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)

We report a new hemoglobin (Hb) variant, Hb Marineo [beta70(E14)Ala --> Val], found in three generations of a family from West Sicily. The mutation is due to a GCC --> GTC substitution at codon 70 of the beta-globin gene. To date, three mutations at codon 70 of the beta-globin gene have been described, presenting with hemolytic anemia. In our case, no anemia or other alteration of hematological indices were found. Cation exchange high performance liquid chromatography (HPLC) showed a peak in the P2 window (VARIANT I), while a peak was detected by VARIANT II HPLC in the P3 window. Reversed phase HPLC analysis showed an abnormal chain amounting to about 40% of the total beta chains.
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PMID:Hb Marineo [beta70(E14)Ala-->Val]: a silent hemoglobin variant with a mutation within the heme pocket. 1679 37

Malaria is a major cause of morbidity and mortality with an annual death toll exceeding one million. Severe malaria is a complex multisystem disorder, including one or more of the following complications: cerebral malaria, anemia, acidosis, jaundice, respiratory distress, renal insufficiency, coagulation anomalies, and hyperparasitemia. Using a combined in vivo/in vitro metabolic-based approach, we investigated the putative pathogenic effects of Plasmodium berghei ANKA on brain, in a mouse strain developing malaria but resistant to cerebral malaria. The purpose was to determine whether the infection could cause a brain dysfunction distinct from the classic cerebral syndrome. Mice resistant to cerebral malaria were infected with P. berghei ANKA and explored during both the symptomless and the severe stage of the disease by using in vivo brain magnetic resonance imaging and spectroscopy. The infected mice did not present the lesional and metabolic hallmarks of cerebral malaria. However, brain dysfunction caused by anemia, parasite burden, and hepatic damage was evidenced. We report an increase in cerebral blood flow, a process allowing temporary maintenance of oxygen supply to brain despite anemia. Besides, we document metabolic anomalies affecting choline-derived compounds, myo-inositol, glutamine, glycine, and alanine. The choline decrease appears related to parasite proliferation. Glutamine, myo-inositol, glycine, and alanine variations together indicate a hepatic encephalopathy, a finding in agreement with the liver damage detected in mice, which is also a feature of the human disease. These results reveal the vulnerability of brain to malaria infection at the severe stage of the disease even in the absence of cerebral malaria.
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PMID:Magnetic resonance spectroscopy reveals an impaired brain metabolic profile in mice resistant to cerebral malaria infected with Plasmodium berghei ANKA. 1736 63

GATA-1 is the key transcription factor for the development of the erythroid, megakaryocytic, eosinophilic, and mast cell lineages. GATA-1 possesses the ability to self-associate, and this characteristic has been suggested to be important for GATA-1 function. To elucidate the roles self-associated GATA-1 plays during hematopoietic cell development in vivo, in this study we prepared GATA-1 mutants in which three lysine residues potentially contributing to the self-association (Lys-245, Lys-246, and Lys-312) are substituted in combination with alanines. Of the mutants, 3KA harboring alanine substitutions in all three lysines showed reduced self-association activity without considerable interference in the modification of GATA-1 by acetylation. We generated transgenic mouse lines that express these GATA-1 mutants utilizing the Gata1 hematopoietic regulatory domain, and crossed the mice to Gata1 knockdown (GATA-1.05) mutant mice. Although NKA (K245A and K246A) and CKA (K312A) mutants almost fully rescued the GATA-1.05 mice from anemia and embryonic lethality, the 3KA mutant only partially rescued the GATA-1.05 mutant mice. Even with the higher than endogenous level expression, GATA-1.05/Y::3KA embryos were prone to die at various stages in mid-to-late gestation. Live birth and an anemic phenotype were restored in some embryos depending on the expression level of the 3KA transgene. The expression of the transferrin receptor and heme biosynthesis enzymes was impaired in the yolk sac and liver of the 3KA-rescued embryos. Immature erythroid cells with insufficient expression of the transferrin receptor accumulated in the livers of 3KA-rescued embryos. These results provide the first convincing line of evidence that the self-association of GATA-1 is important for proper mammalian erythroid development in vivo.
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PMID:GATA-1 self-association controls erythroid development in vivo. 1737 3

