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We describe a new hemoglobin (Hb) variant, found in a 6-year-old Italian male living in Pistoia, Italy. An abnormal pattern compatible with a Hb A2 variant was observed on capillary electrophoresis...

We report a rare mutation, HBA2: c.184A>T on the α2-globin gene, detected in a Chinese proband who presented with Hb H disease and a mild anemia. This frameshift mutation results in a premature ter...

Decades-old findings supporting origin of F cells in adult life from adult-type progenitors and the in vitro and in vivo enhancement of fetal globin under stress conditions have been juxtaposed against recent mechanistic underpinnings. An updated molecular interrogation did not debunk prior conclusions on the origin of F cells. Although fetal globin reactivation by widely diverse approaches in vitro and in response to anemic stresses in vivo is a work in progress, accumulating evidence converges toward an integrated stress response pathway. The newly uncovered developmental regulators of globin gene switching not only have provided answers to the long-awaited quest of transregulation of switching, they are also reaching a clinical threshold. Although the effect of fetal globin silencers has been robustly validated in adult cells, the response of cells at earlier developmental stages has been unclear and inadequately studied.

More than 900 abnormal hemoglobin (Hb) β chain variants have now been characterized. The majority are due to point mutations resulting in a single amino acid substitution within the globin gene involved, with nearly twice as many β chain variants identified compared to α chain variants. Although most of these variants are clinically and hematologically silent, they can interact with different thalassemia mutations, which could sometimes render laboratory diagnostics in a routine setting difficult. In this study, we present a case of coinheritance of Hb City of Hope [β69(E13)Gly→Ser; HBB: c.208G>A] and β-thalassemia (β-thal), that compromises the molecular diagnosis of β-thal trait.

Background and aim of work: Sickle cell disease (SCD) is an inherited disease of the beta globin gene. The βS globin gene haplotypes are Senegal, Benin, Bantu, Cameroon, Arab-Indian and atypical haplotypes. In SCD, stroke is a life-threatening event in both adults and children. In light of paucity of studies on βS globin gene haplotypes in Egypt, we aimed to determine βS globin gene haplotypes in children with SCD and study their impact on stroke risk.Methods: Fifty-two SCD patients were included in the study, they were 26 males and 26 females with age range from 3 to 18 years old. The PCR-RFLP technique was used for the determination of βS globin gene haplotypes. Transcranial Doppler (TCD) was done to identify patients at risk of stroke.Results: Benin/Benin was the most prevalent haplotype detected in 50% followed by Benin/Bantu in 30.8% of studied patients. TCD study showed that 14/52 (26.9%) patients had abnormally high TCD flow velocities (TCD velocities ≥170 cm/s) and thus considered high str...

Hb H disease is generally a moderate form of α-thalassemia (α-thal) that rarely requires regular blood transfusions. In this study, two Chinese families with members carrying transfusion-dependent Hb H disease were investigated for rare mutations on the α-globin genes (HBA1, HBA2). In one family, Hb Zurich-Albisrieden [α59(E8)Gly→Arg; HBA1: c.178G>C] in combination with the Southeast Asian (- -SEA) deletion was the defect responsible for the severe phenotype. In another family, a novel hemoglobin (Hb) variant named Hb Sichuan (HBA1: c.393_394insT), causes α-thal and a severe phenotype when associated with the - -SEA deletion. As these two HBA1 mutations can present as continuous blood transfusion-dependent α-thal, it is important to take this point into account for detecting the carriers, especially in couples in which one partner is already a known α0-thal carrier.

