Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002878 (hemolytic anemia)
 7,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The concentrations of unbound amino acids in erythrocytes and in plasma from 7 normal individuals, 11 patients with various types of aregeneratory anaemia, and 4 patients with hereditary haemolytic anaemias were determined on a Technicon Amino Acid Analyzer (Perry et al 1970). Most amino acids were normally found in higher concentrations in plasma than intracellularly. Cystine, methionine and trypotophan were almost exclusively present in plasma. Aspartic acid, however, was mainly found in erythrocytes, and glutathione only in erythrocytes. Glutamic acid and ornithine were more concentrated in the cells, while glycine and asparagine showed approximately the same concentrations in erythrocytes as in plasma. In the patients, plasma amino acids showed little deviations from normal, but in the erythrocytes there were striking changes. Erythrocyte glutamic acid concentrations were moderately to markedly elevated in all patients studied, and glycine concentrations in 13 out of 15 patients. In addition, the following amino acids were increased intracellularly in more than one patient: glutamine (8 patients), serine (7), asparagine (5), threonine (4), taurine (3), alanine (2), valine (2), ornithine (2), lysine (2), citrulline (2). Aspartic acid was decreased in erythrocytes from 4 patients with aregeneratory and 1 with haemolytic anaemia.
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PMID:Amino acid concentrations in plasma and erythrocytes in aregeneratory and haemolytic anaemias. 119 60

Over 400 supposedly biochemically and genetically distinct variants of glucose-6-phosphate dehydrogenase (G6PD) have been described in the past. In order to investigate these variants at the DNA sequence level we have now determined the relevant sequences of introns of G6PD and describe a method which allows us to rapidly determine the sequence of the entire coding region of G6PD. This technique was applied to six variants that cause G6PD deficiency to be functionally so severe as to result in nonspherocytic hemolytic anemia. Although the patients were all unrelated, G6PD Marion, Gastonia, and Minnesota each had identical mutations, a G----T at nucleotide (nt) 637 in exon 6 leading to a Val----Leu substitution at amino acid 213. The mutations of Nashville and Anaheim were identical to each other, viz. G----A at nt 1178 in exon 10 producing a Arg----His substitution at amino acid 393. G6PD Loma Linda had a C----A substitution at nt 1089 in exon 10, producing a Asn----Lys change at amino acid 363. The results confirm our earlier results suggesting that the NADP-binding site is in a small region of exon 10 and suggest the possibility that this area is also concerned with the binding of glucose-6-P.
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PMID:DNA sequence abnormalities of human glucose-6-phosphate dehydrogenase variants. 199 9

Two unstable hemoglobins (Hbs) causing rather severe hemolytic anemia have been characterized. The beta chain of Hb Birmingham, found in an adult black man, is characterized by the loss of -Leu-Ala-His-Lys- at positions 141, 142, 143, and 144 and their replacement by one Gln residue. These changes are the result of a deletion of nine nucleotides, namely two base pairs (bp) of codon 141, all of codons 142 and 143, and one bp of codon 144; the remaining CAG triplet (C from codon 141 and AG from codon 144) codes for the inserted glutamine. In the beta chain of Hb Galicia from a Spanish patient, His and Val at positions 97 and 98 are replaced by one Leu residue. This is due to an ACG deletion in codons 97 and 98, which causes the removal of one His and one Val residue, while the remaining CTG triplet (C from codon 97 and TG from codon 98) codes for the inserted leucine residue. Two mechanisms, namely slipped mispairing in the presence of short repeats, and misreading by DNA polymerase due to a local distortion of the DNA helix, are considered in explaining the origin of the small deletions.
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PMID:Hemoglobin Birmingham and hemoglobin Galicia: two unstable beta chain variants characterized by small deletions and insertions. 215 27

