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PubMed1990

Beta-thalassemia in Yugoslavia.

This study concerned the evaluation of beta-thalassemia alleles in nearly 50 patients with beta-thalassemia major and in 130 -thalassemia heterozygotes using gene amplification and dot-blot hybridization with synthetic probes. Fourteen different mutations were observed; of these, three (IVS-I-110; IVS-I-6; IVS-I-1) account for some 75% of all beta-thalassemia alleles. Newly discovered variants, i.e. T----C in the initiation codon and AATAAA----AATGAA in the poly A site were observed in a few patients. The poly A mutation with classical beta-thalassemia alleles result in thalassemia intermedia. Hb Lepore is a rather common abnormality and combinations of this variant with beta-thalassemia often result in severe disease; a search for beta-thalassemia mutations among patients affected with this disease should include an analysis to detect this hemoglobin abnormality.

Alleles↗

PubMed1983

Hb Albany-GA or alpha 2(11)(A9)Lys leads to Asn beta 2.

A fast-moving alpha chain abnormal hemoglobin (Hb J) was observed in a black teenager from southern Georgia. Its quantity, i.e. the sum of Hb J and Hb J2, was 23.8%. Its presence did not cause any hematological or clinical abnormalities. Tryptic peptides from a digest of the alpha-J chain were separated by HPLC. Amino acid analysis of these peptides and sequence analysis of the abnormal T-2,3 nonapeptide identified a Lys leads to Asn substitution at position alpha 11(A9).

Adolescent↗

PubMed1990

Tandem mass spectrometry in the clinical analysis of variant hemoglobins.

A combination of mass spectrometric techniques (electrospray mass spectrometry, liquid secondary-ion mass spectrometry (LSIMS), tandem mass spectrometry) has been used for variant hemoglobin detection and characterization. Electrospray mass spectrometry allowed analysis of mixtures of intact globins giving the molecular weights (accuracy 1-2 Da), and information about relative amounts of globins present, simultaneously. Abnormal hemoglobins detected in this way and by other means (screening, clinical symptoms) were fractionated by C-4 reverse phase high-performance liquid chromatography (HPLC), and the separated globin chains (or the mixture of whole precipitated globin) were digested with trypsin. The tryptic peptides were separated by C-18 reverse phase HPLC and analysed by LSIMS to narrow down the mutation site to a single peptide. In some instances, the molecular weight of a variant peptide was sufficient to determine the mutation uniquely. When molecular weight information alone was insufficient to identify the mutation and its site, the peptide was sequenced by tandem mass spectrometry on a 4-sector instrument. In cases where more than one possible mutation site was present in the peptide and the mutation resulted in a change of only 1 Da in the peptide mass, the resolution and mass measurement accuracy of the 4-sector machine were essential in determining the correct sequence. The practical application of the methodologies presented is illustrated by the identification and analysis of Hb G-San Jose, Hb Willamette and D-Iran.

Hemoglobins, Abnormal↗

PubMed1978

[Systematic screening of hemoglobinopathies in blood donors in Guadeloupe (French West Indies)].

We report the results of a systematic survey carried on 8.961 healthy Guadeloupean blood donors, where we looked for hemoglobinopathies. The results are expressed in regard of the race and site of living (urban or rural) of the subjects. Of these 8.961 subjects, aged 18 to 60, 7.75% were sickle cell trait carriers, 2.36% were heterozygous for Hb C and 0,2% had a significant elevation of Hb F. Were also report some less frequent phenotypes : three Hb AD, five Hb SC, one Hb CC, two Hb SF, one Hb CF and one case of isolated Hb, A2 elevation. Two rare hemoglobinopathies are reported: a case of Hb Korle Bu associated with Hb S an a case of Hb N-Baltimore. Our datas regarding race and sex of Hb S and Hb C carriers are evaluated. These results are compared to previous studies carried on healthy blood donors in Guadeloups. Problems related to the detection of hemoglobin abnormalities in a blood transfusion center are reviewed.

Blood Donors↗

PubMed1980

Proportion of hemoglobin G Philadelphia (alpha 268 Asn leads to Lys beta 2) in heterozygotes is determined by alpha-globin gene deletions.

