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)

Disturbances in the biosynthesis of porphyrins in erythrocytes were investigated in 50 patients with chronic nephritis after incubation with delta-aminolevulinic acid. A medium to strong correlation was found among the parameters of porphyrin metabolism and those of haemoglobin synthesis and the functional state of the kidneys. This gives rise to the assumption that the disturbances in porphyrin biosynthesis are to be classified among the pathogenetic mechanisms of anaemia in the course of chronic nephritis.
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PMID:[Chronic nephritis--porphyrin biosynthesis and nephrogenic anemia]. 666 96

For several years, a 4-12-fold increase of the upper normal limit in erythrocyte protoporphyrin concentrations persisted in two men 34 and 39 years of age who were chronically exposed to lead. We are dealing with a zinc protoporphyrinemia in both cases, without lead intoxication or anemia. The 34-year-old had been a regular blood donor for 10 years and had already been treated for iron deficiency several times. Hemoglobin, red cell counts, hematocrit, and iron were at the lower normal limit. The activity of porphobilinogen synthase (PBG-S), uroporphyrinogen-synthase and -decarboxylase as well as urinary porphyrin precursors and porphyrin excretion were normal. Protoporphyrinemia was said to be due to a prelatent/latent iron deficiency. In the 39-year-old, the activity of PBG-S was lowered to 388 mumol/1 . h, as compared to the mean of controls (1,190 +/- 210, x +/- SD, n = 50), in connection with a slightly elevated excretion of delta-aminolevulinic acid and coproporphyrin in the urine and a high-normal blood lead level. In his family there was no history of either a protoporphyrinemia or a hematological disturbance. Six of eight family members in three generations showed a diminished activity of PBG-S: 600 +/- 160, P less than 0.001 compared to controls. These family members are heterozygous with regard to the PBG-S deficiency; they are clinically unobtrusive in comparison to homozygotes with an acute prophyria syndrome. Activation by zinc and reactivation by dithiothreitol were normal in contrast to PBG-S from patients with lead intoxication. The cause of biochemical symptoms of subclinical lead intoxication developed by the propositus is probably due to the hereditary PBG-S deficiency which sensitizes him to low-level lead exposure. The determination of red cell PBG-S activity can be recommended as a test detecting heterozygotes. The hereditary PBG-S deficiency is recognized as a new molecular basis for the pathogenesis of lead intoxication.
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PMID:Persistent protoporphyrinemia in hereditary porphobilinogen synthase (delta-aminolevulinic acid dehydrase) deficiency under low lead exposure. A new molecular basis for the pathogenesis of lead intoxication. 710

The biosynthesis of porphyrins after incubation with 6.25 mmoles/l delta-aminolevulinic acid (ALA) for 4 h, the synthesis of porphobilinogen, the residual ALA, and the activity of the porphobilinogen synthase were determined in erythrocytes. Examined were 568 individuals: healthy males and female, normal pregnancy and nephropathy of pregnancy, newborn infants and various diseases of the kidney. The biosynthesis of porphyrin in erythrocytes after incubation with ALA and the activity of porphobilinogen synthase in erythrocytes in chronic renal disorders progressively decreased depending on the stages of the pathologic process and the development of chronic renal insufficiency. The high correlation between the level of synthesized porphyrins and hemoglobin led us to assume that disorders in porphyrin biosynthesis represent in fact one of the pathogenetic mechanisms of nephrogenic anemia.
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PMID:Studies on the biosynthesis of porphyrins in erythrocytes after incubation with delta-aminolevulinic acid: an attempt to investigate the pathogenesis of nephrogenic anemia. 712 48

The activity of 5-aminolaevulinate (ALA) synthase, the first and rate-limiting of haem synthesis, was markedly reduced (13% of controls) in erythroblasts of a patient with acquired, primary sideroblastic anaemia (PASA). The reduced activity of ALA synthase could not be restored in vitro with 1 mmol/l pyridoxal-5-phosphate (PLP). Treatment of the patient with pyridoxine for several months increased the ALA synthase activity from 13% to 50% of controls in the absence and to 100% in the presence of PLP in the incubation medium. These studies suggest that both increased degradation of apo-ALA synthase and decreased affinity of ALA synthase for PLP may be involved in pyridoxine-responsive PASA.
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PMID:Pyridoxine-responsive primary acquired sideroblastic anaemia. In vitro and in vivo effects of vitamin B6 on decreased 5-aminolaevulinate synthase activity. 715 91

