytosis in a 22-year-old Caucasian woman in 1976. These authors called the abnormal hemoglobin Hb York. Hb York is characterized by a mutation at the beta146 position that changes histidine into proline. A second case of Hb York was observed by Kosugi et al. in 1983. To the best of our knowledge, no further cases have been reported. We have encountered a new case of Hb York, which was detected by agar gel electrophoresis at pH 6.0. Analysis of DNA sequences revealed a CAC-->CCC mutation in codon 146. The proportion of Hb York was approximately 50%. Analysis of oxygen transport function showed a leftward shift of the sigmoidal O2-dissociation curve. P50 was reduced to 15.5 mmHg. Investigation of family members revealed Hb York in the patient's sister, two daughters and a grandson. In retrospect, the mother of the patient may also have been affected. The mode of inheritance is autosomal dominant.

Aged↗

PubMedDate not supplied

Rare thalassemic syndrome caused by interaction of Hb Questembert (alpha1 codon 131, TCT>CCT, Ser>Pro) with an alpha-thalassemia-2 deletion: implications for diagnosis and management.

Abnormal globin chain biosynthesis may result in deficient quantity (thalassemia) or structural variation (abnormal hemoglobins) and traditionally, they represent two phenotypically distinct groups of disorders. However, the phenotypic expression of unstable hemoglobin variants often combine features of thalassemia together with variable peripheral hemolysis. To achieve definitive diagnosis in a child presenting with hemolytic anemia along with features associated with thalassemia intermedia, we evaluated clinical, hematological, biochemical, globin biosynthetic and molecular data. Definitive diagnosis was achieved by DNA analysis which characterized the proband to be a compound heterozygote for a common alpha-thalassemia-2 deletion (3.7 kb) and Hb Questembert (alpha131[H14] Ser>Pro) caused by a C>T mutation in codon 131 of the alpha1 globin gene in trans. The phenotype of thalassemia intermedia with marked dyserythropoiesis, found in patients inheriting alpha-thalassemia mutations along with unstable alpha-globin variants (i.e., alpha-thalassemic hemoglobinopathies), represents a distinct type of thalassemic syndrome. The proband in this study additionally had variable peripheral hemolysis, presumably related to characteristics of the unstable Hb Questembert. There is minimal experience for the management of such atypical cases and this case illustrates that it is probably insufficient to monitor clinical status in patients with such hemoglobinopathies based only on the levels of hemoglobin.

Child, Preschool↗

PubMed2006

Hb F-Emirates [Ggamma59(E3)Lys --> Glu] observed in a family of Sardinian ancestry and characterized by DNA sequencing.

Hb F-Emirates [Ggamma59(E3)Lys --> Glu] was first described in a newborn from the United Arab Emirates. Here we describe the occurrence of this variant in a family of Sardinian ancestry. Direct DNA sequencing analysis of the selectively amplified Ggamma gene shows that the AAA --> GAA transition, corresponding to a Lys --> Glu substitution, is responsible for this abnormal hemoglobin (Hb). Our observation indicates a multiple origin of the mutation. In order to facilitate future studies at the level of population genetics, the structure of the entire Ggamma gene that carries the mutation was assessed and compared with that of normal Ggamma genes.

Alkadienes↗

PubMed2001

Hb Sitia [beta128(H6)Ala-->Val]: an unstable variant with a substitution in the alpha1beta1 interface.

Hb Sitia [beta128(H6)Ala-->Val] was found in a Greek female with slightly reduced red blood cell indices. The abnormal hemoglobin was indistinguishable from Hb A by electrophoresis but eluted after Hb A on cation exchange high performance liquid chromatography. DNA sequence analysis revealed a GCT-->GTT mutation at codon 128, which is predicted to encode an Ala-->Val substitution. This was confirmed by mass spectrometry analyses of the beta-globin chain. Since alanine at beta128(H6) interacts with several amino acids of the alpha1beta1 contact, its replacement by a larger residue results in a mild instability of the molecule and slight modifications of the oxygen binding properties.

Adult↗

PubMed2002

Molecular characterization of Hb D-Punjab [beta121(GH4)Glu-->Gln] in Thailand.