Summary Introduction Mutations in the δ-globin gene are not pathogenically relevant, but co-inheritance of δ-globin variants along with β-globin gene defects can mask the diagnosis of β-thalassaemia trait. Methods Routine haematological parameters were carried out. Molecular analysis of β-globin gene mutations was carried out by CRDB, ARMS and DNA sequencing. δ- globin gene analysis was carried out by DNA sequencing. Results In this case study, we report a β−thalassaemia trait (IVS 1-5GC) (HBB:c.92 + 5GC) with HbA2 of 1% showing the presence of δ-globin gene variant HbA2 St. George CD 81 (CT) (HBD:c.244CT). A similar observation was reported in another unrelated patient who showed near absence of HbA2 level in HPLC. He showed a presence of δ-globin gene mutation HbA2 Saurashtra CD 100(CT) (HBD: c.301CT) and a single 3.7 kb deletion in the α-globin gene. Conclusion In the countries, where β-thalassaemia is prevalent, an awareness and detection of different δ-globin gene mutations is important, as complex interactions between these haemoglobinopathies can lead to the misdiagnosis of β-thalassaemia carriers.

We report a novel mutation on the α2-globin gene, Hb Debao [α31(B12)Arg→Trp; HBA2: c.94A>T] detected in a Chinese family. This mutation gives rise to a previously undescribed hemoglobin (Hb) variant that was undetectable by electrophoretic or chromatographic methods. Hb Debao was associated with an α+-thalassemia (α+-thal) deletion [-α3.7 (rightward)] producing a mild phenotype with significant microcytosis and hypochromia, while the combination of this mutation with an α0-thal deletion (--SEA) resulting in a severe form of Hb H (β4) disease, which is consistent with a thalassemic phenotype associated with the novel mutation.

We report a novel mutation on the α2-globin gene, Hb Nanning (HBA2:c.369_370delinsGA) detected in a Chinese family. This mutation gives rise to a previously undescribed hemoglobin (Hb) variant that was undetectable by various separation techniques. Both carriers of the mutation have mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) values that are below normal, as would be predicted for an α+-thalassemia (α+-thal) patient.

The long-term goal of our research is to understand the genomics underlying clinical expression of β-thalassemia (β-thal) with a particular interest in the developmental regulation of globin gene switching and the pharmacogenomics re-activation of Hb F. Our approach follows two lines of investigation; clinical and experimental, by which observations in patients and families are done followed by experimental genomics. Prospective clinical data were collected over 25 years from patients with homozygous β-thal with different mild or severe mutations, using an innovative clinical severity score that served to quantify minimal response to transfusion and Hb F induction. The data indicated the requirements for transfusion even of mild thalassemia in children and that splenectomy was largely ineffective. Small doses of hydroxyurea (HU) resulted in aggravation of hematological parameters presumably due to medullary inflammation. A small number of critical families with a phenoypic thalassemia variant, or pseudo-thalassemia, due to various degrees of Krüppel-like factor 1 (KLF1) deficiency and various levels of Hb F in adulthood were identified and followed. Extensive experimental genomics confirmed the role of the KLF1 locus both directly and indirectly in regulating γ- to β-globin gene switching within a complex interactome that included FLVCR1 isoforms and that regulated the inter-erythrocytic distribution of the Hb F. Further research is intended to explore the interplay between the loci and the possible effects of new Hb F-inducing agents acting on new pathways in the clinical setting to improve patient outcomes., peer-reviewed

We identified two novel δ-globin gene mutations in two families during routine thalassemia screening. One missense mutation at codon 73 on the δ-globin gene [δ73(E17)Asp→Val, HBD: c.221A>T] which results in a Hb A2 variant homologous to the β-globin gene variant called Hb Mobile [β73(E17)Asp→Val, HBB: c.221A>T] and we have named this variant Hb A2-Henan. The other is a nonsense mutation [δ7(A4)Glu→Stop, HBD: c.22G>T] which gives rise to a stop codon (TAG) at codon 7, resulting in δ0-thalassemia (δ0-thal). The Hb A2 in one individual with homozygous HBD: c.22G>T was absent.

International audience; BACKGROUND Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent beta-thalassemia. After previously establishing that lentiviral transfer of a marked beta-globin (beta(A-T87Q)) gene could substitute for long-term red-cell transfusions in a patient with beta-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent beta-thalassemia. METHODS In two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent beta-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA(T87Q)). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbA(T87Q), transfusion requirements, and average vector copy number. RESULTS At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-beta(0)/beta(0) genotype had stopped receiving red-cell transfusions; the levels of HbA(T87Q) ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a beta(0)/beta(0) genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed. CONCLUSIONS Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe beta-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 ClinicalTrials. gov numbers, NCT01745120 and NCT02151526.)

