Molecular basis of Japanese variants of pyrimidine 5'-nucleotidase deficiency

British Journal of Haematology
Hitoshi KannoHisaichi Fujii

Abstract

The type-I isoform of pyrimidine 5'-nucleotidase (P5N-I) has an important role in the catabolism of pyrimidine mononucleotides during erythroid maturation. Two alternatively spliced forms of P5N-I mRNA have been identified, and we found another alternatively spliced form in reticulocytes, which included an additional 87-bp sequence. The sequence is located 6.2-kb downstream of the exon 2 and 2.7-kb upstream of the exon 3 sequence; consequently, the P5N-I gene encodes 11 exons, which span approximately 48 kb. We identified five novel mutations in nine families with P5N-I deficiency: two missense mutations (425C, 721C), one splice mutation (339C), one 1-bp insertion (251-insA-252) and one 9-bp deletion (del 192-200). All patients were homozygous for each mutation. The mutant P5N-I with 721C (G241R) had lower affinity for cytidine monophosphate, suggesting that Gly241 is important for substrate binding. Haplotype analysis showed that 721C, which had been identified in five unrelated families, was a founder mutation. The mutant P5N was then expressed in Cos-7. The degradation of P5N with 425C (L142P) was significantly faster than a wild-type control, and proteasome inhibitors restored the stability of L142P. These data suggest that...Continue Reading

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Citations

Jun 21, 2005·Pharmacology & Therapeutics·Sally Anne HunsuckerJozef Spychala
Jul 23, 2009·Pharmacogenetics and Genomics·Pinar AksoyLiewei Wang
Jun 15, 2005·British Journal of Haematology·Elisa FermoAlberto Zanella
Apr 14, 2006·British Journal of Haematology·Alberto ZanellaGiovanna Valentini
Sep 1, 2015·International Journal of Cardiology·Jessica MaiuoloVincenzo Mollace
Dec 29, 2004·Leukemia & Lymphoma·Paula Fernandez-CalottiCarlos Maria Galmarini
May 5, 2006·The Journal of Biological Chemistry·Eduard BittoGeorge N Phillips

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