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 Blood, 15 April 2005, Vol. 105, No. 8, pp. 3340-3345.
Prepublished online as a Blood First Edition Paper on December 16, 2004; DOI 10.1182/blood-2004-10-3895.

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RED CELLS

Functional analysis of pyrimidine 5'-nucleotidase mutants causing nonspherocytic hemolytic anemia

Laurent R. Chiarelli, Paola Bianchi, Elisa Fermo, Alessandro Galizzi, Paolo Iadarola, Andrea Mattevi, Alberto Zanella, and Giovanna Valentini

From the Department of Biochemistry "A. Castellani," University of Pavia, Italy; Department of Genetics and Microbiology "A. Buzzati-Traverso," University of Pavia, Italy; and Hematology Division, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Maggiore, Milano, Italy.

Inherited pyrimidine 5'-nucleotidase type I (P5'N-1) deficiency is the third most common erythrocyte enzymopathy that causes hemolysis. Fourteen different mutations have been identified to date. We have investigated the molecular bases of the disease by studying the biochemical properties of the recombinant wild-type human enzyme and 4 variant proteins (D87V, L131P, N179S, and G230R) bearing missense mutations found in patients affected by nonspherocytic hemolytic anemia. P5'N-1 is a relatively stable protein and has essentially identical catalytic efficiency toward cytidine monophosphate (CMP) and uridine monophosphate (UMP). All investigated mutant proteins display impaired catalytic properties and/or reduced thermostability, providing a rationale for the pathological effects of the mutations. Despite the substantial changes in the kinetic and thermostability parameters, the enzyme activity detected in the red blood cells of patients homozygous for mutations L131P and G230R exhibits moderate alterations. This suggests that P5'N-1 deficiency is compensated, possibly by other nucleotidases or alternative pathways in nucleotide metabolism. Therefore, nucleotidase activity may not be considered a prognostic indicator in patients affected by the enzymopathy. (Blood. 2005;105:3340-3345)


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