We report a novel mutation on the α2-globin gene, HBA2: c.184A>T, detected in a Chinese proband. This mutation resulted in a Lys→Term substitution at position 62 of the α2-globin gene, causing a premature termination of translation. This mutation did not cause severe hematological abnormalities in the carriers. From the properties of substituted residues on the α2-globin gene, it is generally expected that this mutation causes unstable and truncated protein, thus this mutation should be detected in couples at-risk for α-thalassemia (α-thal).

There are other types of Hb D due to different point muta-tions in the -globin gene, such as Hb D-Iran (HBB:c.67G>C)and Hb D-Ibadan (HBB:c.263C>A). However, individuals withthese mutations have normal hematologic values and do notsuffer from vaso-occlusive complications, since their red cellsdo not sickle under physiologic conditions.

We report a novel mutation on the α2-globin gene, codon 83 (TG), which was detected in two members of two unrelated families from Khuzestan Province, South Iran, that we named Hb Ahvaz. This mutation was detected by cellulose acetate electrophoresis and characterized by molecular studies. Hb Ahvaz does not seem to be responsible for hematological abnormalities in the carriers, but with α(0)-thalassemia (α(0)-thal) defects, might induce severe clinical symptoms.

We report two new variants of the δ-globin gene: Hb A(2)-Saint-Etienne [δ14(A11)Leu→Pro] and Hb A(2)-Marseille [δ22(B4)Ala→Lys]. The first variant has a low rate of expression, the second results from a double nucleotide mutation on the same codon.

Beta (β) Thalassemia is a common globin gene disorder in India. Although about 65 different mutations are known in the multiethnic populations of India, the group of 9 'core mutations', i.e. IVSI,5 (G > C){HBB:c.925G > C}, 619 base pair deletion(bp del){NG_000007.3:g.71609_72227del619}, FS8/9 (G){HBB:c.27_28insG}, IVSI,1 (G > T) {HBB:c.92G > T}, FS41/42 (-CTTT){HBB:c.124_127del-CTTT}, C15 (G > A){HBB:c.47G > A}, FS16 (-C){HBB:c.51delC}, C30 (G > C){HBB:c.93G > C} and C5 (-CT){HBB:c17_18delCT} cover about 96% of mutations in the carriers. We attempted a multiplex PCR to detect these mutations using ARMS method and strategized it in high risk groups of western India. The system was found reliable, cost effective, fast and most applicable for mutation screening of β Thalassemia in Indian populations.

INTRODUCTION The aim of this review is to study the frequency of common and the occurrence of rare and novel mutations of the delta-globin gene and of Hb Lepore defects that might interfere with thalassemia diagnostics and to report the rationale of HbA2 estimation in the presence of delta- or alpha-gene mutations. METHODS A total of 135 cases suspected to have a delta-globin gene defect collected in a diagnostic center in the USA and in a reference laboratory in the Netherlands were characterized by molecular analysis. RESULTS Hb B2 was found at a frequency of at least 0.5% in the USA and 0.87% in the Netherlands. Known variants such as Hb A2-Babinga, Hb A2-Sphakia, Hb A2-Fitzroy, Hb A2-Flatbush, Hb A2-NYU, Hb A2-Grovetown, HbA2-Yialousa, Hb A2-Indonesia and several delta-thalassemia mutations were found together with 13 new mutations and two new polymorphisms, while Hb Lepores were regularly observed. CONCLUSION HbA2 mutations either structurally stable and visible or undetectable because of a thalassemia effect or instability are clinically asymptomatic but may compromise the diagnosis of beta-thalassemia minor. Stable mutations result in two HbA2 fractions of about half of the expected value. Expression defects are undetectable as a protein fraction but reduce the amount of HbA2 by half.