We report here that compound heterozygosity for hemoglobin Korle-Bu (HbKB) and HbC (beta 6 Glu-->Lys) is associated with moderate chronic hemolytic anemia with microcytosis. To understand the pathogenesis of this syndrome, we have studied the effect of Hb Korle-Bu (KB = beta 73 Asp-->Asn) on the crystallization of HbC. We have previously established that fetal Hb (HbF) inhibits the crystallization of HbC. In contrast, HbS accelerates crystallization affecting the pathogenesis of SC disease. We now report on in vitro crystallization of mixtures of HbKB, HbC, and various amounts of HbF and the native hemolysate of a child who is a compound heterozygote for HbKB and HbC. At 6 months of age, the propositus' hemolysate contained 55% HbKB, 39% HbC, and 6% HbF. Crystal formed within 2 minutes compared with 30 minutes for the mixture of 40% HbC:60% HbS and with 180 minutes for 40% HbC:60% HbA. The morphology of the crystals formed was cubic, in contrast with the tetragonal crystals observed in CC and SC disease. Early crystals did not exhibit "sharp edges" until 45 minutes. Purified HbKB formed aggregates but not crystals after 24 hours. Isopycnic gradients showed that the KB/C compound heterozygotes have red blood cell (RBC) densities intermediate between the AC and CC phenotype and similar to SC disease. The surface residue beta 73, known to participate in areas of interaction of the deoxy HbS polymer, can now be assigned to areas of contact in HbC containing crystals. The hemolysis observed in the HbKB/C compound heterozygote is likely to be secondary to the acceleration of Hb crystallization. The microcytosis and increased RBC density is clearly the consequence of the presence of HbC, but the basis of the increased RBC pathology compared with AC trait, despite the low proportion of HbC (35% to 40%), remains to be elucidated.
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PMID:Compound heterozygosity for hemoglobin C and Korle-Bu: moderate microcytic hemolytic anemia and acceleration of crystal formation [corrected]. 769 Dec 42

Among over 50 distinct mutations causing glucose-6-phosphate dehydrogenase (G6PD) deficiency, only two deletion mutations have so far been reported. Using nonradioisotopic single-strand conformation polymorphism analysis, we found two additional deletion mutations in two Japanese G6PD-deficient patients with nonspherocytic hemolytic anemia. Case no. 1 had a 3-nucleotide deletion in exon 6 predicting a deletion of a serine at amino acid 188 or 189, which caused a class 1 variant G6PD Tsukui. Case no. 2 had a 3-nucleotide deletion in exon 5 predicting a deletion of a lysine at residue 95, which caused a class 2 variant G6PD Urayasu. The 188th serine, which might be deleted in G6PD Tsukui, is located close to the putative G6P binding site. The 188th serine is also involved in the amino acid substitution in G6PD Mediterranean, but the kinetics of these two variants are totally different. The residue with an amino acid deletion in G6PD Urayasu was distant from the substrate binding sites and was located in a region with low sequence homology among species. The different properties of variants having mutations in exons 5 and 6 suggest that these two exons code distinct functional domains of the enzyme.
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PMID:Identification of two novel deletion mutations in glucose-6-phosphate dehydrogenase gene causing hemolytic anemia. 784 99

We identified four distinct point mutations in homozygous pyruvate kinase (PK) variants in Japanese and Chinese patients with chronic nonspherocytic hemolytic anemia. All gene abnormalities were missense mutations that caused single amino acid substitutions. 1261A (Q421K) and 1436A (R436H), which were identified in PK Sendai and PK Shinshu, had been found in unrelated Japanese and Amish PK variants, respectively. The clinical severity and extremely low residual erythrocyte PK activity of PK Shinshu as well as of the Amish PK might be caused partly by aberrant splicing, because the 1436A mutation changes a nucleotide at the last nucleotide in the exon 10. Recently, we diagnosed a 42-year-old Japanese woman with chronic nonspherocytic hemolytic anemia as having a homozygous PK deficiency. DNA sequencing of the variant PK gene showed a homozygous missense mutation at 1403GCT-->GTT, resulting in a single amino acid substitution from 468la-->Val. The gene mutation is likely to impair the allostericity of this enzyme, speculated from the tertiary structure. A homozygous missense mutation in PK Hong Kong, a boy of a non-Han southern Chinese minority group, was identified in exon 7 of the human L-PK gene, 941ATT-->ACT, resulting in a single amino acid substitution from 314lle-->Thr. The R-PK activity is expected to be severely affected, because the mutated amino acid residue is located between the 313 Lys and the 315 Glu, which are very important for acid-base catalysis and magnesium binding, respectively. Both the R- and M2-type PK were shown by polyacrylamide gel electrophoresis of the PK Hong Kong erythrocyte lysate, and this is the first report of a homozygous individual whose erythrocytes contain the immature (M2)-type isozyme.
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PMID:Hereditary hemolytic anemia caused by diverse point mutations of pyruvate kinase gene found in Japan and Hong Kong. 794 4

