Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A recently initiated collaboration between Russian and American institutions has resulted in the characterization of several known or new beta-thalassemia alleles and unstable hemoglobin types. Nine known beta-thalassemia alleles were present which have also been found in Mediterranean, East Asian, and Black populations; the possibility of independent mutations for some of the rare alleles should be considered. Hb Durham-N.C./Brescia with a codon 114 (CTG-->CCG; Leu-->Pro) change was present in six members of two families. This condition and two new variants have the characteristics of a dominant type of beta-thalassemia heterozygosity with moderate anemia, Heinz body formation, splenomegaly, etc. One new beta-thalassemia allele is a frame-shift at codon 124 (-A), while another is characterized by the introduction of an extra proline residue (codon: CCA) between residues Thr (beta 123) and Val (beta 126) to give the sequence -Thr-Pro-Pro-Pro-Val-.
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PMID:Beta-thalassemia alleles and unstable hemoglobin types among Russian pediatric patients. 803 85

A molecular model has been built of the equine infectious anemia virus (EIAV) proteinase on the basis of the crystal structures of the related Rous sarcoma virus (RSV) and human immunodeficiency virus (HIV) proteinases. The 104 residue long EIAV proteinase has 30 identical and 11 similar amino acids compared to those in HIV-1 proteinase and 25 identical and 18 similar amino acids compared to RSV proteinase. The overall structure is predicted to be close to that of HIV-1 proteinase. Two regions show differences: there are 6 additional residues leading to the tip of the flap, which is predicted to be involved in interactions with substrate, and there is a single residue deletion in the beta b' strand at a position equivalent to residue 60 in HIV-1 proteinase. The conformation of the residues leading to the flap was modeled by analogy to the corresponding region of RSV proteinase. The peptide substrate, VSQNYPIVQ, was modeled by analogy to the inhibitors in the co-crystal structures of HIV-1 proteinase, and the residues forming the substrate binding sites of EIAV proteinase were identified. EIAV proteinase showed several non-conservative substitutions in these residues compared to HIV-1 proteinase: Thr 30 instead of Asp in subsites S2, S2', S4, and S4', Ile 54 instead of Gly 48 in subsites S1, S1', S3, and S3', Arg 79 instead of Thr 74 in S4 and S4', and Ile 85 instead of Thr 80 in subsites S1 and S1'.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular model of equine infectious anemia virus proteinase and kinetic measurements for peptide substrates with single amino acid substitutions. 838 80

To explore the mechanism of erythropoietin action on differentiation of erythroblasts, we have examined its effect on regulating phosphorylation of the 25-kD mRNA cap binding protein (eIF-4E). Erythroblasts from the spleens of mice infected with the anemia strain of Friend virus (FVA cells) were studied. Erythropoietin stimulated phosphorylation of eIF-4E in FVA cells within 30 minutes, and this effect was maximal at 60 minutes. Phosphoamino acid analysis and tryptic phosphopeptide map analysis of eIF-4E isolated from both control and erythropoietin-treated cells identified a predominant phosphopeptide containing phosphoserine. However, when cells were incubated with 1 muM okadaic acid, eIF-4E was phosphorylated on both serine and threonine residues and three additional tryptic phosphopeptides were detected. We also identified a 37-kD phosphoprotein (pp37) that bound specifically to the m7GTP cap structure and coimmunoprecipitated with eIF-kD protein was phosphorylated on both serine and threonine residues. These results indicate that phosphorylation of eIF-4E is a target in erythropoietin-initiated signal transduction events and that this phosphorylation precedes observable effects of erythropoietin on macromolecular biosynthesis. Although of pp37 remains to be studied, it may represent a developmentally regulated mRNA cap binding protein.
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PMID:Erythropoietin stimulates phosphorylation of eIF-4E and identification of a 37-kD phosphoprotein that binds mRNA caps in erythroblasts. 859 71

