title: Cytosolic 5'-nucleotidase hyperactivity in erythrocytes of Lesch-Nyhan syndrome patients.
abstract: Lesch-Nyhan syndrome is a metabolic-neurological syndrome caused by the X-linked deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Metabolic consequences of HGPRT deficiency have been clarified, but the connection with the neurological manifestations is still unknown. Much effort has been directed to finding other alterations in purine nucleotides in different cells of Lesch-Nyhan patients. A peculiar finding was the measure of appreciable amount of Z-nucleotides in red cells. We found significantly higher IMP-GMP-specific 5'-nucleotidase activity in the erythrocytes of seven patients with Lesch-Nyhan syndrome than in healthy controls. The same alteration was found in one individual with partial HGPRT deficiency displaying a severe neurological syndrome, and in two slightly hyperuricemic patients with a psychomotor delay. Since ZMP was a good substrate of 5'-nucleotidase producing Z-riboside, we incubated murine and human cultured neuronal cells with this nucleoside and found that it is toxic for our models, promoting apoptosis. This finding suggests an involvement of the toxicity of the Z-riboside in the pathogenesis of neurological disorders in Lesch-Nyhan syndrome and possibly in other pediatric neurological syndromes of uncertain origin.
authors.affiliation: Dipartimento di Fisiologia e Biochimica, Università di Pisa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Pesi
authors.forename: V
authors.initials: V
authors.lastname: Micheli
authors.forename: G
authors.initials: G
authors.lastname: Jacomelli
authors.forename: L
authors.initials: L
authors.lastname: Peruzzi
authors.forename: M
authors.initials: M
authors.lastname: Camici
authors.forename: M
authors.initials: M
authors.lastname: Garcia-Gil
authors.forename: S
authors.initials: S
authors.lastname: Allegrini
authors.forename: M G
authors.initials: MG
authors.lastname: Tozzi
mesh_terms: D015720:5'-Nucleotidase / Q000097:blood* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001321:Autistic Disorder / Q000097:blood; D002648:Child; D003600:Cytosol / Q000201:enzymology*; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D007926:Lesch-Nyhan Syndrome / Q000097:blood*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009422:Nervous System Diseases / Q000097:blood; D012016:Reference Values; D012263:Ribonucleosides / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014527:Uric Acid / Q000097:blood
chemical_list: D012263:Ribonucleosides; D012265:Ribonucleotides; D014527:Uric Acid; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D007041:Hypoxanthine Phosphoribosyltransferase; D015720:5'-Nucleotidase; C031143:AICA ribonucleotide