Dominantly inherited beta-thalassemia (thal) or "inclusion body beta-thalassemias" are heterogeneous at the molecular level and are due to mutations at or near the beta-globin gene locus. Many of these involve mutations of exon 3 of the beta-globin gene. They include frameshifts, premature chain termination (nonsense) mutations, and complex rearrangements that lead to the synthesis of truncated or elongated and highly unstable beta-globin gene products. The resulting beta chain variants are very unstable, and in many cases, the products of the dominantly inherited beta-thal are not detectable. Hematological and clinical observations made in several families with comparable forms of beta-thal and with certain highly unstable hemoglobin (Hb) variants, have indicated a striking overlap; many subjects with detectable unstable Hb variants and with a dominant type of beta-thal without a detectable abnormal Hb, have similar phenotypes. Here, a review of dominantly inherited beta-thal is given, and new examples of hyperunstable Hbs (Hb Stara Zagora and Hb Jambol) are presented. The first example is a hyperunstable variant named Hb Stara Zagora that was found in a 2-year-old Bulgarian boy. The abnormal Hb is associated with severe hemolytic anemia as a consequence of its hyper instability. The anemia was noticed at the age of 2 months and since then he has been on a regular monthly blood transfusion regimen. Hemoglobin analysis revealed no abnormalities, except the presence of inclusion bodies. Sequencing of the beta-globin gene revealed a heterozygosity for a 6 bp deletion (-TGGCTA) at codons 137 (the second and third bp), 138 and 139 (the first bp), thus forming a new codon at position 139 (GAT). This event eliminates three amino acids (Val-Ala-Asn) and introduces a new residue (Asp). It creates a new restriction site for HphI. The parents and his twin brother had no history of hemolysis. The paternity of the child was confirmed by DNA analysis. The second example is a new hyperunstable variant named Hb Jambol, found as a de novo mutation in a 2-year-old Bulgarian girl with severe hemolytic anemia. The mutation was detected through RNA/DNA analysis. It represents a complex genomic rearrangement involving an insertion of 23 nucleotides (nts) after IVS-II-535, a deletion of 310 nts extending from IVS-II-550 to the first nt of codon 108, and an insertion of 28 nts at the deletion junctions (derived from inverted sequence between nts +3707 and +3734 3' to the beta-globin gene termination codon). At the protein level, this mutation leads to a deletion of four amino acid residues (Leu-Leu-Glu-Asn) at positions 105, 106, 107 and 108, and an insertion of nine residues (Val-Pro-Ser-Val-Thr-Leu-Phe-Phe-Asp) at the same location, creating an abnormal elongated beta chain of 151 amino acid residues. The parents had no history of hemolysis. The paternity of the child was confirmed by DNA analysis.
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PMID:Dominantly Inherited beta-Thalassemia. 1748 3

An attenuated chicken anaemia virus (CAV) isolate, cloned isolate 10, which was molecularly cloned from the Cuxhaven-1 CAV after 173 cell-culture passages, was shown previously to recover pathogenicity following 10 passages in young chicks. The consensus nucleotide sequence of the 'revertant' (Rev) virus, present as a tissue homogenate, differed from cloned isolate 10 at a single nucleotide residue (nucleotide 1739) that changed amino acid 287 of the capsid protein from alanine to aspartic acid. Subjecting Rev virus to 10 cell-culture passages reselected viruses with an alanine at this amino acid position. Experimental infections using a molecularly cloned Rev virus isolate demonstrated that the mutation at nucleotide 1739 was not in itself responsible for the recovery of pathogenicity exhibited by the Rev virus. Additional sequence analyses of cloned amplicons provided evidence that the Rev virus population comprised minor, genetically different subpopulations, and provided an indication of CAV's potential for genetic change.
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PMID:Investigation of the unstable attenuation exhibited by a chicken anaemia virus isolate. 1758 61