We report two new point mutations of the α1-globin gene found in a Greek and a Burmese patient, both living in Western Australia. The patients were initially selected for their microcytic hypochromic parameters as belonging to a group suspected for uncommon (deletion) defects. Gap-polymerase chain reaction (gap-PCR) and multiplex ligation-dependent probe amplification (MLPA) technologies were applied, and in those cases not showing deletions, direct sequencing was performed. We have found 1) HBA1:c.86C>T, Hb Nedlands [α28(B9)Ala→Val] which, based on the red cell indices and phenotype prediction scores, is presumed to be clinically silent, and 2) HBA1:c.98T>A, Hb Queens Park [α32(B13)Met→Lys] which seems to be associated with a mild α-thalassemia (α-thal) phenotype. The phenotype/genotype correlation is briefly described.

beta-Thalassemia, originally named Cooley anemia, is an inherited blood disease. Various types of thalassemia are inherited anemias caused by mutations at the globin gene loci on chromosomes 16 and 11, affecting the production of alpha- or beta-globin protein, respectively. The combination of early diagnosis, improvements in monitoring for organ complications, and advances in supportive care have enabled many patients who have severe thalassemia syndromes to live productive, active lives well into adulthood.

We report the identification of two different mutations involving the first nucleotide of intron 1 of the α2-globin gene: IVS-I-1 G→A and G→T. The available data indicated that both mutations reduce the efficiency of proper mRNA splicing, resulting in α+-thalassemia (α+-thal).

The hemoglobin (Hb) lepore-Boston is a beta-globin structural variant, produced in a reduced amount and formed from the fusion of N-terminus delta-(residues 1-87) and C-terminus beta-chains (residues 116-146). This type of fusion protein is quite common in Southern Italy (Campania, Calabria, and Sicily). We report here the hematological and hemoglobin data on 96 unrelated Sicilians with Hb lepore trait. Particularly interesting are the subjects where Hb lepore occurs with Hb S or Sicilian type delta beta-thalassemia. In these individuals, striking features are clinical variability and different hematological pictures. These observations underscore the importance of thalassemia screening in these geographic areas, such as Southern Italy, principally Sicily, where the mutations in globin gene clusters are especially prevalent. Moreover, as from the second half of the last century, owing to high migratory flux from Sicily to Northern Europe, North and South America, and Australia, the Hb lepore, as well as other hemoglobin variants, have become prevalent, making the identification of the heterozygotes a problem of general interest.

We have characterized 14 patients in 10 families with a mild form of homozygous beta thalassemia which has not been previously well defined. As these patients originate from a small area of northern Portugal we propose to call this beta + thalassaemia--Portuguese type. Clinically, the homozygotes range from asymptomatic to thalassaemia intermedia and they are characterized by low levels of HbF, less than 20%, indicating only a mild deficit in beta globin production. Heterozygotes are indistinguishable from those with the more common types of beta thalassaemia as regards red cell morphology, haemoglobin analysis and globin chain synthesis studies. Globin gene mapping excluded the presence of alpha thalassaemia in these patients and demonstrated no abnormalities in the beta-like globin gene cluster. Restriction enzyme site polymorphisms around the beta gene cluster are identical on both chromosomes in all of the homozygotes, confirming their homogeneity.

We report here restriction endonuclease maps of the β-like globin gene cluster for the British form of HPFH and for a case of Gγβ+ HPFH, and also confirm and extend previous reports of the map for the Greek form of HPFH. These results show that all these conditions belong to a group lacking any substantial deletion or rearrangement of DNA sequence in this gene cluster. The absence of any gross disruption of the structure of this region of the genome, together with evidence that the HPFH genotype is either allelic with, or closely linked to, the β-like globin gene cluster, suggests that the responsible lesions are nearer to being purely regulatory in nature than in forms of HPFH due to substantial deletions. Thus these conditions promise to provide less equivocal evidence about the regulation of β-like globin gene expression than has so far been available.

