Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recombinant congenic mouse strains AcB55 and AcB61 are extremely resistant to malaria (Plasmodium chabaudi AS) despite the presence of susceptibility alleles at the known Char1/Char2 resistance loci. Resistance in AcB55 and AcB61 is controlled by a locus on chromosome 3 (Char4) shown to be allelic with or tightly linked to a loss-of-function mutation in pyruvate kinase (Pklr). AcB55 and AcB61 show important splenomegaly prior to infection caused by the expansion of the red pulp, and display histological signs of extramedullary erythropoiesis in the liver. Examination of splenic cell populations by flow cytometry demonstrates elevated numbers of TER119-positive erythroid precursor cells (>30% of total spleen cells), while RNA expression studies show elevated expression of erythrocyte-specific transcripts such as globin, transferrin receptor, and Nramp2/Slc11a2 in the spleen of both strains. Hematological profiling in both strains is consistent with the presence of anemia as evidenced by low total erythrocyte counts, decreased hemoglobin, as well as abnormally high numbers of circulating reticulocytes (15-20%). These results strongly suggest that the mutant Pklr allele (Pklr(269A)) of AcB55/61 strains causes hemolytic anemia compensated by constitutive erythropoiesis, which in turn protects the mice against P. chabaudi infection. The possible molecular basis of the Pklr protective effect is discussed and is under current investigation in these two strains.
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PMID:Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model. 1502 38

Natural resistance-associated macrophage protein 1 (Nramp1) is a divalent metal transporter expressed exclusively in phagocytic cells. We hypothesized that macrophage Nramp1 may participate in the recycling of iron acquired from phagocytosed senescent erythrocytes. To evaluate the role of Nramp1 in vivo, the iron parameters of WT and KO mice were analyzed after acute and chronic induction of hemolytic anemia. We found that untreated KO mice exhibited greater serum transferrin saturation and splenic iron content with higher duodenal ferroportin (Fpn) and divalent metal transporter 1 (DMT1) expression. Furthermore, hepatocyte iron content and hepcidin mRNA levels were dramatically lower in KO mice, indicating that hepcidin levels can be regulated by low-hepatocyte iron stores despite increased transferrin saturation. After acute treatment with the hemolytic agent phenylhydrazine (Phz), KO mice experienced a significant decrease in transferrin saturation and hematocrit, whereas WT mice were relatively unaffected. After a month-long Phz regimen, KO mice retained markedly increased quantities of iron within the liver and spleen and exhibited more pronounced splenomegaly and reticulocytosis than WT mice. After injection of (59)Fe-labeled heat-damaged reticulocytes, KO animals accumulated erythrophagocytosed (59)Fe within their liver and spleen, whereas WT animals efficiently recycled phagocytosed (59)Fe to the marrow and erythrocytes. These data imply that without Nramp1, iron accumulates within the liver and spleen during erythrophagocytosis and hemolytic anemia, supporting our hypothesis that Nramp1 promotes efficient hemoglobin iron recycling in macrophages. Our observations suggest that mutations in Nramp1 could result in a novel form of human hereditary iron overload.
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PMID:Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo. 1932 19