We describe the hematological and DNA characterization of Hb D-Punjab [beta121(GH4)Glu-->Gln] in Thailand. Nine patients from five unrelated families were studied; four patients were simple carriers of Hb D-Punjab, two were compound heterozygotes for Hb D-Punjab/beta+-thalassemia; another two patients were double heterozygotes for Hb D-Punjab and alpha-thalassemia-2, and one patient was a compound heterozygote for Hb D-Punjab and Hb E [beta26(B8)Glu-->Lys]. Typical thalassemic indices with hypochromic microcytosis were observed in compound Hb D-Punjab/ beta+-thalassemia and Hb D-Punjab/Hb E but normal hematological profiles were observed in the remaining cases. DNA sequencing of the beta-globin gene identified the GAA-->CAA substitution at codon 121 causing Hb D-Punjab in all cases, and the -28 (A-->G) mutation for the beta+-thalassemia alleles. beta-Globin gene haplotype analysis demonstrated, for the first time, that all these Asian beta(D-Punjab) globin genes were associated with haplotype [-++-+++], previously undescribed in other populations. The finding of Hb D-Punjab in Thailand is compatible either with an independent origin of this abnormal hemoglobin or a spread of the Hb D-Punjab gene with a single origin among Asians.

DNA Mutational Analysis↗

PubMed2004

Study on molecular epidemiology of the alpha-thalassemias in Liuzhou City, Guangxi Autonomous Region, China.

Guangxi is one of the provinces of Southern China with the highest incidence of alpha-thalassemia (thal). Liuzhou is the second biggest city in Guangxi. To find out the incidence of the various alpha-thal genotypes, and their distribution in the Liuzhou area, an F820 Blood Cell Analysis System was used to measure the parameters of red blood cells. A SPIFE Rapid Auto-Electrophoresis System was used to analyze the normal and abnormal hemoglobins (Hbs). Multiplex polymerase chain reaction (mPCR) was used to detect the alpha-globin genotypes. Thirty-two (2.05%) out of 7805 young couples undergoing pre-marriage counseling, were diagnosed as having an Hb H (beta4) disease. The study of 1228 cord blood samples revealed 138 newborn children carrying an alpha-thal determinant with nine different genotypes, thus making the total incidence of alpha-thal 11.24%. Among 185 cases of Hb H, 119 (64.1%) were confirmed as being deletional, and 66 cases (35.7%) nondeletional types. The severity of the Hb H diseases could be classified in the following order: alphaCSalpha/--SEA (alphaConstant (Spring)alpha/--Southeast Asia); alpha(-4.2)/--SEA; alpha(-3.7)/--SEA. Ten cases of alpha-thal determinants were found in combination with beta-thal. The mPCR technique can detect all kinds of combinations of the three common large deletions (--SEA, alpha(-4.2) and alpha(-3.7)) accurately and conveniently.

China↗

PubMed1979

Phenotyping of eight erythrocytic enzymes in one acrylamide gel.

A procedure has been developed to phenotype eight erythrocytic enzymes, phosphoglucomutase (PGM1), adenylate kinase (AK), 6-phosphogluconate dehydrogenase (6PGD), adenosine deaminase (ADA), glyoxalase (GLO), esterase-D (EsD), acid phosphatase (AcP), and glutamic pyruvate transaminase (GPT) in one acrylamide gel and also to detect the presence of common abnormal hemoglobins. The agar overlay technic has been eliminated. This simplified procedure renders the phenotyping of erythrocytic enzymes practical in paternity testing.

Acid Phosphatase↗

PubMed2004

Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies.

Abnormalities of hemoglobin synthesis are usually inherited but may also arise as a secondary manifestation of another disease, most commonly hematologic neoplasia. Acquired hemoglobin disorders can be seen in any population and are not restricted to areas of the world with high incidences of inherited hemoglobinopathies. In fact, the acquired hemoglobinopathies may be more readily recognized where inherited hemoglobin abnormalities are rare and less likely to cause diagnostic confusion. Acquired alpha-thalassemia is the best characterized of the acquired red blood cell disorders in patients with hematologic malignancy, and it is almost always associated with a myelodysplastic syndrome (MDS). At least 2 molecular mechanisms for acquired alpha-thalassemia are now recognized: acquired deletion of the alpha-globin gene cluster limited to the neoplastic clone and, more commonly, inactivating somatic mutations of the trans-acting chromatin-associated factor ATRX, which cause dramatic down-regulation of alpha-globin gene expression. Here we review the clinical, hematologic, and molecular genetic features of alpha-thalassemia arising in a clonal myeloid disorder, and we discuss howATRX might affect gene expression in normal and abnormal hematopoiesis through epigenetic mechanisms.