The Hb Gerland [α55(E4)Val→Ala] mutation has been described in the α2-globin gene. We report here the same mutation in the paralogous α1-globin gene. This variant was found in a healthy 18-month-old boy of Chinese origin. Abnormal hemoglobin (Hb) fractions were visible on isoelectric focusing (IEF) and cation exchange high performance liquid chromatography (HPLC), with elution patterns differing from one system to another. Direct sequencing of the α-globin genes revealed a GTT>GCT (Val→Ala) transversion at codon 55 of the α1-globin gene. We propose to name the variant encoded by the α1-globin gene Hb Gerland [A1], and the variant that is encoded by the α2-globin gene Hb Gerland [A2].

Human globin gene therapy is a potential cure for sickle cell disease and beta-thalassemia (Cooley anemia). A clinical trial of this treatment is currently under way in Paris using lentiglobin vectors.

We recently observed a heterozygote for Hb Hekinan in a Taiwanese subject. The molecular lesion of Hb Hekinan is a substitution of G--T at codon 27 of the alpha1-globin gene, which abolishes an HaeIII restriction enzyme site. Hb Hekinan [alpha27(B8)Glu--Asp, GAG--GAC (alpha2)] has not been found in Taiwan. This variant can be detected by high performance liquid chromatography (HPLC) but not by capillary or cellulose electrophoresis.

The total number of hemoglobin (Hb) variants currently included in the globin gene server database is 1626 (November 12 2014), of which 131 are fetal Hb variants. These variants are observed as two different subunits of fetal Hb, (G)γ- and (A)γ-globin chains. Of the 131 documented fetal Hb variants, 73 are (G)γ- and 58 are (A)γ-globin chain variants. Although they are easily detected at birth, as the quantity of γ chains progressively decreases over the first few months of life, they are essentially undetectable after 6 months of age. In this report we discuss the molecular characteristics and diagnostic criteria of a new (A)γ chain variant that was detected during newborn screening and named Hb F-Sykesville MD [(A)γ113(G15)Val → Ile; HBG1: c.340GA].

Although δ-thalassemia (δ-thal) is not categorized as a severe disease, it is essential to know the molecular spectrum of the δ gene mutations frequently occurring in specific areas, particularly if these areas are characterized by a high rate of β-thalassemia (β-thal) such as Oman. This is because coinherited δ-globin gene defects can interfere with the basic diagnosis of a β-thal carrier when this is based upon the measurement of the Hb A2 only. Because of that, we have investigated 33 patients with low Hb A2 levels, collected from different hospitals in Oman. Some cases had a second Hb A2 fraction, while others had only significantly lower Hb A2 levels. Among these patients, 20 did carry a δ-globin gene mutation, the rest were carriers of α thalassemia (α-thal) defects or could be iron depleted or both. In total, eight different known mutations and two novel δ variants were found. The characterization of the δ-globin gene mutation spectrum will improve carrier diagnostics and genetic counseling in the Omani population screened for β-thal.

The genes of the beta globin locus of sheep and goats undergo three developmental switches, from embryonic epsilon to fetal gamma to juvenile beta(C) and from beta(C) to adult beta(A). The juvenile beta(C) gene of adult goats and sheep are strikingly induced by erythropoietin (Epo). To obtain insights on the mechanism of beta(C) induction by Epo, we produced transgenic mice carrying various beta(C) gene constructs and examined the inducibility of the beta(C) gene following administration of high doses of erythropoietin. None of the treatments resulted in reproducible induction of the beta(C) gene by erythropoietin. We conclude that the Epo inducibility elements are not contained in the 4.7 kb (which included 0.88 kb of the beta(C) promoter and 2.3 kb downstream sequence) beta(C) gene we used or that a trans-acting environment specific to the goat and sheep erythroid cell lineage is required for induction of the beta(C) globin gene by erythropoietin.

Two new δ-globin gene mutations have been detected: one leads to a fairly stable Hb A2 variant differing electrophoretically only minimally from normal Hb A2, and the second causes a δ+-thalassemia (thal) phenotype.