Certain disturbances in heme biosynthesis induced by aluminum chloride were examined. The experiment was performed on female rats that received AlCl3 orally at the dose 100 mg Al/kg daily for 21 d. The effects of aluminum on the activity of delta-aminolevulinic acid synthetase (ALA-S), dehydratase (ALA-D), and heme oxygenase (O.H.) were observed on 3, 7, 14, and 21 d in liver and kidneys of rats. Also the activity of ALA-D in blood and the concentration of delta-aminolevulinic acid (ALA-U) in urine were observed. Orally administered aluminum caused increase in the activity of ALA-D in the liver and blood, and parallel decrease of ALA-U in urine (r = -0.85) of rats. Aluminum chloride also induced an increase of ALA-S and O.H. in the liver but not in the kidneys. The changes of the enzymes activity participating in heme biosynthesis after administration of aluminum may be correlated with anemia and iron metabolism in rats.
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PMID:The effect of aluminum chloride on some steps of heme biosynthesis in rats after oral exposure. 751 18

A large pedigree showing a history of pyridoxine responsive X linked sideroblastic anaemia was screened with several polymorphic DNA markers from the X chromosome. Linkage analysis between each marker and disease status was performed, giving a maximum two point lod score of 3.64 at zero recombination with the microsatellite marker PGK1P1 at Xq11.2-12. Close linkage to PGK at Xq13.3, one of the candidate regions for X linked sideroblastic anaemia, was excluded. Linkage to DNA markers distal to PGK and at Xp21 was also excluded. Multipoint linkage analysis was performed with markers located between Xq11.2-21. The maximum map specific lod score obtained was 3.56 at PGK1P1 (Xq11.2-12). Linkage remained significant over the interval 20 cM proximal to PGK1P1 and 5 cM distal to PGK1P1, with definite exclusion around the PGK locus. The most likely location of the gene involved in sideroblastic anaemia in this pedigree is therefore within the pericentromeric region of the X chromosome. This region includes the erythroid 5-aminolaevulinate synthetase gene of the haem synthesis pathway, which is a candidate gene for X linked sideroblastic anaemia located at Xp11.21.
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PMID:Linkage analysis of a large pedigree with hereditary sideroblastic anaemia. 761 48

An experimental study on Japanese White (JW) rabbits was conducted to clarify the sex difference in FEP level. Male and female rabbits (n = 14 of each sex) were used. The animals of the same sex were divided into 3 groups; i.e., control group (5% glucose solution only, n = 4), low lead dose group (Pb 0.4 mg/kg.BW, n = 5) and high lead dose group (Pb 2 mg/kg.BW, n = 5). Lead was injected intravenously twice a week for 5 wk. The following parameters were determined once a week for 5 wk: blood lead (Pb-B), FEP, Ht, Hb, erythrocyte ALA-D activity, erythrocyte pyrimidine 5'-nucleotidase (P5N), urinary coproporphyrin (CP-U), urinary delta-aminolevulinic acid (ALA-U), iron in serum (Fe-S), and serum GOT and GTP. Average levels of FEP in female rabbits were higher than those in males between the 1st and 3rd week after the lead injection in the low lead dose groups, and in the final week in the high lead dose groups. In the periods without lead injection, the average levels of FEP in the female groups were not significantly higher than the corresponding levels in the male groups in every week except in the first week in the control. However, the mean of FEP levels in all female rabbits without Pb treatment was higher than that in male rabbits (t-test). By the analysis of variance for the gains of FEP from the initial value, only the low lead dose group showed a significant sex difference (female > male); that is, the female group tended to increase when compared with the male group. Furthermore, the week when FEP began to increase in the female groups was earlier than that in the male groups in the low lead dose group. In the high lead dose group, both sexes reacted to the lead exposure from the same early week. As for the parameters of anemia, the average levels of Ht and Hb tended to be lower in females than in males, but Fe-S levels were not affected by lead in both sexes and no consistent sex difference could be observed. By lead exposure, ALA-D and P5N were inhibited, and ALA-U was increased, but these parameters showed no evident sex difference. The average levels of CP-U tended to be higher in females than in males in the administration of low lead dose and to be inversely higher in males than in females in the administration of high lead dose.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sex difference in free erythrocyte protoporphyrin (FEP) level. IV. Sex difference in FEP level in rabbits exposed to lead. 844 24