In humans the alpha-globin genes are duplicated and closely linked. Whereas individuals heterozygous for most alpha-chain mutations possess approximately 25% abnormal hemoglobin, heterozygotes for the alpha-chain variant Hb G Philadelphia synthesize either 33% or 50% Hb G. Both variable gene dosage and interaction with alpha-thalassemia have been proposed to explain this observation. To differentiate between these models, we have performed restriction endonuclease mapping and hematological studies on individuals with Hb G from four families. In every case the alpha G locus was carried on an EcoRI or EcoRI + BamHI fragment approximately 4 kilobases shorter than that bearing the two linked alpha A loci of hematologically normal individuals. Bgl II digestion revealed that the alpha G gene is the only alpha locus on the affected chromosome. Erythrocyte indices and alpha/beta synthesis ratios indicated that the alpha G chromosome confers alpha-thalassemia. In addition to the alpha G gene, subjects who synthesized 33% Hb G possessed two alpha A genes on the homologous chromosome and exhibited the mild form of alpha-thalassemia trait ("silent carrier"). Subjects who synthesized 50% Hb G possessed a single alpha A gene trans to the alpha G locus and displayed the more pronounced form of alpha-thalassemia trait. One subject, who synthesized 100% alpha G chains and had Hb G-Hb H disease, was found to have a single nonfunctional alpha gene trans to the alpha G gene. Thus the proportion of Hb G synthesized by heterozygotes is determined by interaction with alpha-globin gene deletions cis and trans to the alpha G locus.

Base Sequence↗

PubMed1981

Heterozygosity and homozygosity for the high oxygen affinity hemoglobin Tarrant or alpha 126 (H9) Asp replaced by Asn in two Mexican families.

Two Mexican families from the State of Jalisco have been studied in which 11 members were carriers of Hb Tarrant. Ten subjects were Hb Tarrant heterozygotes producing about 25% of the abnormal hemoglobin. One 9-year-old boy was homozygous for Hb Tarrant. About 50% of his hemoglobin was of the variant type. The heterozygotes had mild erythrocytosis which was considerably more severe in the homozygote. The average P50 value for blood of the heterozygote was 15.1 mm Hg (controls: 22.5 mm Hg) while this value was decreased to 9 mm Hg in the homozygote. The clinical condition of the homozygote is compatible with a mild chronic tissue hypoxia.

Aspartic Acid↗

PubMed1992

Two new human hemoglobin variants caused by unusual mutational events: Hb Zaïre contains a five residue repetition within the alpha-chain and Hb Duino has two residues substituted in the beta-chain.

With rare exceptions, the more than 600 human hemoglobin variants described are caused by a single point mutation. Other abnormal features, such as unequal crossing-over, frameshift mutagenesis or double mutations in the same polypeptide chain, have seldom been encountered. We report two new variants caused by such rare mutational events. Hb Zaïre [alpha 116(GH4)-His-Leu-Pro-Ala-Glu-117 (GH5)] is the second example in which a short amino acid sequence is inserted within the alpha-chain. This abnormal hemoglobin results from a tandem repetition of 5 amino-acid residues, from sequence 112 through 116, at the end of the GH corner. Hb Duino is an unstable hemoglobin. It presents within the same beta-chain, the association of two rare point mutations; these substitutions are those found in Hb Newcastle [beta 92(F8)His----Pro] and in Hb Camperdown [beta 104(G6)Arg----Ser]. Family studies demonstrated that the Hb Newcastle abnormality was a de novo mutation of a gene already carrying the Hb Camperdown substitution.

Adult↗

PubMed1992

Screening cord blood for hemoglobinopathies and thalassemia by HPLC.

We evaluated the use of an HPLC method for screening hemoglobins in cord blood. We studied the genotype frequencies of the structural hemoglobin variants HbS and HbC and the synthesis variants alpha- and beta(+)-thalassemia in babies born on Curaçao. During three months, 67.2% of all (748) newborns were screened: 122 (24.3%) had an abnormal hemoglobin pattern, of which 53 (43.4%) had a hemoglobinopathy (HbS or HbC), 64 (52.2%) had alpha-thalassemia (HbBarts greater than 0.5%, corresponding to heterozygous or homozygous alpha-thalassemia-2), and 5 (4.1%) had a hemoglobinopathy plus alpha-thalassemia. None of the newborns with heterozygous HbS and HbC had concomitant beta(+)-thalassemia. The population genotype frequency of heterozygous alpha-thalassemia-2 was calculated to be 30.7%. The data are in excellent agreement with those previously established for the adult population and those available from the black population in the United States and Jamaica. Based on the HPLC results, we estimate that 67.1% of newborns with heterozygous alpha-thalassemia-2 remain undetected. A coincidental finding was a relation between demonstrable alpha-thalassemia and short gestation. Because of its superior separating power and high sensitivity for quantifying relatively low percentages of hemoglobins in the presence of HbF0, the HPLC method was preeminently suitable for screening cord-blood samples.

Chromatography, High Pressure Liquid↗

PubMed1987

Hemoglobin Chico [beta 66(E10)Lys----Thr]: a new variant with decreased oxygen affinity.