We identified and characterized a novel beta-thalassemia (beta-thal) mutation due to a deletion of cytosine at codons 77/78 (-C) [CAC(His) CA- or CTG(Leu)---TG] found in a heterozygous state in four members of a Mexican family. The beta haplotype analysis performed on the family revealed that the frameshift at codons 77/78 (-C) mutation in this family is associated with haplotype V [- + - - - + ] and framework 2. Ten beta-thal alleles with a cytosine deletion are described at the Globin Gene Server, two of which are very near codon 77. The molecular pathology of beta-thal in the Mexican population has been shown to be heterogeneous, because some Mediterranean, Asian, private and rare alleles have been observed, a similar fact as has been observed in populations with a low frequency of beta-thal.

An elevated Hb A2 (α2δ2 level) is a diagnostic marker for heterozygous β-thalassemia (β-thal). Mutations in the δ-globin gene can cause decreased expression of Hb A2, compromising screening for heterozygous β-thal. In this report, we describe a novel missense mutation of the δ-globin [Hb A2-Fengshun or δ121(GH4)Glu→Lys, HBD: c.364G > A] in a Chinese individual who had coinherited a heterozygous β-thal with a normal Hb A2 level.

Fetal hemoglobin (HbF) level and the HbF responses to hydroxyurea (HU) vary among patients with sickle cell disease and are, at least in part, genetically regulated. We hypothesized that siblings with sickle cell disease are likely to share the same parental β-like globin gene clusters with their cis-acting regulatory sequences and therefore, if regulation of this response is linked to the β-globin gene cluster, might have concordant HbF responses to HU. Accordingly, we studied 26 families (30 sib pairings), 20 with sickle cell anemia (three families had three siblings) and 6 families with HbS-β-thalassemia (one family had three siblings, and one family consisted of monozygotic twins), to see if siblings with sickle cell disease had discordant or concordant changes in HbF during HU treatment. Intraclass correlation coefficients (r) showed a high, positive correlation between sibs for HbF levels before and during HU treatment and a concordant change in HbF response from baseline to treatment-associated levels. Changes in mean corpuscular volume (MCV) paralleled HbF levels, while the expected correlations between treatment-associated fall in leukocyte count and increase in MCV were also present. Our results provide additional evidence that some elements that regulate HbF expression are linked to the β-globin gene cluster. Am. J. Hematol. 72:121–126, 2003. © 2003 Wiley-Liss, Inc.

