Nonspherocytic Haemolytic Anaemia with Increased Red Cell Adenine Nucleotides, Glutathione and Basophilic Stippling and Ribosephosphate Pyrophosphokinase (RPK) Deficiency: Studies on Two New Kindreds

Valentine, William N.; Bennett, John M.; Krivit, William; Konrad, Patricia N.; Lowman, James T.; Paglia, Donald E.; Wakem, Christopher J.

doi:10.1111/j.1365-2141.1973.tb05736.x

Cited by 43 publications

(16 citation statements)

References 23 publications

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“…In patient R., the hematological and biochemical findings coincided with those observed in patients previously reported (1,2). Hemolysis was marked, and increased basophilic stippling was a very prominent feature of the Wright's-stained blood film (Fig.…”

Section: Resultssupporting

confidence: 72%

“…Reexamination of the recorded assays of the earlier patients revealed identical findings, which were absent in hemolysate extracts of all other hemolytic anemias studied in this laboratory over a period of several years. This report documents subsequent investigations indicating (a) the red cells of subjects with this hereditary hemolytic syndrome uniquely contain very large amounts of cytidine and uridine nucleotides, (b) the latter are partially reflected in the enzymatic assays for nucleotides and were the basis for our initial misinterpretation that adenine nucleotides were increased in patient erythrocytes (1,2), and (c) the genetically determined lesion is a severe deficiency of a pyrimidine-specific 5'-nucleotidase, an enzyme readily demonstrable in normal erythrocytes, that exhibits increased activity in reticulocytes. As will be discussed, RPK deficiency is believed to be an epiphenomenon, secondary to the relatively enormous concentrations of pyrimidine nucleotides in circulating erythrocytes and presumably in marrow nucleated precursor cells.…”

Section: Introductionmentioning

confidence: 74%

“…(1), Vi. T., and Va. T. (2) have been previously reported in detail and were restudied as part of the present investigation.…”

Section: Case Materialsmentioning

confidence: 99%

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Hereditary Hemolytic Anemia with Human Erythrocyte Pyrimidine 5′-Nucleotidase Deficiency

Valentine¹,

Fink²,

Paglia³

et al. 1974

J. Clin. Invest.

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259

141

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A B S T R A C T A severe deficiency of a red cell pyrimidine 5'-nucleotidase was found to be associated with hereditary hemolytic anemia in four members of three kindreds. The syndrome was characterized by marked increases above normal in red cell basophilic stippling, total nucleotides, and GSH and by a fairly severe deficiency of ribosephosphate pyrophosphokinase (EC 2.7. 6.1.). Patient erythrocytes uniquely contained large amounts of pyrimidine 5'-ribonucleotides. In earlier studies, these were erroneously considered to be adenosine phosphates, since all previous investigations of the nucleotides of human red cells and reticulocytes have shown 97% or more to contain adenine. Total nucleotides in patient cells were present in amounts 3-6 times greater than normal, and approximately 80% contained pyrimidine. The ultraviolet spectral curves of deproteinized red cell extracts exhibited a shift in maximum absorbance from the usual 256-257 nm to approximately 266-270 nm, and absorbance at 250, 270, 280, and 290 nm, expressed as a ratio of that at 260 nm, differed greatly from normal. The spectral characteristics of extracts provide the basis of a readily performed screening procedure, which does not require enzyme assay. The nucleotidase activity in deficient red cells assayed less than 14%, and usually less than 10%, of normal and much less in terms of reticulocyte-rich blood, where it was consistently found to be increased. The enzyme has a pH optimum of 7.5-8.0, is inhibited by EDTA, and does not utilize purine 5'-ribonucleotides or 8-glycerophosphate as substrates. While comparatively few family members have been available thus far for study, initial data are compatible with an autosomal, recessive

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Section: Resultssupporting

confidence: 72%

Section: Introductionmentioning

confidence: 74%

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Hereditary Hemolytic Anemia with Human Erythrocyte Pyrimidine 5′-Nucleotidase Deficiency

Valentine¹,

Fink²,

Paglia³

et al. 1974

J. Clin. Invest.

Self Cite

259

141

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“…This enzyme was inhibited at lead concentrations that exerted minimal effects on a wide variety of other erythrocyte enzymes assayed simultaneously. Such lead-induced impairment of pyrimidine-5'-nucleotidase activity prompts comparison with the genetically induced, severe deficiency state involving this same enzyme (13,29,30). The latter is characterized clinically by severe chronic hemolytic anemia with pronounced basophilic stippling of the erythrocytes that uniquely contain large amounts of uridine and cytidine nucleotides.…”

Section: Resultsmentioning

confidence: 99%

Effects of low-level lead exposure on pyrimidine 5'-nucleotidase and other erythrocyte enzymes. Possible role of pyrimidine 5'-nucleotidase in the pathogenesis of lead-induced anemia.

