Hereditary pyrimidine 5′‐nucleotidase deficiency: from genetics to clinical manifestations

Abstract

SummaryHereditary pyrimidine 5¢-nucleotidase (P5¢N) deficiency is the most frequent abnormality of the red cell nucleotide metabolism causing hereditary non-spherocytic haemolytic anaemia. The disorder is usually characterised by mild-to-moderate haemolytic anaemia associated with the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. The precise mechanisms leading to the destruction of P5¢N deficient red cells are still unclear. The pyrimidine 5¢-nucleotidase type-I (P5¢N-1) gene is localised on 7p15-p14 and the cDNA has been cloned and sequenced; 20 mutations have been identified so far in 30 unrelated families, most of them at the homozygous level. Recently, the comparison of recombinant mutants of human P5¢N-1 with the wild-type enzyme has enabled the effects of amino acid replacements on the enzyme molecular properties to be determined and help to correlate genotype to clinical phenotype.

Identification of Drosophila and Human 7-Methyl GMP-specific Nucleotidases

“…5Ј-Nucleotidases play a role in the regulation of intracellular nucleotide pools. Homozygous mutations in 5Ј-deoxyribonucleotidase C3 cause hemolytic anemia (33,34). The 5Ј nucleotidases are also of interest because of their role in the metabolism of nucleoside analogs used as antiviral and anti-cancer drugs (27).…”

Structural Basis of Substrate Specificity and Selectivity of Murine Cytosolic 5′-Nucleotidase III

“…17 Clinically, lack of pyrimidine 5′-nucleotidase activity ultimately manifests as a mild nonspherocytic anemia (OMIM ID: 266120). 20 The deficiency may be familial or it can also be acquired during severe lead poisoning, because Pb 2 + , as well as some other heavy metal ions, inhibits activity of this enzyme. 21 Several dozen mutations in the gene encoding cN-III have been described in literature and biochemical defects of many missense mutations have been studied at the protein level.…”

“…21 Several dozen mutations in the gene encoding cN-III have been described in literature and biochemical defects of many missense mutations have been studied at the protein level. 20,[22][23][24] The structures of murine cN-III (mcN-III; UniProt ID: Q9D020) as well as human cN-III that provide snapshots of several states of the catalytic cycle have been previously reported. 12,13 These studies so far did not address important questions such as how the substrate is recognized by cN-III and how this enzyme at a structural level achieves the selectivity against purine nucleotides.…”

Lead Poisoning Induced Severe Hemolytic Anemia, Basophilic Stippling, Mimicking Erythrocyte Pyrimidine 5'-nucleotidase Deficiency in Beta Thalassemia Minor

“…First case had severe anemia (Hb 4.3 g/dl) and both cases had reduced MCV levels and raised Hb A2.The clinical and hematological features of both the cases of lead poisoning not distinctive, although the blood film gives a strong clue as to the diagnosis when marked red cell basophilic stippling is seen. Basophilic stippling is a constant but not specific finding in this disease, occasionally occurring in other congenital or acquired conditions, such as β-thalassemia trait, some hemoglobin variants, sideroblastic anemia or pyrimidine 5'nucleotidase deficiency [8][9][10]. The lead poisoning diagnosis ultimately depends upon the high level of lead content in blood and high concentrations of pyrimidine nucleotides and a reduced P5'N-1 activity in red blood cells [11].…”