Hematologic Neoplasms↗

PubMed1995

Hb Gunma (beta Gunma) with pulmonary embolism.

A 67-year-old woman with pulmonary embolism was suspected to have beta-thalassemia based on microcytosis, hemolysis and a negative red cell stability test. The DNA sequencing analysis of beta-globin gene, however, revealed the deletion of three nucleotides within codon 127-128, leading to substitution of glutamine and alanine residues at 127 and 128 by proline, namely Hb Gunma. This mutant is characterized by the fact that no abnormal hemoglobin is detected in the circulating blood, and is classified as a thalassemic hemoglobinopathy. The present case showed a relatively hemolytic manifestation.

Aged↗

PubMed1982

Hb Belfast (beta 15 Trp replaced by Arg) in an Italian family.

An uncommon abnormal hemoglobin, Hb Belfast (beta 15 Trp replaced by Arg) was discovered in a patient of Italian origin. The patient was a 42-year-old man who developed two episodes of jaundice after a prolonged administration of an antituberculous drugs. Family studies revealed that several members were asymptomatic carriers of Hb Belfast.

Adult↗

PubMed1983

Oxygen equilibrium studies of Hb Willamette alpha 2 beta (2)51(D2)Pro leads to Arg.

The homotropic and heterotropic effects of isolated Hb Willamette were studied using an automatic recording oxygen equilibrium analyzer. The results indicate that Hb Willamette displays normal intrinsic oxygen binding in the stripped condition. An apparent decrease of the Bohr effect is explained by the decrease of allosteric effects in this abnormal hemoglobin. Furthermore, the lack of clinical manifestations in the original patient is consistent with the red cell oxygen equilibrium studies.

Chlorides↗

PubMed1985

Hb Aztec or alpha 2 76 (EF5) Met----Thr beta 2 detection of a silent mutant by high performance liquid chromatography.

High performance liquid chromatography has detected 14 abnormal hematological states in 600 randomly selected samples of blood. Two of these are silent mutations which are not apparent from chromatographic or electrophoretic examination. One of these has the substitution alpha 76 (EF5) Met----Thr and has been named Hb Aztec. The variant was first detected in a 9-day-old baby girl who had inherited it from her mother. This abnormal hemoglobin has no obviously deleterious effect on hematological status or health.

Adolescent↗

PubMed1989

Thermal stability and cross-linking of Hb New York [beta 113(G15)Val----Glu].

Hb New York [beta 113(G15)Val----Glu] has been cross-linked with bis (3,5-dibromosalicyl) fumarate, a reagent known to cross-link Lys 82 beta 1 and Lys 82 beta 2. Thermal denaturations of met Hb New York and its derivative have been compared to those of the corresponding Hb A samples. The structural transitions, observed as absorbance changes at 418 nm, were at 40.2 degrees C for Hb New York, 42.2 degrees C for Hb A, 53.7 degrees C for cross-linked Hb New York, and 56.2 degrees C for cross-linked Hb A. Transitions observed at 280 nm were approximately 2 degrees C higher. Thus, a single inter-subunit cross-link can stabilize an abnormal hemoglobin. A model of Hb New York in which Glu beta 113 forms a salt bridge to His beta 117 can explain the small changes in both the stability and the electrophoretic mobility of this protein.

Aspirin↗

PubMed1990

Beta-thalassemia in Turkey.

A review is presented of the various beta-thalassemia alleles observed in nearly 191 patients with beta-thalassemia major and their 182 heterozygous relatives. Determination was by gene amplification and dot-blot hybridization with synthetic probes, specific for 27 different mutations. Eighteen mutations have been observed; six of these account for nearly 83% of all thalassemia abnormalities. A new mutation, i.e. a G----C mutation at the acceptor splice site of IVS-I, was found in one teenager who was homozygous for this disease. The high consanguinity among the families was considered the main reason for the high number of patients with a homozygosity for the IVS-I-110 (G----A) mutation. Combinations of different mutations were present in many patients; some were mildly affected because of the specific mutation present on one chromosome. Combinations of classical beta-thalassemia and an abnormal hemoglobin mainly concerned Hb S. Hbs Knossos and Lepore were rare occurrences. A comparison of hematological data for adults with heterozygosities for some of the common alleles confirmed the low Hb A2 values in IVS-I-6 (T----C) heterozygotes and the high Hb F values for codon 8 (-AA), IVS-II-1 (G----A), and IVS-I-1 (G----A) heterozygotes.