Paglia¹,

Valentine²,

Dahlgren³

1975

J. Clin. Invest.

125

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“…It (37) and for an individual suffering from nonspherocytic hemolytic anemia (36). The observed inhibition of PRPP synthetase from KC62 by nucleotides suggests that the PRPP synthetase has been altered by mutation.…”

mentioning

confidence: 94%

Isolation of a Chinese Hamster Cell Mutant with Low Intracellular Phosphoribosylpyrophosphate Concentration

Crawford¹,

Bryant²

1982

Mol. Cell. Biol.

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A tritium-adenine suicide procedure was used to select for mutants with reduced uptake of adenine from a population of Chinese hamster V79 cells mutagenized with ethyl methane sulfonate. In one of the mutant lines isolated, designated KC62, the uptake of adenine, hypoxanthine, and guanine was reduced by approximately 70%. The specific activities, Km values, and Vma values of adenine phosphoribosyltransferase and of hypoxanthine phosphoribosyltransferase were the same in extracts from KC62 and from the parental cell line. Metabolic fate studies of incorporated [3H]adenine and [3H]hypoxanthine revealed a metabolic block at the level of phosphoribosylation. Determination of phosphoribosylpyrophosphate pool size showed that the mutant contained only 25% of the phosphoribosylpyrophosphate found in the parent. Its reduced availability in KC62 appears to result in a decreased ability to salvage adenine, hypoxanthine, and guaninine via phosphoribosylation. Phosphoribosylpyrophosphate synthetase from KC62 was shown to have an increased sensitivity to inhibition by a variety of nucleotides.In recent years, numerous variant cell lines have been isolated which are resistant to the toxic effects of adenine analogs. Cell lines resistant to 2,6-diaminopurine have been isolated from Chinese hamster ovary (CHO) lines (7, 33), from human and mouse fibroblasts (19,24), and from human and mouse lymphocytes (4, 30). Other adenine analog-resistant lines have been selected with 2-fluoroadenine and 8-azaadenine. Lines resistant to 2-fluoroadenine have been reported for human and mouse fibroblasts (3,17). Mutants resistant to 8-azaadenine in CHO cell lines (15) and human lymphocytes (30) have also been reported.Adenine analog resistance in all of the cases above was shown to result from decreased activity of the adenine salvage enzyme adenine phosphoribosyltransferase (APRT). Decreased APRT activity affords these cell lines resistance to toxic analogs since phosphoribosylation is necessary for the toxic effects of adenine analogs to be expressed. The requirement for metabolic activation, generally by phosphoribosylation in the case of purines and pyrimidines, conceivably could restrict the variety of mutant cell types which can be isolated with structural analogs.It should be possible to obtain a wider variety of mutant phenotypes with the selection procedure known as tritium suicide. The killing effects of tritium depend upon radiolytic decay of an incorporated compound and not upon metabolic activation of a potential metabolite.

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Nonspherocytic Haemolytic Anaemia with Increased Red Cell Adenine Nucleotides, Glutathione and Basophilic Stippling and Ribosephosphate Pyrophosphokinase (RPK) Deficiency: Studies on Two New Kindreds

Cited by 43 publications

References 23 publications

Hereditary Hemolytic Anemia with Human Erythrocyte Pyrimidine 5′-Nucleotidase Deficiency

Hereditary Hemolytic Anemia with Human Erythrocyte Pyrimidine 5′-Nucleotidase Deficiency

Effects of low-level lead exposure on pyrimidine 5'-nucleotidase and other erythrocyte enzymes. Possible role of pyrimidine 5'-nucleotidase in the pathogenesis of lead-induced anemia.

Isolation of a Chinese Hamster Cell Mutant with Low Intracellular Phosphoribosylpyrophosphate Concentration

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