Hemoglobin Chico was discovered in an asymptomatic 3-year-old boy when a mild anemia was detected by a routine blood count. Affected individuals in three generations are also mildly anemic. The abnormal hemoglobin amounts to about 45% of the total. It separates from Hb A by cellulose acetate electrophoresis at pH 8.5 with a mobility similar to Hb J but does not separate in citrate agar at pH 6.2. Stability in isopropanol is slightly decreased. Its structure differs from the normal by the substitution of a threonyl residue for lysyl residue at position 66(E10) of the beta chain. The P50 of the oxygen equilibrium curve of whole blood at 37 degrees C was 38 torr compared with controls of 27 +/- 2 torr. The P50 binding studies of the isolated Hb Chico revealed a unique right shift of the equilibrium curve with an oxygen binding constant (1/P50) about half of normal. The remaining allosteric properties were essentially normal. This significant decrease in oxygen affinity appears to be due to changes in the heme region which result from the substitution of the normal beta 66 lysyl by the threonyl residue.

Anemia↗

PubMedDate not supplied

Acute lymphoblastic leukemia in a child with hemoglobins S and Q-Iran.

A 13-year-old girl with acute lymphoblastic leukemia is presented. The peripheral smear showed, in addition to lymphoblasts, marked anisocytosis, poikilocytosis, and polychromasia. In vitro sickling test was positive. Hemoglobin electrophoresis at pH 9.0 on starch gel revealed the presence of hemoglobin A, hemoglobin S, and a band with a mobility of hemoglobin A2. Structural analysis revealed the presence of hemoglobin S and an alpha-chain variant, hemoglobin Q-Iran. The patient attained remission with the initial therapy administered but a relapse occurred five months later. Our study indicates the need for detailed investigation of leukemia patients in which abnormal hemoglobins are prevalent.

Child↗

PubMed2003

Hb Trento: an elongated C-terminal beta chain due to a new frameshift mutation [beta144 (-A)].

An elongated C-terminal hemoglobin variant, due to the deletion of nucleotide A in codon 144 (nucleotide 63600 GenBank entry UO1317) was found in a 31-year-old woman from Trento (northeastern Italy). This deletion led to the replacement of lysine at beta144 by a serine residue, the disappearance of the stop codon at position 147, and the presence of 12 additional residues, identical to those observed in Hbs Saveme, Tak and Cranston, which result from a similar mechanism. Hb Trento, amounting to 29% of the total hemoglobin, was unstable and had, as the other variants of this group, an increased oxygen affinity. It led to a mild compensated hemolytic anemia with red cell inclusion bodies. Functional studies of the isolated abnormal hemoglobin were difficult to perform because of autoxidation, precipitation, and formation of hybrids with Hb A.

Adult↗

PubMed2002

Hb Groene Hart: a new Pro-->Ser amino acid substitution at position 119 of the alpha1-globin chain is associated with a mild alpha-thalassemia phenotype.

Alpha-Thalassemia (thal) is generally considered to be an expression defect caused mostly by deletions silencing one or more alpha-globin genes. Although nondeletional alpha-thalassemia is considered rare, in our laboratory we frequently observe alpha-thal phenotypes induced by point mutations. We report a new point mutation generating an abnormal hemoglobin (Hb) associated with a mild alpha-thal phenotype in two members of a Moroccan family, who presented with mild but persistent microcytic hypochromic parameters and a balanced beta/alpha synthetic ratio. All attempts to separate an abnormal native or denatured fraction were unsuccessful using electrophoresis, isoelectrofocusing (IEE), ion exchange and reversed phase high performance liquid chromatography (HPLC), denaturing polyacrylamide gel electrophoresis (PAGE), and electrospray mass spectrometry (ES/MS). The anomalous protein was only predictable by DNA analysis. The mutated gene product, not separable with any of the techniques used, could be a monomer unsuitable for tetramer formation, which is proteolyzed at an early stage. Alternatively, this mutation could perhaps lead to an abnormal splicing. The CCTCT sequence generated by the mutant, not found in the translated region of the gene, but normally present at the end of the IVS-II, could induce a possible exon skipping. This mutant could generate a mild or a critical Hb H disease in combination with one of the common alpha0-thal deletion defects.

Adult↗

PubMed1978

[Hemoglobin anomalies and medico-biological data in 10,000 Africans (author's transl)].

Since 1962, the hemoglobin of all the foundation scholars of the French Cooperation addressed to the C.E.A.B.H. for a medical examination at their arrival in France was systematically studied. The distribution and the incidence of hemoglobin S and hemoglobin C were recorded in fourthy ethnic groups from Africa South of Sahara. Few significant correlations between the frequency of anomalies detected by the medico-biological check-up and the presence of an abnormal hemoglobin were found; AC seems to be less asymptomatic than AS. Some rare hemoglobins were detected.

Adult↗

PubMed1994

Hb Cemenelum [alpha 92 (FG4) Arg-->Trp]: a hemoglobin variant of the alpha 1/beta 2 interface that displays a moderate increase in oxygen affinity.