We investigated the DNA of 29 unrelated pyruvate kinase (PK) deficiency (PKD) patients from Central Europe with hereditary nonspherocytic hemolytic anemia for mutations in the PK-L/R gene. Among 58 potentially affected alleles, 53 mutations were identified, of which 17 were different from each other. Of these 17 mutations, 13 were single-nucleotide (nt) substitutions resulting in amino acid exchanges, G787A (Gly263-Arg), G994A (Gly332-Ser), G1006T (Ala336-Ser), G1010A (Arg337-Gln), A1081G (Asn361-Asp), G1127T (Ser376-Ile), G1174A (Ala392-Thr), G1281T (Glu427-Asp), C1454T (Ser485-Phe), C1456T (Arg486-Trp), G1493A (Arg498-His), G1529A (Arg510-Gin), and C1594T (Arg532-Trp); 1 in-frame triplet deletion, 1060delAAG (delLys354); 1 in-frame triplet insertion, 1203insAGC (insSer after Cys401); 1 splicesite mutation, 101-1G-A; and 1 frameshift deletion, 628delGT. Six mutations, 628delGT, G787A, G1010A, G1127T, G1281T, and C1454T, are described for the first time. To test the hypothesis of a single origin of the most common PK mutation in the European population, G1529A, we investigated all patients at four polymorphic sites in the PK-L/R gene: C/A at nt 1705, C/T at nt 1992, the (ATT)n microsatellite in intron J, and a polymorphism (T)10/(T)19 in intron I. Nine patients homozygous for mutation G1529A were consistent in all four markers. In the group of patients homozygous for mutation G1529A, the hematologic parameters and clinical manifestations have been studied in detail. Although having an identical mutation in the PK-L/R gene, the patients are affected differently. Their appearance ranges from a very mild compensated hemolysis to a severe anemia. Possible molecular explanations are discussed.
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PMID:Molecular analysis of 29 pyruvate kinase-deficient patients from central Europe with hereditary hemolytic anemia. 905 65

A 12-year-old boy was referred because of abdominal pain, gross hematuria, and passage of stones. Further evaluation showed growth delay, low average range of intellectual functioning, and a speech articulation disorder. No signs of self-mutilation or self-injurious behavior were present. He had hyperuricemia, hyperuricosuria, uric acid crystalluria, uric acid calculi, macrocytosis, megaloblastic bone marrow changes, and mild anemia. Hypoxanthine phosphoribosyltransferase (HPRT) enzyme activity was reduced to approximately 26% of normal. Polymerase chain reaction-single strand conformational polymorphism analysis of the HPRT gene in DNA isolated from the patient's blood lymphocytes revealed a single nucleotide substitution at codon 200 in exon 8. The base change was a guanine to cytosine transversion, resulting in the conservative amino acid substitution of threonine in place of arginine. To our knowledge, this mutation has not previously been reported.
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PMID:A new point mutation in a hypoxanthine phosphoribosyltransferase-deficient patient. 932 99

Alpha-thalassemia is among the world's most common single gene disorders, caused primarily by gene deletions. In Israel, where alpha(o)-trait thalassemia is uncommon, it is of particular importance because of its phenotypic interactions with beta-thalassemia in hetero- and homozygotes. In a study of 232 individuals referred for molecular evaluation of anemia, 303 chromosomes carried alpha-globin gene abnormalities; 6 gene rearrangements and 11 point mutations were identified. This unexpected heterogeneity is in part due to the many ethnic subgroups represented by these patients. Our findings include nine unique Israeli alleles, 3 of which are described here for the first time. An equal number of point mutations was found in the alpha2-globin gene as compared to alpha1. A threonine deletion in codon 39 of the alpha1-globin gene, found frequently in Arabs, is unique to Israel and probably represents one of several indigenous alleles. Among Arabs, point mutations were more frequent than large deletions. Surprisingly, in Ashkenazi Jews, who resided for many centuries in a nonmalarial environment, a single alpha-globin gene deletion -alpha(3.7) was found in many cases. The clinical presentation of individuals carrying two or more alpha-globin lesions was highly variable. In general, the severity correlated inversely with the number of functional alpha-globin genes. In some cases, impairment of two alpha-globin genes by point mutations led to a thalassemia-intermedia-like picture which could be misdiagnosed as beta-thalassemia. We conclude that alpha-thalassemia is phenotypically and genotypically more heterogeneous than previously recognized. DNA analysis is invaluable as it provides a specific diagnosis and enables reliable genetic counseling.
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PMID:Diversity of alpha-globin mutations and clinical presentation of alpha-thalassemia in Israel. 1107 35

Drug resistance in Plasmodium falciparum affects prevention of malaria in pregnancy. In a cross-sectional study of 530 pregnant Ghanaian women, P. falciparum dihydrofolate reductase (DHFR) gene mutations linked with pyrimethamine resistance were assessed and associations with pyrimethamine intake were analyzed. P. falciparum infected 69% of women without pyrimethamine use, 59% of those who had a history of pyrimethamine consumption but a negative urine test, and 53% of individuals with a positive urine test. Eighty-one percent, 43%, and 74% of the isolates contained the mutations Asn-108, Ile-51, and Arg-59, respectively. Thr-108 occurred in 8%. Pyrimethamine use was associated with increased frequencies of Asn-108 and Arg-59 but not of Ile-51 or Thr-108. In women with prophylaxis, wild-type parasites were absent and anemia tended to be more common with an increasing number of DHFR gene mutations. Pyrimethamine appears to be not adequately effective in this part of Ghana, most likely due to the predominance of resistant parasites. Selection for resistance following insufficient prophylaxis could possibly affect the efficacy of future intermittent sulfadoxine-pyrimethamine treatment.
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PMID:Plasmodium falciparum dihydrofolate reductase alleles and pyrimethamine use in pregnant Ghanaian women. 1150 2