Recent studies have indicated that nitric oxide may affect iron metabolism through disruption of the iron-sulfur complex of iron regulatory protein-1, a translational regulator. In the present study, we report that heterologous expression of murine macrophage nitric oxide synthase (NOS-2) in the human erythroleukemic K562 cell line results in constitutive production of nitric oxide associated with inhibition of hemoglobin expression. K562 cells were transfected with an episomally-maintained, hygromycin-selectable expression vector bearing the coding region of NOS-2. Constitutive NOS expression was detected by Western blotting of cell lysates and by the accumulation of nitrite in the culture media. Although NOS-transfected cells grew more slowly than control cells, they were able to maintain constitutive expression of NOS and production of nitric oxide for more than 1 month following transfection. The hemoglobin content of NOS-transfected K562 cells was less than one-fifth that of control cells, but increased markedly if NOS inhibitor was included in the culture media. The nitric oxide-mediated inhibition of hemoglobin expression was reversed by supplementing the culture media with 20 mumol/L hemin or 0.5 mmol/L 5-amino-levulinate, indicating that nitric oxide did not directly inhibit hemoglobin synthesis, but likely acted on a step in heme synthesis. mRNA levels for globin and erythroid aminolevulinic acid synthase (eALAS) were the same in both NOS-transfected and control cells. Our observations indicate that hemoglobin expression is inhibited by nitric oxide in NOS-transfected K562 cells by posttranscriptional repression of eALAS, the first enzyme of the heme biosynthetic pathway. The most likely mechanism is a nitric oxide-mediated translational repression of eALAS, as was recently demonstrated for ferritin synthesis. These observations further illustrate the potential for endogenously produced nitric oxide to regulate cellular posttranscriptional events. In particular, our observations may be relevant to the role of nitric oxide in anemia and lowered blood hemoglobin concentrations that are associated with chronic infections, such as tuberculosis or parasitic disease.
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PMID:Inhibition of hemoglobin expression by heterologous production of nitric oxide synthase in the K562 erythroleukemic cell line. 870 16

The coding region of the erythroid 5-aminolaevulinate synthetase gene (ALAS2) from a large pedigree with pyridoxine-responsive X-linked hereditary sideroblastic anaemia was examined for mutations. In three affected males from this pedigree, single strand conformational polymorphism (SSCP) analysis showed anomalous migration of a PCR product spanning exon 9. Sequencing of amplified genomic DNA from one of these affected males revealed a guanine to adenine transition at nucleotide 1407 of the cDNA sequence in exon 9 of the gene. This mutation results in the loss of an HhaI restriction enzyme digest site. An HhaI digest assay demonstrated the presence of this mutation in other affected males but not in unaffected males and unrelated individuals. The point mutation results in an arginine to histidine substitution at amino acid residue 452. The arginine residue is conserved in both the erythroid and housekeeping ALAS genes in all known vertebrate sequences. This arginine is located in the middle of a predicted alpha-helix.
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PMID:Identification of an arginine452 to histidine substitution in the erythroid 5-aminolaevulinate synthetase gene in a large pedigree with X-linked hereditary sideroblastic anaemia. 902 Mar 66

DNA sequencing of the coding region of the erythroid 5-aminolaevulinate synthase (ALAS2) cDNA from a male with pyridoxine-responsive sideroblastic anaemia revealed a missense mutation C1622G and a closely linked polymorphism C1612A in exon 10 of the gene. Sequence analysis of the genomic DNA from other family members revealed that the proband's mother and daughter were heterozygous carriers of the mutation, consistent with the X-linked inheritance. The C1622G mutation results in a histidine to aspartic acid substitution at amino acid residue 524. The histidine residue is conserved in both the erythroid and housekeeping ALAS proteins in vertebrates, all other known ALAS proteins and other oxamine synthases that have pyridoxal 5'-phosphate as a co-factor. This histidine is located in a predicted loop, preceding a long alpha-helix region near the carboxy-terminus.
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PMID:Hereditary sideroblastic anaemia due to a mutation in exon 10 of the erythroid 5-aminolaevulinate synthase gene. 948 33


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