Red blood cell (RBC) protein 4.2 deficiency is often associated with a moderate nonimmune hemolytic anemia, splenomegaly, and osmotically fragile RBCs resembling, but not identical to, hereditary spherocytosis (HS). In the Japanese type of protein 4.2 deficiency (protein 4.2Nippon), the anemia is associated with a point mutation in the protein 4.2 cDNA. In this report, we describe a patient with moderate and apparently episodic nonimmune hemolytic anemia with splenomegaly, spherocytosis, osmotically fragile RBCs, reduced whole cell deformability, and abnormally dense cells. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the proposita's RBC membrane proteins showed an 88% deficiency of protein 4.2 and a 30% deficiency of glyceraldehyde-3-phosphate dehydrogenase (band 6). Structural and molecular analyses of the proposita's protein 4.2 were normal. In contrast, limited tryptic digestion of the proposita's band 3 showed a homozygous abnormality in the cytoplasmic domain. Analysis of the pedigree disclosed six members who were heterozygotes for the band 3 structural abnormality and one member who was a normal homozygote. Direct sequence analysis of the abnormal band 3 tryptic peptide suggested that the structural abnormality resided at or near residue 40. Sequence analysis of the proposita's band 3 cDNA showed a 232G-->A mutation resulting in a 40glutamic acid-->lysine substitution (band 3Montefiore). Allele-specific oligonucleotide hybridization was used to probe for the mutation in the pedigree, showing that the proposita was homozygous, and the pedigree members who were heterozygous for the band 3 structural abnormality were also heterozygous for the band 3Montefiore mutation. The band 3Montefiore mutation was absent in 26 chromosomes from race-matched controls and in one pedigree member who did not express the band 3 structural abnormality. In coincidence with splenectomy, the proposita's anemia was largely corrected along with the disappearance of most spherocytes and considerable improvements of RBC osmotic fragility, whole cell deformability, and cell density. We conclude that this hereditary hemolytic anemia is associated with the homozygous state for band 3Montefiore (40glutamic acid-->lysine) and a decreased RBC membrane content of protein 4.2. We speculate that band 3 structural abnormalities can result in defective interactions with protein 4.2 and band 6, and in particular, that the region of band 3 containing 40glutamic acid is involved directly or indirectly in interactions with these proteins.
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PMID:Human erythrocyte protein 4.2 deficiency associated with hemolytic anemia and a homozygous 40glutamic acid-->lysine substitution in the cytoplasmic domain of band 3 (band 3Montefiore). 847 74

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X-linked enzyme defect. We report a new variant, G6PD Durham713G, that is associated with chronic nonspherocytic hemolytic anemia. The G6PD Durham713G variant has a unique biochemical and enzymatic profile and a novel A-->G substitution mutation at nucleotide 713, changing lysine to arginine at amino acid 238. This mutation was not found in the mother of our patient, indicating that G6PD Durham713G resulted from a de novo mutation.
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PMID:Glucose-6-phosphate dehydrogenase Durham: a de novo mutation associated with chronic hemolytic anemia. 929 Jun 17

The structural basis of the crystallizing tendencies of oxyHbC (beta 6Glu-->Lys), that produces haemolytic anaemia in homozygotes, is unknown. Using a fluorescent organic phosphate analogue (8-hydroxy-1,3,6-pyrenetrisulphonate), and conventional oxygen equilibrium studies, data suggest that the binding of inositolhexaphosphate (IHP) to oxyHbC differs from HbA, indicating perturbations of the oxyHbC central cavity, which was predicted from our earlier spectroscopic findings. To define the relationship between this conformational change in oxyHbC and its tendency to crystallize, the effect of four central cavity ligands on the crystallization rate was studied: a peptide containing 11 residues from the N-terminal portion of band 3, the full cytoplasmic domain of band 3, 2,3-diphosphoglycerate and IHP. OxyHbC crystallization was accelerated by all these central cavity ligands and not by the appropriate controls. These central cavity changes become an excellent candidate for the dramatic increase in the crystallization rate of oxyHbC.
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PMID:A potential determinant of enhanced crystallization of Hbc: spectroscopic and functional evidence of an alteration in the central cavity of oxyHbC. 933 11

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


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