The function of viral protein 2 (VP2) of the immunosuppressive circovirus chicken anemia virus (CAV) has not yet been established. We show that the CAV VP2 amino acid sequence has some similarity to a number of eukaryotic, receptor, protein-tyrosine phosphatase (PTPase) alpha proteins as well as to a cluster of human TT viruses within the Sanban group. To investigate if CAV VP2 functions as a PTPase, purified glutathione S-transferase (GST)-VP2 fusion protein was assayed for PTPase activity using the generalized peptide substrates ENDpYINASL and DADEpYLIPQQG (where pY represents phosphotyrosine), with free phosphate detected using the malachite green colorimetric assay. CAV GST-VP2 was shown to catalyze dephosphorylation of both substrates. CAV GST-VP2 PTPase activity for the ENDpYINASL substrate had a V(max) of 14,925 units/mg.min and a K(m) of 18.88 microm. Optimal activity was observed between pH 6 and 7, and activity was specifically inhibited by 0.01 mm orthovanadate. We also show that the ORF2 sequence of the CAV-related human virus TT-like minivirus (TLMV) possessed PTPase activity and steady state kinetics equivalent to CAV GST-VP2 when expressed as a GST fusion protein. To establish whether these viral proteins were dual specificity protein phosphatases, the CAV GST-VP2 and TLMV GST-ORF2 fusion proteins were also assayed for serine/threonine phosphatase (S/T PPase) activity using the generalized peptide substrate RRApTVA, with free phosphate detected using the malachite green colorimetric assay. Both CAV GST-VP2 and TLMV GST-ORF2 fusion proteins possessed S/T PPase activity, which was specifically inhibited by 50 mm sodium fluoride. CAV GST-VP2 exhibited S/T PPase activity with a V(max) of 28,600 units/mg.min and a K(m) of 76 microm. Mutagenesis of residue Cys(95) to serine in CAV GST-VP2 abrogated both PTPase and S/T PPase activity, identifying it as the catalytic cysteine within the proposed signature motif. These studies thus show that the circoviruses CAV and TLMV encode dual specificity protein phosphatases (DSP) with an unusual signature motif that may play a role in intracellular signaling during viral replication. This is the first DSP gene to be identified in a small viral genome.
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PMID:Chicken anemia virus VP2 is a novel dual specificity protein phosphatase. 1215 84

Apoptin, a chicken anemia virus-encoded protein, is thought to be activated by a general tumor-specific pathway, because it induces apoptosis in a large number of human tumor or transformed cells but not in their normal, healthy counterparts. Here, we show that Apoptin is phosphorylated robustly both in vitro and in vivo in tumor cells but negligibly in normal cells, and we map the site to threonine 108. A gain-of-function point mutation (T108E) conferred upon Apoptin the ability to accumulate in the nucleus and kill normal cells, implying that phosphorylation is a key regulator of the tumor-specific properties of Apoptin. An activity that could phosphorylate Apoptin on threonine 108 was found specifically in tumor and transformed cells from a variety of tissue origins, suggesting that activation of this kinase is generally associated with the cancerous or pre-cancerous state. Moreover, analyses of human tissue samples confirm that Apoptin kinase activity is detectable in primary malignancies but not in tissue derived from healthy individuals. Taken together, our results support a model whereby the dysregulation of the cellular pathway leading to the phosphorylation of Apoptin contributes to human tumorigenesis.
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PMID:A tumor-specific kinase activity regulates the viral death protein Apoptin. 1239 3

We investigated the interrelationships between behavior and serum amino acid concentrations in iron-deficient anemic rats. Concentrations of proline, alanine, glycine, and phenylalanine in serum samples were significantly higher than those in rats fed a normal diet, while serum threonine, glutamic acid, and valine levels were significantly lower. Activities of locomotion, rearing, hole-poking, and grooming, determined by using a hole board apparatus, were significantly reduced in anemic rats. The supplementation of inorganic iron and amino acids proline, arginine, or glutamic acid to the normal diet lead to the recovery of normal behavior. Proline enhanced a significant increase in the number of red blood cells and hemoglobin by the supplementation of iron alone. We propose that the combination of amino acid (especially proline) and inorganic iron might lead to an improvement in behavioral disorders caused by iron-deficient anemia.
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PMID:Co-administration of proline and inorganic iron enhance the improvement of behavioral and hematological function of iron-deficient anemic rats. 1288 90


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