The transcriptional activator HIF (hypoxia-inducible factor) is a focal point of biomedical research because many situations in physiology and in pathology coincide with hypoxia. The effects of HIF activation may be a facet of normal growth, as in embryonic development, they may counterbalance a disease, as seen in the stimulation of erythropoiesis in anaemia, and they may be part of the pathological processes, as exemplified by tumour angiogenesis. The oxygen-sensitive alpha-subunits of HIF are primarily regulated by the enzymatic hydroxylation that induces rapid proteasomal degradation. The HIFalpha hydroxylases belong to a superfamily of dioxygenases that require the co-substrates oxygen and 2-oxoglutarate as well as the cofactors Fe2+ and ascorbate. The regulation of enzyme turnover by the concentration of the cosubstrate oxygen constitutes the interface between tissue oxygen level and the activity of HIF. The HIFalpha prolyl hydroxylases, termed PHDs/EGLNs (prolyl hydroxylase domain proteins/EGL nine homologues), bind to a conserved Leu-Xaa-Xaa-Leu-Ala-Pro motif present in all substrates identified so far. This recognition motif is present twice in HIF1alpha, which gives rise to a NODD [N-terminal ODD (oxygen-dependent degradation domain)] containing Pro402 of HIF1alpha and a CODD (C-terminal ODD) where Pro564 is hydroxylated. PHD1/EGLN2 and PHD2/EGLN1 hydroxylate both ODDs with higher activity towards CODD, whereas PHD3/EGLN3 is specific for CODD. The reason for this behaviour has been unclear. In this issue of the Biochemical Journal, Villar and colleagues demonstrate that distinct PHD/EGLN domains, that are remote from the catalytic site, function in substrate discrimination. This elegant study improves our understanding of the interaction of the oxygen-sensing PHDs/EGLNs with their substrates, which include, but are not limited to, the HIFalpha proteins.
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PMID:Enzyme substrate recognition in oxygen sensing: how the HIF trap snaps. 1772 46

Infection of domestic cats with feline immunodeficiency virus (FIV) is an important model system for studying human immunodeficiency virus type 1 (HIV-1) infection due to numerous similarities in pathogenesis induced by these two lentiviruses. However, many molecular aspects of FIV replication remain poorly understood. It is well established that retroviruses use short peptide motifs in Gag, known as late domains, to usurp cellular endosomal sorting machinery and promote virus release from infected cells. For example, the Pro-Thr/Ser-Ala-Pro [P(T/S)AP] motif of HIV-1 Gag interacts directly with Tsg101, a component of the endosomal sorting complex required for transport I (ESCRT-I). A Tyr-Pro-Asp-Leu (YPDL) motif in equine infectious anemia virus (EIAV), and a related sequence in HIV-1, bind the endosomal sorting factor Alix. In this study we sought to identify and characterize FIV late domain(s) and elucidate cellular machinery involved in FIV release. We determined that mutagenesis of a PSAP motif in FIV Gag, small interfering RNA-mediated knockdown of Tsg101 expression, and overexpression of a P(T/S)AP-binding fragment of Tsg101 (TSG-5') each inhibited FIV release. We also observed direct binding of FIV Gag peptides to Tsg101. In contrast, mutagenesis of a potential Alix-binding motif in FIV Gag did not affect FIV release. Similarly, expression of the HIV-1/EIAV Gag-binding domain of Alix (Alix-V) did not disrupt FIV budding, and FIV Gag peptides showed no affinity for Alix-V. Our data demonstrate that FIV relies predominantly on a Tsg101-binding PSAP motif in the C terminus of Gag to promote virus release in HeLa cells, and this budding mechanism is highly conserved in feline cells.
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PMID:Molecular characterization of feline immunodeficiency virus budding. 1809 66

