Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:HbS-oman heterozygote: a new dominant sickle syndrome. 983 44

The unstable Hb Khartoum with a Pro-->Arg replacement at position beta124 was identified by isoelectrofocusing, high performance liquid chromatography, and peptide mapping in a mother and two male children of a Sudanese family. All three were heterozygous for the abnormal hemoglobin; the father and a third male child did not carry the mutation. The mother was also homozygous for two putative gamma+-thalassemia point mutations, one affecting both Agamma and Ggamma genes at IVS-II-115 (A-->G), and one affecting the Ggamma gene at the 3' untranslated region (-A) at position -6 from the polyadenylation site. The father had normal gamma genes. All three children were heterozygous for both the gamma+-thalassemia mutations. The two older children, who were compound heterozygotes for Hb Khartoum/gamma+-thalassemia, presented at birth with severe neonatal jaundice which necessitated exchange blood transfusions. Other causes of neonatal jaundice were excluded. The third male child, who did not carry the Hb Khartoum anomaly but was heterozygous for gamma+-thalassemia, did not develop neonatal jaundice. It is concluded that the instability of Hb Khartoum in combination with gamma+-thalassemia is responsible for neonatal hemolytic anemia in this family.
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PMID:The association of Hb Khartoum [beta124(H2)Pro-->Arg] with gamma+-thalassemia is responsible for hemolytic disease in the newborn of a Sudanese family. 1008 84

A new unstable alpha-globin chain associated with alpha-thalassemia phenotype has been found in a Spanish patient. Molecular analysis of the alpha-globin gene complex using PCR and non-radioactive single-strand conformation analysis, allowed to identify a new mutation in the second exon of the alpha-globin gene. Direct sequencing of the abnormal fragment revealed a 3 bp deletion, which led to the loss of a single codon corresponding to a Lys (K) residue at position 60 or 61 DK60 or DK61. Theoretical structural analysis, performed by computational methods, indicated that the loss of an amino acid residue at this position disturbed the contact region between the B and E-helices, affecting the overall stability of the molecule. Therefore, the DK60 and DK61 results in a structurally abnormal alpha-globin chain, not previously described, named Hb Clinic, which leads to the alpha-thalassemia phenotype in the heterozygote patient. No abnormal hemoglobin was detected by standard electrophoretic procedures, suggesting that this alpha-globin chain variant is so unstable that it may be catabolized immediately after its synthesis. This mutation was confirmed by PCR using an allele specific primer.
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PMID:alpha-Thalassaemia due to a single codon deletion in the alpha1-globin gene. Computational structural analysis of the new alpha-chain variant. Mutations in brief no. 132. Online. 1020 81

Our previous studies have shown that iron is released in a free (desferrioxamine-chelatable) form when erythrocytes undergo oxidative stress (incubation with oxidizing agents or aerobic incubation in buffer for 24-60 h (a model of rapid in vitro ageing)). The release is accompanied by oxidative alterations of membrane proteins as well as by the appearance of senescent antigen, a signal for termination of old erythrocytes. In hemolytic anemias by hereditary hemoglobin alterations an accelerated removal of erythrocytes occurs. An increased susceptibility to oxidative damage has been reported in beta-thalassemic erythrocytes. Therefore we have investigated whether an increased iron level and an increased susceptibility to iron release could be observed in the erythrocytes from patients with beta-thalassemia. Erythrocytes from subjects with thalassemia intermedia showed an extremely higher content (0 time value) of free iron and methemoglobin as compared to controls. An increase, although non-statistically-significant, was seen in erythrocytes from subjects with thalassemia major. Upon aerobic incubation for 24 h the release of iron in beta-thalassemic erythrocytes was by far greater than in controls, with the exception of thalassemia minor. When the individual values for free iron content (0 time) seen in thalassemia major and intermedia were plotted against the corresponding values for HbF, a positive correlation (P < 0.001) was observed. Also, a positive correlation (P < 0.01) was seen between the values for free iron release (24 h incubation) and the values for HbF. These results suggest that the presence of HbF is a condition favourable to iron release. Since in beta-thalassemia the persistance of HbF is related to the lack or deficiency of beta chains and therefore to the excess of alpha chains, the observed correlation between free iron and HbF, is consistent with the hypothesis by others that excess of alpha chains represents a prooxidant factor.
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PMID:Iron release in erythrocytes from patients with beta-thalassemia. 1034 33

Thalassemia is one of the most common single gene disorders. The geographic distribution of thalassemia and abnormal hemoglobin has been known for many years. A worldwide significant spread of these abnormal genes, especially from Southeast Asia, occurred in the last two decades. This has resulted in a dramatic increase of Hb E disorders and various Southeast Asian thalassemia genotypes, which means that requests for hemoglobinopathy investigations are likely to increase in many laboratories worldwide. Hemoglobinopathy screening and diagnosis may need to be undertaken antenatally, neonatally and in certain hematological situations. The introduction of automation for hemoglobinopathy screening, including the automated cell counting and HPLC system, is an important advance in technology for hematology laboratories. The instruments need to be calibrated and standardized to get an accurate data for interpretation. Internal and external control samples are also needed. Combination of test results is usually required to achieve a proper diagnosis, which in turn, provide a self-check for each laboratory test.
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PMID:Standardization on laboratory diagnosis of thalassemia and abnormal hemoglobin. 1092 67