Submitted by Guilherme Lemeszenski (guilherme@nead.unesp.br) on 2013-08-22T18:40:35Z No. of bitstreams: 1 S1516-84842003000300007.pdf: 98127 bytes, checksum: 0fb56fda2526013d5caefa9e67f6dacf (MD5) Made available in DSpace on 2013-08-22T18:40:35Z (GMT). No. of bitstreams: 1 S1516-84842003000300007.pdf: 98127 bytes, checksum: 0fb56fda2526013d5caefa9e67f6dacf (MD5) Previous issue date: 2003-01-01 Made available in DSpace on 2013-09-30T19:26:24Z (GMT). No. of bitstreams: 2 S1516-84842003000300007.pdf: 98127 bytes, checksum: 0fb56fda2526013d5caefa9e67f6dacf (MD5) S1516-84842003000300007.pdf.txt: 35238 bytes, checksum: 2d3127ac963586a2ce65623e3f6d4743 (MD5) Previous issue date: 2003-01-01 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T14:00:37Z No. of bitstreams: 2 S1516-84842003000300007.pdf: 98127 bytes, checksum: 0fb56fda2526013d5caefa9e67f6dacf (MD5) S1516-84842003000300007.pdf.txt: 35238 bytes, checksum: 2d3127ac963586a2ce65623e3f6d4743 (MD5) Made available in DSpace on 2014-05-20T14:00:37Z (GMT). No. of bitstreams: 2 S1516-84842003000300007.pdf: 98127 bytes, checksum: 0fb56fda2526013d5caefa9e67f6dacf (MD5) S1516-84842003000300007.pdf.txt: 35238 bytes, checksum: 2d3127ac963586a2ce65623e3f6d4743 (MD5) Previous issue date: 2003-01-01 A variante de hemoglobina (Hb) D mais comum, Hb D Los Angeles ou D Punjab, é originada de uma transversão GAA->CAA no códon 121 da globina beta; essa mutação resulta na substituição do ácido glutâmico por glutamina na proteína. É a terceira variante de hemoglobina mais freqüente da população brasileira. Como as hemoglobinas D apresentam migração similar à hemoglobina S em pH alcalino, e com a hemoglobina A em pH ácido, são necessários vários testes para o correto diagnóstico. No presente estudo objetivou-se relacionar os diferentes procedimentos laboratoriais de rotina diagnóstica, além da análise molecular, para estabelecer o perfil de Hb D Los Angeles no Brasil. Foram analisados 47 indivíduos da população brasileira com provável Hb D Los Angeles, por vários procedimentos eletroforéticos em diferentes condições de pH, além da cromatografia líquida de alta pressão, e testes moleculares para confirmação da mutação. Foram encontrados quatro tipos de combinações de hemoglobinas: 42 indivíduos portadores de hemoglobina AD Los Angeles, dois indivíduos com doença de Hb S/D Los Angeles, dois indivíduos com Hb D Los Angeles e talassemia beta e um indivíduo com Hb D Los Angeles e Hb Lepore. Os indivíduos heterozigotos para D Los Angeles são assintomáticos, entretanto, em associação com outras variantes e talassemias podem apresentar graus variáveis de manifestações clínicas. Os resultados apresentados enfatizaram a necessidade da associação de várias metodologias para a identificação da Hb D Los Angeles, além de auxiliar na elucidação de combinações raras. The most common Hb D variant, the Hb D-Los Angeles, also know as Hb D-Punjab, originates through a GAA->CAA change at the 121 codon of the beta globin gene; this mutation results in the replacement of glutamic acid for glutamine in the protein. It is the third most common hemoglobin variant in the Brazilian population. This variant has electrophoretic migration in alkaline pHs similar to Hb S and identical migration to hemoglobin A in acidic pHs. Thus, several techniques are necessary for its correct diagnosis. The purpose of this work was to relate the different laboratorial techniques and molecular analyses to determine the profile of Hb D Los Angeles in Brazil. Forty-seven individuals from the Brazilian population with Hb D Los Angeles were studied. Multiple electrophoresis in several experimental conditions were carried out, in addition to high performance liquid chromatography (HPLC) and molecular analysis to confirm this mutation. Four compound heterozygotes were observed: 42 individuals heterozygous Hb AD Los Angeles, two with Hb S/D Los Angeles disease, two individuals with Hb D Los Angeles and beta-thalassemia and one with Hb D Los Angeles and Hb Lepore. The heterozygous hemoglobin D Los Angeles is asymptomatic, even though its association with other variants and thalassemias may present varying degrees of clinical manifestations. The results presented emphasize the significance of the association of different laboratorial techniques for D Los Angeles diagnosis, and help to elucidate rare combinations. Unic Faculdade de Farmácia Laboratório de Hematologia Fundação de Apoio ao Hemosc e Cepon Centro de Hematologia e Hemoterapia de Santa Catarina Laboratório de Hematologia Hemocentro Unesp Instituto de Biociências, Letras e Ciências Exatas Laboratório de Hemoglobinas e Genética das Doenças Hematológicas Unesp Instituto de Biociências, Letras e Ciências Exatas Laboratório de Hemoglobinas e Genética das Doenças Hematológicas

Hb Chartres [α33(B14)Phe→Ser (α2)] was found in a 31‐year‐old female of French origin, presenting with a mild microcytic hypochromic anemia. Her RBC parameters were as follows: Hb 11.4 g/dL, RBC 4....