Adolescent↗

PubMed1993

Hb Shelby [beta 131(H9)Gln-->Lys] in association with Hb S [beta 6(A3)Glu-->Val]: characterization, stability, and effects on Hb S polymerization.

When first tested for abnormal hemoglobins, a 2-year-old boy, appeared to have Hb F, Hb S and Hb A2. Confirmatory testing revealed a beta chain variant inherited from his father and beta S from his mother. Analysis of tryptic peptides in conjunction with automated DNA sequence analysis showed that the variant hemoglobin was Hb Shelby [beta 131(H9)Gln-->Lys (CAG-->AAG)]. Heat and mechanical stabilities of various liganded Hb Shelby tetramers were compared to those of Hb A and Hb S. Oxy-Hb Shelby precipitated more readily than oxy-Hb A, but was much more stable than oxy-Hb S during mechanical agitation. In contrast, oxy-Hb Shelby was much less stable than oxy-Hb A and oxy-Hb S following heat treatment. Met-Hb Shelby was most unstable compared to other liganded forms of Hb Shelby, while deoxy- and carbonmonoxy-forms of Hb Shelby showed similar heat-induced precipitation rates. These data indicate that heat instability of Hb Shelby is accompanied by heme oxidation, and that denaturation by mechanical agitation occurs in the absence of heme oxidation. Hb Shelby, like Hb A, can form hybrids with Hb S which participate in polymer formation in vitro. However, Hb S/Hb Shelby hybrids copolymerized with Hb S less than A/S hybrids. Since the patient's MCHC value is normal, this finding coupled with the elevated Hb A2 and Hb F levels, both of which are known to inhibit polymerization of Hb S, may contribute to the patient's mild clinical presentation.

Base Sequence↗

PubMed1993

Hb Sinai-Baltimore or alpha 2 beta (2)18(A15)Val->Gly, a silent, mildly unstable beta chain variant detected by isoelectrofocusing and high performance liquid chromatography.

Isoelectrofocusing and high performance liquid chromatographic methods were used to study an abnormal hemoglobin present in a Black male infant and his mother. The variant, named Hb Sinai-Baltimore, focused slightly behind Hb A and separated incompletely from Hb A by cation exchange high performance liquid chromatography, while the separation of the beta A and beta X chains by reversed phase high performance liquid chromatography was complete. The variant was identified through an analysis of peptides in a tryptic digest of the isolated beta X chain and by sequencing of amplified DNA which included the beta-globin gene. The Val->Gly replacement at position beta 18 (codon 18; GTG->GGG) or at the last position of the A helix decreases the stability of the variant without affecting the hematological parameters of its carrier. The propositus was a compound heterozygote for Hb Sinai-Baltimore and Hb S; the relative quantities of the two variant chains were somewhat different from those of the beta X and beta A chains in the mother with the simple Hb Sinai-Baltimore heterozygosity. An uncertainty about the alpha-globin gene status in the child prevented a further evaluation of these differences.

Chromatography, High Pressure Liquid↗

PubMed1997

Multivariant confirmation of sickle cell disease using a non-radioactive minisequencing reaction.

A non-radioactive solid-phase minisequencing method for confirmation of abnormal hemoglobin variants causing sickle cell disease has been developed. In this method amplified 5'-biotinylated target sequences containing normal and mutation sites are immobilized onto streptavidin-coated microplates. Detection primers corresponding to target sequences are annealed immediately adjacent to the mutation site and single-step, hapten-labeled nucleotide primer extension reactions are performed. The incorporation of the labeled nucleotide is detected through immunological reaction with an enzyme-labeled anti-hapten conjugate and a substrate. The method enables confirmation of mutations of the beta-globin gene variants (Hbs S, C, E D-Punjab, O-Arab) and the alpha-globin gene variant (Hb G-Philadelphia). The test was evaluated using characterized dried blood spot specimens (n = 100) The advantages of the procedure are easy performance and objectiveness. The non-radioactive minisequencing assay will prove helpful for genotyping in neonatal screening for hemoglobinopathies and in prenatal and pre-implantational diagnostics.

Anemia, Sickle Cell↗