Hemoglobin (Hb) Bart's is present in the red blood cells of millions of people worldwide who suffer from alpha-thalassemia. alpha-Thalassemia is a disease in which there is a deletion of one or more of the four alpha-chain genes, and excess gamma and beta chains spontaneously form homotetramers. The gamma(4) homotetrameric protein known as Hb Bart's is a stable species that exhibits neither a Bohr effect nor heme-heme cooperativity. Although Hb Bart's has a higher O(2) affinity than either adult (alpha(2)beta(2)) or fetal (alpha(2)gamma(2)) Hbs, it has a lower affinity for O(2) than HbH (beta(4)). To better understand the association and ligand binding properties of the gamma(4) tetramer, we have solved the structure of Hb Bart's in two different oxidation and ligation states. The crystal structure of ferrous carbonmonoxy (CO) Hb Bart's was determined by molecular replacement and refined at 1.7 A resolution (R = 21.1%, R(free) = 24.4%), and that of ferric azide (N(3)(-)) Hb Bart's was similarly determined at 1.86 A resolution (R = 18.4%, R(free) = 22.0%). In the carbonmonoxy-Hb structure, the CO ligand is bound at an angle of 140 degrees, and with an unusually long Fe-C bond of 2.25 A. This geometry is attributed to repulsion from the distal His63 at the low pH of crystallization (4.5). In contrast, azide is bound to the oxidized heme iron in the methemoglobin crystals at an angle of 112 degrees, in a perfect orientation to accept a hydrogen bond from His63. Compared to the three known quaternary structures of human Hb (T, R, and R2), both structures most closely resemble the R state. Comparisons with the structures of adult Hb and HbH explain the association and dissociation behaviour of Hb homotetramers relative to the heterotetrameric Hbs.
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PMID:Oligomerization and ligand binding in a homotetrameric hemoglobin: two high-resolution crystal structures of hemoglobin Bart's (gamma(4)), a marker for alpha-thalassemia. 1151 64

A 30-year-old female who is homozygous for a Hb E-like abnormal hemoglobin and her immediate relatives were studied. Clinical examination of the proband revealed no abnormality. Routine hematological analysis showed that her hemoglobin level was 12 g/dL, MCV 82 fL, MCH 28 pg, RDW 15%. DNA sequence analysis indicated the presence of a G-->A substitution at codon 22 corresponding to an abnormal hemoglobin, namely Hb E-Saskatoon [beta22(B4)Glu-->Lys (GAA-->AAA)]. Absence of any abnormalities in clinical and routine hematological investigations of the homozygous patient indicated that the phenotypical expression of the Hb E-Saskatoon is very mild. Using a reverse transcription-polymerase chain reaction technique, the alpha/beta and betaX/betaA-mRNA (X = Hb E-Saskatoon) ratios were determined. Normal alpha/beta and betaX/betaA-mRNA ratios were found in the homozygous patient and in all heterozygotes, indicating that the respective mutation did not alter the stability of the mRNA. FokI restriction enzyme analysis of the polymerase chain reaction products obtained from the genomic DNA and/or beta-globin mRNA made it possible for rapid diagnosis of Hb E-Saskatoon, and for its differentiation from Hb E [beta26(B8)Glu-->Lys (GAG-->AAG)]. Analysis of the restriction fragment length polymorphism (RFLP) in the beta-globin gene complex of the index patient and of another unrelated family with a compound heterozygosity for Hb E-Saskatoon and beta-thalassemia revealed that the Hb E-Saskatoon mutation shared a common allele.
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PMID:Homozygosity for Hb E-Saskatoon [beta22(B4)Glu-->Lys] in a Turkish patient. 1179 74

Hemoglobin E is very common in parts of Southeast Asia. The possible malaria protective effects of this and other inherited hemoglobin abnormalities prevalent in Thailand were assessed in a mixed erythrocyte invasion assay. In vitro, starting at 1% parasitemia, Plasmodium falciparum preferentially invaded normal (HbAA) compared to abnormal hemoglobin (HbH, AE, EE, HCS, beta-thalassemia E) red cells (HRBCs). The median (range) ratio of parasitization of HRBCs (n = 109) compared to the controls of different major blood groups was 0.40 (0.08, 0.98), less than half that of the normal red cells (NRBCs) compared to their controls 0.88 (0.53, 1.4; P =.001). The median (range) parasitemia in the HRBCs was 2% (0.1%-9%) compared to 5.2% (1.2%-16.3%) in the NRBCs (P =.001). The proportion of the RBC population that is susceptible to malaria parasite invasion can be described by a selectivity index (SI; observed number of multiply invaded RBCs/number predicted). The heterozygote AE cells differed markedly from all the other cells tested with invasion restricted to approximately 25% of the RBCs; the median (range) SI was 3.8 (1-15) compared with 0.75 (0.1-0.9) for EE RBCs (P <.01). Despite their microcytosis, AE cells are functionally relatively normal in contrast to the RBCs from the other hemoglobinopathies studied. These findings suggest that HbAE erythrocytes have an unidentified membrane abnormality that renders the majority of the RBC population relatively resistant to invasion by P falciparum. This would not protect from uncomplicated malaria infections but would prevent the development of heavy parasite burdens and is consistent with the "Haldane" hypothesis of heterozygote protection against severe malaria for hemoglobin E.
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PMID:Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria. 1214 84

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.
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PMID: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. 1240 90

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.
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PMID:Molecular characterization of Hb D-Punjab [beta121(GH4)Glu-->Gln] in Thailand. 1240 91


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