We report a new mutation on the α2-globin gene causing α(+)-thalassemia (α(+)-thal) with a deletion of a single nucleotide (T) at amino acid residue 43 [HBA2:c.130delT or HBA2:c.131delT]. This frameshift deletion gives rise to a premature termination codon at codon 47.

We report preliminary data for three previously unrecognized hemoglobin (Hb) variants due to mutations of the α1-globin gene, that were initially ascertained by either chromatographic, electrophore...

We report here the spectrum of δ-globin gene mutations found in the UK population. Nine different δ chain variants and two δ-thalassemia (δ-thal) mutations were characterized in a study of 127 alleles in patients with either a low Hb A2 value or a split Hb A2 peak on high performance liquid chromatography (HPLC). The most common δ chain variant was Hb [Formula: see text] (or Hb B2) [δ16(A13)Gly → Arg; HBD: c.49G > C] (77.0%), followed by Hb A2-Yialousa [δ27(B9)Ala → Ser; HBD: c.82G > T] (12.0%), Hb A2-Babinga [δ136(H14)Gly → Asp; HBD: c.410G > A] (3.0%), Hb A2-Troodos [δ116(G18)Arg → Cys; HBD: c.349C > T] (1.0%), Hb A2-Coburg [δ116(G18)Arg → His; HBD: c.350G > A] (2.0%) and Hb A2-Indonesia [δ69(E13)Gly → Arg; HBD: c.208G > C] (1.0%). Three novel variants were identified: Hb A2-Calderdale [codon 2 (CAT > AAT), His → Asn; HBD: c.7C > A], Hb A2-Walsgrave [codon 52 (GAT > CAT), Asp → His; HBD: c.157G > C] and Hb A2-St. George's [codon 81 (CTC > TTC), Leu → Phe; HBD: c.244C > T]. In addition, two known δ-thal mutations were observed: -68 (C > T); HBD: c.-118C > T and codon 4 (ACT > ATT); HBD: c.14C > T. Amplification refractory mutation system (ARMS) primers were developed to provide a simple molecular diagnostic test for the most common variant, Hb [Formula: see text]. Three of the variants had a characteristic HPLC retention time that can be used for a presumptive diagnosis.

We report a novel mutation at alpha66(E15)Leu-->Pro (alpha2) (CTG-->CCG), that we have named Hb Dartmouth for the medical center at which the patients were cared for, in monozygotic twins who also inherited the Southeast Asian alpha-thalassemia-1 deletion. The mother, of Khmer ancestry, is heterozygous for alpha-thalassemia-1. The father, who is of Scottish-Irish ancestry, is a silent carrier of the codon 66 mutation. The twins had severe neonatal anemia requiring transfusion.

Building on the pioneering efforts of Professor Huisman, several different databases of hemoglobin variants have been developed, each with progressively increased capacity for sophisticated queries and prompt updating. These resources are reviewed in the context of a larger plan for providing related resources on hemoglobins, benign and pathological variation in these proteins and the genes that encode them, and the regulation of the globin genes.

Recent advances in the study of globin gene switching in the context of the complete locus have contributed greatly to our understanding of the mechanisms of developmental regulation. It has become clear that the interactions between the distant locus control region and the individual globin genes, as well as the trans-acting factors and physical parameters that affect these interactions, are crucial determinants in the developmental modulation of globin gene expression. This review concentrates on recent advances in the highly studied human beta-globin locus and will compare and contrast data from the human alpha-globin locus as well as the alpha and beta loci from other species where appropriate.

We report the case of a father and daughter who are heterozygous for a duplication of 65 bp within exon 2 of the β-globin gene, resulting in an altered and truncated β-globin chain that is predicted to be non functional. The β-globin gene mutation is in cis with the common Hb A2 ' missense mutation of the δ-globin gene (HBD: c.49GC), resulting in β-thalassemia (β-thal) trait with normal levels of Hb A2. This is the second report of this β(0)-thal mutation, and both families were associated with the Hb A2 ' variant and normal levels of Hb A2. Laboratories should be aware of the rare occurrence of β-thal trait with normal levels of Hb A2.