Hb Cemenelum [alpha 92 (FG4) Arg-->Trp] carries a structural modification at the same position as Hb Chesapeake, a very high oxygen affinity variant. Hb Cemenelum was found in a French diabetic patient with no abnormal hematological features. The purified abnormal hemoglobin, like Hb J Cape Town, another variant of position alpha 92(FG4), displayed only a 1.5- to 2-fold increased oxygen affinity and a reduced cooperativity. This hemoglobin demonstrates that, even for some key residues of the alpha 1/beta 2 interface, the degree at which the functional properties are altered depends upon the specific residue occupying this position.

Amino Acid Sequence↗

PubMed1975

Identification of human hemoglobins by use of isoelectric focusing in gel.

Newly-developed gel isoelectric focusing techniques provide for rapid and correct identification of human hemoblobins. With this technique, we examined samples previously identified by the National Hemoglobinopathy Standardization Laboratory of the Center for Disease Control. A wide variety of both normal and abnormal hemoglobins was included in the 134 different specimens examined. The isoelectric points (pl's) were precisely determined; no discrepancies with results by standard techniques of identification were found. The method is accurate and precise. It is proposed as a powerful adjunct to other laboratory methods suitable for use in a hemoglobinopathy reference laboratory or specialized hematology service laboratory.

Electrophoresis, Polyacrylamide Gel↗

PubMed2005

High incidence of Hb D-Los Angeles [beta121(GH4)Glu-->Gln] in Denizli Province, Aegean region of Turkey.

Denizli Province is located in the inner part of the Aegean region of Turkey and is one of the target areas for premarital screening. Here we report the abnormal hemoglobins (Hbs) observed during a premarital screening program in our region. According to our results, Hb D-Los Angeles [beta1211(GH4)Glu-->Gln (GAA-->CAA] (also known as D-Punjab, D-North Carolina, D-Portugal, Oak Ridge and D-Chicago), is the most frequent abnormal Hb in this region.

Gene Frequency↗

PubMed1991

Hemoglobin Terre Haute arginine beta 106. A posthumous correction to the original structure of hemoglobin Indianapolis.

The initial report of Hb Indianapolis described two affected individuals with the phenotype of severe beta-thalassemia that was dominantly inherited. The structure of this variant could not be deduced by standard techniques because of its extreme instability. Because of this limitation, the structure was ascertained by analysis of the abnormal globin chain, which had been radioactively labeled. These studies strongly suggested that the structure of this variant was cysteine beta 112 to arginine. Subsequent to this report, two additional families with Hb Indianapolis were found. The carriers were minimally affected and the abnormal hemoglobin was only mildly unstable. This major difference in phenotypic expression suggested that further investigation of the original family should be carried out. Unfortunately, both of the original carriers of the variant succumbed to their severe anemia prior to the subsequent reports. However, by the use of the polymerase chain reaction, enough DNA was obtained to sequence the third exon of the beta-globin gene in the original family from the DNA scraped off a 10-year-old bone marrow microscope slide. These studies revealed a substitution of leucine to arginine at position 106 of the beta-globin chain. The polymerase chain reaction results may be consistent with the original protein structural data, if incomplete tryptic cleavage of this arginine residue occurred in the original sample. We have renamed this variant Hb Terre Haute in an attempt to avoid confusion with the Cys beta 112----Arg substitution.

Arginine↗

PubMed1980

The reaction of hemoglobin Zürich with oxygen and carbon monoxide.

The present paper reports a spectroscopic and kinetic study of the reaction with oxygen and carbon monoxide of (a) the abnormal hemoglobin Zürich (beta 63, E7 His leads to Arg), (b) its isolated abnormal chains (beta ZH), and (c) a reconstituted hybrid containing cobalt instead of iron on the normal alpha chains (Co alpha)2-(Fe beta ZH)2. The abnormal beta ZH chains, isolated from hemoglobin Zürich (HbZH) tetramer, display very peculiar spectral properties in the Soret region which were determined, for the oxy and deoxy derivatives, by kinetic difference spectra. The spectral properties of abnormal chains are maintained in the native and reconstituted hybrid tetramer. The rate constants for CO and O2 binding to isolated beta ZH chains were compared with those of the normal alpha and beta chains, It is confirmed that the CO combination rate constant to beta ZH is much higher than that of normal chains, whereas that for O2 is similar for the normal and abnormal chains. The CO binding rate constant for Fe beta ZH chains in the hybrid tetramer is the same as in the native HbZH molecule, i.e. much higher than that of normal chain. The new data are fully consistent with the sequential mechanism for CO binding previously proposed by us; on the other hand, on the basis of the spectral and kinetic results, and contrary to what has been suggested by other authors, a sequential binding of the ligand is excluded in the case of O2.

Carbon Monoxide↗