title: Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in Italian Lesch-Nyhan patients: identification of nine novel mutations.
abstract: Lesch-Nyhan syndrome (LSN, McKusick 300322) is an X-linked genetic disease due, in its typical form, to the complete absence of hypoxanthine-guanine phosphoribosyltransferase (HPRT, EC 2.4.2.8) enzyme activity. It is characterized by hyperuricaemia, leading to gout and kidney stones, accompanied by severe neurological dysfunction with self-injurious behaviour, choreoathetosis and spasticity. Based on a worldwide birth incidence estimate of about 1:380000, one or two new cases are expected every year in Italy. We performed biochemical and molecular genetic studies on 28 Italian patients from 25 families who are likely to represent most living individuals with the syndrome in the country. They all had absent HPRT activity and a typical LNS phenotype. Genetic analysis identified 24 HPRT mutations, 9 of which had not been previously reported: 74C>G (P25R), IVS2+1G>C, 194-195delTC, 329-332delCAAC insTCTs, IVS9-1G>A, 506insC, IVS8-1G>C, 606G>T (L202F), 418G>C (G140R). No mutation hotspots were identified. Only two mutations were found in more than one family, indicating the lack of any major mutation causing LNS in Italy. Three mutations arose de novo , two in the proband's mother, one in the maternal grandmother. The virtual complete absence of HPRT activity was related to deletions, nonsense, or missense mutations leading to nonconservative amino acid changes.
authors.affiliation: Istituto Malattie Rare Mauro Baschirotto BIRD Foundation Onlus, Costozza, Vicenza, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bertelli
authors.forename: D
authors.initials: D
authors.lastname: Randi
authors.forename: V
authors.initials: V
authors.lastname: Micheli
authors.forename: S
authors.initials: S
authors.lastname: Gallo
authors.forename: G
authors.initials: G
authors.lastname: Andrighetto
authors.forename: P
authors.initials: P
authors.lastname: Parmigiani
authors.forename: G
authors.initials: G
authors.lastname: Jacomelli
authors.forename: M
authors.initials: M
authors.lastname: Carella
authors.forename: C
authors.initials: C
authors.lastname: Lievore
authors.forename: M
authors.initials: M
authors.lastname: Pandolfo
mesh_terms: D000293:Adolescent; D000328:Adult; D004247:DNA / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency*; D007558:Italy; D007926:Lesch-Nyhan Syndrome / Q000235:genetics*; D008214:Lymphocytes / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation
chemical_list: D004247:DNA; D007041:Hypoxanthine Phosphoribosyltransferase