Hepatitis C (HCV) infection is commonly seen in dialysis patients, but its long-term deleterious effects in these patients are unknown. We evaluated the effect of HCV infection on anemia in our hemodialysis population. This retrospective case control study was carried out from January 1999 to February 2007. The HCV positive patients were assessed for a 12-month period by quarterly lab results for the prevalence of anemia, iron stores, dialysis adequacy, and alanine aminotranferase levels. Their requirements of erythropoietin (EPO) and intravenous (IV) iron were assessed during these months of clinical stability. A control group of age-matched, race-matched, and gender-matched hemodialysis patients with no history of HCV was similarly assessed for anemia, iron stores, and EPO and IV-iron requirements. Twenty-two HCV-positive patients were included for comparison analysis with 44 control patients for 1:2 matching. The mean EPO requirement for the hepatitis group was 17,307 +/- 14,708 U/month in comparison with the control group, which required 49,134 +/- 49,375 U/month (p value <0.01). The mean dose of IV-iron was 120 +/- 143 mg/month for hepatitis patients and 163 +/- 112 mg/month in the control group (p=0.07). The patients with HCV have lower requirement of exogenous EPO replacement compared with their age-matched, gender-matched, and race-matched dialysis counterparts. The IV-iron requirement was not significantly different between the 2 groups but had a suggestive lower trend in the hepatitis group. This needs to be further studied in larger trials.
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PMID:Effect of hepatitis C infection on anemia in hemodialysis patients. 1827 49

Phosphorylations within N- and C-terminal degrons independently control the binding of cyclin E to the SCF(Fbw7) and thus its ubiquitination and proteasomal degradation. We have now determined the physiologic significance of cyclin E degradation by this pathway. We describe the construction of a knockin mouse in which both degrons were mutated by threonine to alanine substitutions (cyclin E(T74A T393A)) and report that ablation of both degrons abolished regulation of cyclin E by Fbw7. The cyclin E(T74A T393A) mutation disrupted cyclin E periodicity and caused cyclin E to continuously accumulate as cells reentered the cell cycle from quiescence. In vivo, the cyclin E(T74A T393A) mutation greatly increased cyclin E activity and caused proliferative anomalies. Cyclin E(T74A T393A) mice exhibited abnormal erythropoiesis characterized by a large expansion of abnormally proliferating progenitors, impaired differentiation, dysplasia, and anemia. This syndrome recapitulates many features of early stage human refractory anemia/myelodysplastic syndrome, including ineffective erythropoiesis. Epithelial cells also proliferated abnormally in cyclin E knockin mice, and the cyclin E(T74A T393A) mutation delayed mammary gland involution, implicating cyclin E degradation in this anti-mitogenic response. Hyperproliferative mammary epithelia contained increased apoptotic cells, suggesting that apoptosis contributes to tissue homeostasis in the setting of cyclin E deregulation. Overall these data show the critical role of both degrons in regulating cyclin E activity and reveal that complete loss of Fbw7-mediated cyclin E degradation causes spontaneous and cell type-specific proliferative anomalies.
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PMID:Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo. 1855 82

In response to DNA damage or replication fork stress, the Fanconi anemia pathway is activated, leading to monoubiquitination of FANCD2 and FANCI and their colocalization in foci. Here we show that, in the chicken DT40 cell system, multiple alanine-substitution mutations in six conserved and clustered Ser/Thr-Gln motifs of FANCI largely abrogate monoubiquitination and focus formation of both FANCI and FANCD2, resulting in loss of DNA repair function. Conversely, FANCI carrying phosphomimic mutations on the same six residues induces constitutive monoubiquitination and focus formation of FANCI and FANCD2, and protects against cell killing and chromosome breakage by DNA interstrand cross-linking agents. We propose that the multiple phosphorylation of FANCI serves as a molecular switch in activation of the Fanconi anemia pathway. Mutational analysis of putative phosphorylation sites in human FANCI indicates that this switch is evolutionarily conserved.
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PMID:FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. 1898 65


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